Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[C:19]1([C:25]2[CH:26]=[C:27]([C:34](Cl)=O)[S:28][C:29]=2[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:19]1([C:25]2[CH:26]=[C:27]([C:34]3[O:18][N:17]=[C:15]([C:13]4[S:14][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[N:16]=3)[S:28][C:29]=2[C:30]([F:33])([F:31])[F:32])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1
Reactant: O=C(Cl)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1e) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-2-carboximidamide (0.43 g, 1.5 mmol) that was obtained in Example 4 (4b), 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N,N-diisopropylethylamine (0.52 ml, 3.0 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (3.0 ml, 3.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.60 g) in a yield of 99% as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1
Reactant: COc1ccc(-c2ccccc2Br)cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=c1ccc(-c2ccccc2Br)c[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To a solution of 5-(2-bromophenyl)-2-methoxypyridine (7.2 g) in 1,2-dichloroethane (75 mL) was added aluminum chloride (9.09 g) at ambient temperature. The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was poured into ice and was extracted with a mixed solvent (THF:EtOAc=3:1) and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was added silica gel (150 g), and the mixture of the filtrate and silica gel was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=97:3) to afford 5-(2-bromophenyl)pyridin-2(1H)-one (4.72 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([OH:24])=[O:23].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([C:20]1[CH:19]=[C:18]([C:22]([OH:24])=[O:23])[NH:17][CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a 120 mL DCM solution of 2,4,6-trifluorobenzoyl chloride (4.3 g, 0.022 mol) was added AlCl3 (8.8 g, 0.066 mol) under N2 at room temperature. After stirring for 15 min, 1H-pyrrole-2-carboxylic acid (2.4 g, 0.022 mol) was added in small portions over a 10 min period. After stirring at room temperature for 1 hr, the reaction mixture was treated with dropwise addition of ice-water (20 mL) and 1N HCl to adjust pH to 1, stirred for another 30 min, extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (5.8g, 97% yield). 1H-NMR (500 MHz, CDCl3): δ 12.48 (br.s, 1H), 7.48 (s, 1H), 7.28-7.38 (m, 2H), 6.83 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:7][CH:6]=1)[CH3:2].O=S(Cl)[Cl:28]>C(Cl)Cl>[Cl:28][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)[C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[O:23])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc3cccnc23)cc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound II (2.0 g, 6.6 mmol) was dissolved in dry CH2Cl2 (25 mL) and SOCl2 (0.53 mL, 7.3 mmol) was added. The solution was stirred at 25° C. for 30 min and the solvent was evaporated in vacuo. Compound III was obtained as an oil (˜100%) and used in the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1>>[C:5]1([CH2:4][O:3][CH2:2][N:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]2=[O:18])[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOCc1cccs1
Agent: Cl
Product: O=c1ncc(Cl)cn1COCc1cccs1

Procedure:
was prepared as described in Example 3 from 2-(chloromethyloxymethyl)thiophene (see Preparation 8a and 8b) (10 mmol) and 5-chloropyrimidin-2-one hydrochloride (10 mmol) in 57%. yield (1.45 g), m.p. 132° C. 1H NMR (CDCl3): δ4.80 (CH2Thioph.), 5.28 (CH2O), 6.7-7.2 (3H-Thioph.), 7.63 and 8.35 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O=C1CCC(=O)N1[O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN1C(=O)CCC1>[C:38]([O:37][C:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:19])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To 4-(Aminomethyl)benzoic acid (0.2 g, 1.32 mmol) was added in NMP (5 mL). Hexadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.58 g, 1.32 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water (100 mL), the precipitate was isolated by filtration and dried in vacuo. The crude material was recrystallized from toluene to give 4-[(15-tert-butoxycarbonylpentadecanoylamino)methyl]benzoic acid (413 mg).
Reaction SMILES: [N:1]12[CH2:10][N:5]3[CH2:6][P:7]([CH2:9][N:3]([CH2:4]3)[S:2]1(=[O:12])=[O:11])[CH2:8]2.C([O:17]O)(C)(C)C>>[N:1]12[CH2:10][N:5]3[CH2:6][P:7](=[O:17])([CH2:9][N:3]([CH2:4]3)[S:2]1(=[O:12])=[O:11])[CH2:8]2
Reactant: O=S1(=O)N2CN3CN1CP(C3)C2
Reactant: CC(C)(C)OO
Product: O=P12CN3CN(C1)S(=O)(=O)N(C3)C2
Yield: 93.3 %

Procedure:
2-Thia-1,3,5-triaza-7-phosphaadamantane 2,2-dioxide (0.5g, 0.0024 mole) and t-butyl hydroperoxide (70% solution, 0.3 g, 0.0024 mole) were stirred in a 25 ml acetone-25 ethanol solution for 1 hour at room temperature. The solution was filtered to yield 0.5 g of crude 2-thia-1,3,5-triaza-7-phosphaadamantane 2,2,7-trioxide (92% yield) [MP 245°-6° (propanol)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([O:37]C(=O)CCl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:33])[CH3:34])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([OH:37])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4OC(=O)CCl)cc2OCC3)n(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Yield: 6.6 %

Procedure:
A solution of impure racemic-cis-3-(2-chloro-acetoxy)-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.297 g) in dioxane (5 mL) was stirred with aqueous sodium hydroxide (1M, 4.2 mL) at room temperature for 16 h, followed by heating at 50° C. for approx. 24 h. The cooled mixture was extracted three times with ethyl acetate, the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give racemic-cis-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (17 mg). LCMS RT=4.50, [M+H]+ 509
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:55])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][CH3:52])[CH:47]([O:53][CH3:54])[CH2:46]2)[CH:8]([CH3:56])[CH:7](O)[CH2:6][C:5]1=[O:58])[CH:2]=[CH2:3].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:55])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][CH3:52])[CH:47]([O:53][CH3:54])[CH2:46]2)[CH:8]([CH3:56])[CH:7]=[CH:6][C:5]1=[O:58])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 81.8 %

Procedure:
A stirred solution of 17-Allyl-1,14-dihydroxy-12-[2-(3,4-dimethoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (10 mg, prepared by methylation of macrolide FR 900506), in toluene (5 ml) containing a trace of tosic acid was heated on a steam bath for 5 minutes. Removal of solvent in vacuo and chromatography on silica eluting with ethyl acetate gave the title compound as an oil (8 mg).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>>[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:22]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC(F)F)cc3)co2)cc1
Yield: 21 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 4-difluoromethoxylphenacyl bromide to obtain methyl 4-[4-(4-difluoromethoxylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 160 to 161° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N:3]1[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH:21]1([CH2:24][N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][N:3]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]2=[O:1])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O

Procedure:
A stirred mixture of tert-butyl (2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetate from Step B (107 mg, 0.39 mmol), cyclopropylmethyl bromide (105 mg, 0.78 mmol), and cesium carbonate (153 mg, 0.47 mmol) in acetone (5 mL) was heated at reflux for 3 days. The reaction mixture was concentrated under reduced pressure, partitioned between brine and CH2Cl2, and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50 to provide the title compound. MS: m/z=273 (M-C4H7).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[CH3:25].C[O-].[Na+]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][C@H:24]([CH3:25])[C:26]([OH:28])=[O:27])=[O:5])[C:7]=3[OH:22])[S:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: C[C@@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1ncc2snc(-c3ccc(Cl)cc3)c2c1O)C(=O)O
Yield: 69.6 %

Procedure:
A mixture of 3-(4-Chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (50 mg, 0.149 mmol), D-alanine (400 mg, 4.49 mmol) and NaOMe (7.45 mL, 3.72 mmol, 0.5 M solution in MeOH) was refluxed for 48 h before it was concentrated in vacuo. The residue was dissolved in water (50 mL) and washed with CH2Cl2 (2×20 mL). The aqueous solution was then acidified by addition of 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound as a white solid (39.2 mg): MS (m/z) 376.0 (M−1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1
Product: O=C(C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 7d and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[CH3:9][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][N+:1]=1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(C)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 25 °C

Procedure:
To a dichloromethane (dehydrated) (150 ml) solution of a 2,3,5-collidine (11.0 g, 90.8 mmol), 3-chloroperbenzoic acid (24.8 g, 93.4 mmol as the content was regarded as 65%) was added at 1° C. in a nitrogen atmosphere. The mixture was stirred while the temperature was gradually raised to room temperature for 13.5 hours. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1) to obtain a crude product of the title compound as a pale yellow oil. After the crude product was diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate, the mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1) to obtain the title compound (11.0 g, yield: 88.3%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][NH2:12])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([CH2:11][NH:12][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]([CH:26]4[CH2:28][CH2:27]4)[NH:24][N:25]=3)[CH:17]=[CH:16][N:15]=2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: NCc1cc2nc[nH]c2cc1Cl
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2[nH]cnc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A tube was charged with 252 (110 mg, 0.608 mmol), 53 (143 mg, 0.608 mmol), and DIPEA (235 mg, 1.823 mmol) in IPA (3 mL), sealed and heated 120° C. for 18 h with stirring. The reaction was cooled to RT and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 72 mg (31.3%) of I-94 as white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].C(Cl)Cl.Cl>O>[OH:16][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Sc2cccc(O)n2)cc1

Procedure:
A solution of 5 grams (0.023 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol and 2.72 grams (0.68 mole) of sodium hydroxide in 15 milliliters of water was heated at reflux for 21/2 hours. The resulting solution was poured over a mixture of ice and methylene chloride and the resulting mixture was vigorously stirred. The mixture was acidified by the dropwise addition of concentrated hydrochloric acid. The white crystalline solid 4-((6-hydroxy-2-pyridyl)thio)-phenol product which precipitated out was recovered by filtration and washed with methylene chloride. The product was recovered in a yield of 4.35 grams (88 percent of theoretical) and melted at 234°-238° 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][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.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:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:19][C:21]1[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc2cc(CNc3ncnc4[nH]ccc34)c(-c3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenylquinolin-3-yl)meth-anamine (0.050 g, 0.186 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.034 g, 0.22 mmol, 1.2 eq) and DIEA (0.38 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [PI3Kδ IC50=270 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.65-8.76 (m, 1 H), 8.53 (s, 1 H), 8.11-8.20 (m, 4 H), 8.07 (d, J=1.96 Hz, 1 H), 7.91-8.00 (m, 2 H), 7.86 (s, 1 H), 7.51-7.58 (m, 2 H), 4.73-4.85 (m, 2 H), Mass Spectrum (ESI) m/e=386 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 53.8 %

Procedure:
4-Chlorothiosalicylic acid (2.3 g, 12.2 mmol) and tert-butyl 3-(2-cyano-4-pyridyl)propanoate (1.4 g, 6.0 mmol) were dissolved in pyridine (20 ml), and the mixture was refluxed for 16 hrs. The solvent was evaporated and the residue was subjected to a silica gel column chromatography. The fraction eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.3 g, 52%) as white crystals.
Reaction SMILES: C1([C:6]2[C:14]3[C:9](=[CH:10][C:11](C(NC4(C(NC5C=CC(/C=C/C(O)=O)=C(OCC)C=5)=O)CCC4)=O)=[CH:12][CH:13]=3)[N:8](C)[C:7]=2[C:40]2C=CC=CN=2)CCCC1.[Li]CCCC.CI>C1COCC1>[CH3:40][C:7]1[NH:8][C:9]2[C:14]([CH:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCOc1cc(NC(=O)C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5ccccn5)n(C)c4c3)CCC2)ccc1/C=C/C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 3-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. MeI (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0–15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 18-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 18-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 18-2 in 96% yield: MS-ES m/z258.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=C1CCCN1c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCC3=O)cc2F)cn1

Procedure:
Title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)pyrrolidin-2-one. MS (ESI): mass calcd. for C20H17FN4O, 348.14; m/z found, 349.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.54-7.14 (m, 6H), 6.72 (s, 2H), 3.44 (t, J=6.7, 2H), 2.26 (t, J=7.9, 2H), 1.97-1.87 (m, 2H).