Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1
Reactant: Nc1c(F)cccc1F
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Solvent: c1ccncc1
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 72.5 %

Procedure:
The starting 2,6-difluoroaniline (18.1 g, 0.140 mol) was dissolved in 45 ml of pyridine and 36.1 g (0.155 mol) of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was stirred at room temperature for 15.5 hours. The pyridine was removed by evaporation at reduced pressure, and the residue was treated with 600 ml of 0.5N naOH. After stirring to dissolve all soluble material the mixture was filtered through celite and the filtrate was acifified with 3N HCl. The precipitate which separated upon acidification was collected by filtration and dried to yield 33.0 g (73%) of the desired product as a pale red solid, m.p. 245°-247° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCCCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and piperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=371.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([NH:31][CH2:32][CH2:33][CH3:34])=[C:7]([O:12][CH2:13][CH:14]([OH:30])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:8]=[CH:9][C:10]=1[CH3:11].[C:35](Cl)(Cl)=[O:36]>>[OH:30][CH:14]([CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:21]1)[CH2:13][O:12][C:7]1[C:6]2[N:31]([CH2:32][CH2:33][CH3:34])[C:35](=[O:36])[NH:4][C:5]=2[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: CCCNc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)ccc(C)c1N
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CCCn1c(=O)[nH]c2c(C)ccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c21
Yield: 54 %

Procedure:
In a manner analogous to that described in Example 1, from 3-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylaminobenzene trihydrochloride and phosgene, there is obtained, in a yield of 54% of theory, 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-7-methyl-3-propyl-2-benzimidazolinone; m.p. 234°-235° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[I:14].[I:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH2:3][CH2:2][O:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[I:15])=[C:7]([I:14])[CH:8]=1
Reactant: Cc1cc(Cl)cc(I)c1OCCCBr
Reactant: Oc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)cc(I)c1OCCCOc1ccc(Cl)cc1I
Yield: 87.8 %

Procedure:
In 70 mL of acetone combine 4.08 g (10.48 mmol) of 2-(3-bromopropoxy)-5-chloro-1-iodo-3-methylbenzene, 2.67 g (10.49 mmol) of 2-iodo-4-chlorophenol (Prepared in a manner similar to Preparation 7) and 3.06 g (22.14 mmol) of potassium carbonate. Reflux overnight, filter, cool and concentrate to give an off white solid, which is crystallized using acetonitrile to yield 5.18 g (88%) of 5-chloro-2-(3-(4-chloro-2-iodophenoxy)propoxy)-1-iodo-3-methylbenzene as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=2.5 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.31-7.23 (m, 1H), 7.16-7.10 (m, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.28 (t, J=5.8 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.36 (p, J=5.9 Hz, 2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.17, 155.57, 138.56, 136.17, 133.37, 131.34, 129.89, 129.24, 126.36, 112.21, 92.21, 86.64, 68.85, 65.57, 29.85, 17.02. GCMS (m/e): 562 (M+).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:16][CH3:17])=[C:8]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:9](O)=[O:10]>>[Cl:5][C:6]1[C:7]([O:16][CH3:17])=[C:8]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)O
Product: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Temperature: 60 °C

Procedure:
To 4.0 kg thionyl chloride, was added 5.0 kg of 3,6-dichloro-2-methoxybenzoic acid. This was stirred and heated to reflux (ca. 60° C.) for 1.5 hours. The reaction mixture was allowed to cool and excess thionyl chloride evaporated in vacuo. The crude product was then distilled under reduced pressure to give 3,6-dichloro-2-methoxybenzoyl chloride as a liquid, b.p. 117° C. @ 0.6 mm Hg.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].O.[NH2:21]N>CCO>[CH3:7][C:6]([C:5]1[NH:21][N:2]=[CH:3][CH:4]=1)([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccn[nH]1
Temperature: 50 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4 mmol) and hydrazine hydrate (1.0 g, 6.25 mmol) in EtOH was heated at 50° C. for 3 h. The mixture was concentrated, and the residue was diluted with H2O and EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the titled compound as a yellow solid. MS: (ES+) 232 (M+H.) Calc'd for C12H14N3O2—232.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](OC2C=NC(Cl)=CC=2)=[N:6][CH:7]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Oc2ncc(Br)cn2)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ncc(Br)cn2)cc1

Procedure:
5-Bromo-2-(6-chloropyridin-3-yloxy)pyrimidine (500 mg, 1.745 mmol) and N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (362 mg, 1.745 mmol) were reacted in analogy to example 2c. Yield: 509 mg (80%), M+H+: 364.03.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(F)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(F)cccc2c1Nc1ccc(O)cc1C
Yield: 50.7 %

Procedure:
3-butyryl-4-chloro-8-fluoroquinoline (1.75 g, 7 mmol), 4-amino-3-methylphenol (1.3 g, 10 mmol) and 1,4-dioxan (50 ml) were heated at reflux for 6.5 hours, then the solvent evaporated and the product converted to free base. Recrystallisation from methanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline (1.2 g), m.p. 205°-207°.
Reaction SMILES: [C:1]([C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[CH:24]1([CH2:23][C@H:10]2[C@H:9]([C@@H:1]([OH:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:13][C:12]([CH3:15])([CH3:14])[N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)c2ccccc2)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)c2ccccc2)OC1(C)C
Yield: 20.6 %

Procedure:
290 mg (0.72 mmol) of t-butyl (4S,5R)-5-benzoyl-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 5 ml of methanol are stirred at room temperature for 1 hour with 27 mg (0.7 mmol) of sodium borohydride. Thereafter, the reaction mixture is treated with two drops of glacial acetic acid and evaporated to dryness. The residue is chromatographed on 30 g of silica gel with a 4:1 mixture of hexane and ether as the eluting agent, with a methylene chloride solution of the crude product being applied to the column. In this manner there are obtained 60 mg of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-α-hydroxybenzyl]-2,2-dimethyl-3-oxazolidinecarboxylate as a white solid, MS: 403 (M)+, as well as 210 mg of the epimeric t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-α-hydroxybenzyl]-2,2-dimethyl-3-oxazolidinecarboxylate also as a white solid, MS: 403 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH2:23][CH3:24].I([O-])(=O)(=O)=[O:26].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:22][CH2:23][CH3:24])=[O:26]
Reactant: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCS(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 40 °C
Yield: 73.9 %

Procedure:
A mixture of 3-methyl-2-(2-propylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.22 g), sodium periodate (0.27 g), methanol (2 ml), and water (4 ml) was stirred with heating at 40° C. for 1.5 hours. To the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were added, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.17 g of 3-methyl-2-(2-propylsulfinylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Yield: 87.4 %

Procedure:
1.5 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 40 ml of methanol, 5 ml of water and 1.5 g of potassium hydroxide are treated in the same manner as described in Example 16. 1.2 g of 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.6%
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1.CI>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH3:1])=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1
Reactant: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2nc(C)n(-c3ccc(F)cc3)c2C)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n-butyllithium (1.6 mL, 1.6 M in hexane, 2.6 mmol) were added at −78° C. and the mixture was kept at −78° C. for 10 min. 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine (1) (500 mg, 1.72 mmol) in 5 mL dry tetrahydrofurane was added at −78° C. and stirring was continued for 45 min at this temperature. Methyl iodide (410 mg, 2.9 mmol) was added at −78° C. and the reaction mixture was slowly warmed to RT. The reaction mixture was quenched by addition of 50 mL water and extracted three times with diethylether (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (methylenchloride/methanol 9:1) and the desired compound was obtained as a white solid (325 mg, 62%), MS: m/e=306.4 (M+H+).
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]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[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:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cc(F)cc(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(3,5-difluorophenyl)-quinolin-3-yl)methanamine (0.105 g, 0.345 mmol), 6-chloropurine (0.064 g, 0.41 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(3,5-difluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=76 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) 8 ppm 8.48 (s, 1 H), 8.35 (s, 1 H), 8.24 (s, 1 H), 7.86-7.94 (m, 2 H), 7.52-7.61 (m, 1 H), 7.27-7.35 (m, 2 H), 6.96-7.06 (m, 1 H), 4.73 (d, J=5.71, 2 H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[NH:21]1[C:25]2([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][C:25]2([N:21]([C:18]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:9]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[N:8]=3)=[O:20])[CH2:22][CH2:23][CH2:24]2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2)CC1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (937729-06-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=494.6 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][C:4]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(C(=O)O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of methyl 4-(1-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzoate (0.700 g), 1 M aqueous sodium hydroxide solution (4.8 ml), tetrahydrofuran (10 ml) and methanol (5 ml) was stirred at room temperature for 2 hrs., and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-(1-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzoic acid (0.650 g, yield 97%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 243–244° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:37][NH:38][OH:39].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:38]([OH:39])[CH3:37])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(O)C(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 5 °C
Reaction time: 1.17 h
Yield: 79.6 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (9.0 g 23.50 mmol) in anhydrous DMF (285 mL) was added CDMT (4.95 g 28.20 mmol 1.2 eq.) and NMM (N-methyl morpholine) (2.85 g 28.2 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 70 min. N-Methylhydroxylamine hydrochloride (23.6 g 282.0 mmol 12.0 eq) was added and stirring continued for 3 hours. The reaction was judged to be complete by HPLC-MS analysis, and was quenched by adding water (100 mL) to the reaction mixture. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a residue. Saturated aqueous sodium bicarbonate (120 mL) was added to neutralize to pH 7. White solid precipitated out, and the mixture was cooled to 5° C. The solid was filtered, washed with cold water (100 mL), and dried in vacuo to afford 7.7 g (85%) of 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide at >95% purity by 1HNMR analysis. To obtain 99% purity, 7.7 g of the product was dissolved in a boiling mixture (700 mL) of methanol and isopropanol (1:9). The hot solution was filtered to remove trace impurities, and the filtrate was allowed to cool to room temperature. The product crystallized out as needle-like crystals, which was filtered, washed with isopropanol, and dried in vacuo to afford (3.0 g) 99% purity. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—2.27 min, m/e=412.30 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.29 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.32 (s, 3H) 3.73 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.71 (s, 1H) 7.83 (s, 1H) 8.09 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: O=C1CCC(CO)(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 66 %

Procedure:
The 4-hydroxymethyl-4-(4-chlorophenyl)cyclohexanone is dissolved in 60 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness to give 12.8 g. (66% yield) of 4-acetoxymethyl-4-(4-chlorophenyl)cyclohexanone, as an amorphous gum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:28])=[C:4]([CH:10]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC>CCOC(C)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:29][O:28][C:3]=2[C:4]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: COc1ccc2ncoc2c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (100 mg; 0.26 mmol; synthesis described in example 279), commercially available p-TsOH (2 mg; 0.01 mmol), and commercially available triethyl orthoformate (264 mg; 1.69 mmol) was refluxed (100° C.) for 1 h. After cooling to rt, AcOEt was added, and the obtained mixture was filtered over a pad of celite. The filtrate was then washed with water and brine, and the mixed aq. layers were further extracted with AcOEt. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=20/1) afforded the target compound. LC-MS (conditions A): tR=0.53 min.; [M+H]+: 388.05 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[C:23]([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)=[CH:22][N:21]=[C:20]([NH:29][CH2:30][CH2:31][NH:32]C2C=CC([N+]([O-])=O)=CN=2)[N:19]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[C:23]([C:24]2[NH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][N:21]=[C:20]([NH:29][CH2:30][CH2:31][NH:32][C:2]2[N:3]=[CH:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=2)[N:19]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O-:8])=[O:7])=[N:2]1.[ClH:9].[CH2:10](O)[CH3:11]>>[ClH:9].[NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH2:10][CH3:11])=[O:7])=[N:2]1
Reactant: CCO
Reactant: O=C([O-])c1nc[nH]n1
Agent: Cl
Product: CCOC(=O)c1nc[nH]n1
Reaction time: 72 h
Yield: 48 %

Procedure:
1,2,4-Triazole-3-carboxylate (16 g) [G. I. Chipen and V. Ya. Grinshtein, Chem. Heterocyclic Compd. (U.S.S.R), 1,420 (1965)] dissolved in ethanol (400 ml) was saturated with HCl gas. Ice-bath cooling was applied to avoid overheating during saturation and the reaction was left stirring for three days. The product which had precipitated out was filtered off and washed with cold ethanol and then diethyl ether before being dried under vacuum giving 12 g of the product, 48% yield. νmax (Nujol Mull) 1754 cm-1.