Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[CH3:41])=[O:29].O>CN(C=O)C>[F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=2[CH3:41])=[O:29])=[N:6][N:7]=1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(CF)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (87 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered. Purified by reverse phase HPLC resulted product as a solid in (53.3 mg, 50% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71-7.53 (m, 7H), 7.26 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 5.34 (dd, J=12.0, 27.3 Hz, 1H), 5.18 (dd, J=12.3, 26.4 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-hydroxymethylpyrrolidine (5.3 g) and methanesulfonyl chloride (1.49 ml) in dichloromethane (40 ml) was added dropwise triethylamine (3.2 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, and evaporated to give an oil, which was chromatographed on silica gel (250 ml) eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methanesulfonyloxymethylpyrrolidine (6.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=5)=[N:9][C:10]=34)=[O:23])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 580.2 [(M+H)+]; mp 251° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([NH:1][CH2:2][CH2:3][CH2:4][O:5][S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCOS(C)(=O)=O
Yield: 69.8 %

Procedure:
To a solution of 3-amino-1-propanol (11.47 ml, 150 mmoles) and triethylamine (46 ml, 330 mmoles) in dichloromethane (250 ml) was added methylsulfonyl chloride (25.5 ml, 330 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarbnonate and water and dried. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 24.22 g of the desired product (69.8%, white crystals).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]([F:39])([F:38])[CH2:35][CH:36]=O>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([CH2:36][CH2:35][C:34]([F:39])([F:38])[F:33])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=CCC(F)(F)F
Product: Cc1c(N2CCN(CCC(F)(F)F)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure L using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (25.0 mg, 0.056 mmol) and 3,3,3-trifluoropropanal to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 2.07 (br s, 3H), 2.50 (m(buried), 2H), 2.60 (br s, 6H), 3.04 (br s, 4H), 3.29-3.31 (m, 4H), 3.69 (br s, 4H), 6.49 (s, 1H), 7.10-7.16 (m, 1H), 7.26-7.28 (m, 1H), 7.51 (s, 1H), 7.77 (s, 1H), 8.32 (s, 1H). Mass Spectrum (ESI) m/e=537.1 (M+1).
Reaction SMILES: ClC1C=CC(C2C=CN3[C:14](=[O:17])NN=C3C=2C2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44](S(C)(=O)=O)=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:17][CH3:14])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Product: COc1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.213 min, [M+H]+=444.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.O[C:21]1[CH:22]=[C:23]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=CC=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[O:9][C:10]3[CH:21]=[CH:22][C:23]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:12]=3[O:11]2)=[CH:6][CH:7]=1
Reactant: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2c(c1)OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)O2
Temperature: 60 °C
Yield: 37.7 %

Procedure:
A mixture of di(4-chlorophenyl)dimethoxymethane (26 g) (see Preparation 13) and methyl (3,4-dihydroxyphenyl)acetate (16 g) (see Preparation 12) in toluene (200 ml) was heated under reflux in a Dean-Stark apparatus for one hour. The reaction was cooled to 60° C. and p-toluenesulphonic acid was added (50 mg). After heating under reflux for 16 hours the solution was cooled, washed with aqueous sodium bicarbonate (100 ml, dried (MgSO4) and evaporated to a brown gum. Flash chromatography (silica, eluant=4:1 hexane/ethyl acetate) gave the title compound as a pale yellow gum (13.7 g). LRMS m/z=415(m)+.
Reaction SMILES: [CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:29]1[CH:33]=[N:32][N:31]=[C:30]1[NH2:34].Cl>N1C=CC=CC=1>[CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:34][C:30]2[S:29][CH:33]=[N:32][N:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
To a solution of p-octadecylbenzenesulfonyl chloride (500 mg, 1.17 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (177 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (296 mg, 0.60 mmol, 51% yield), mp 116-117° C.; 1H NMR (300 MHz, CDCl3) δ 0.86 (t, 3H, J=6.9 Hz), 1.25 (m, 30H), 1.60 (m, 2H), 2.64 (t, 2H, J=7.8 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.82 (d, 2H, J=7.8 Hz), 8.21 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.0, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; MS (LCQ, ESI+) Calcd for C26H44N3O2S2 494.3, found 494.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C26H44N3O2S2 494.2869, found 494.2869 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[ClH:22].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: Clc1ccc(CCBr)cc1
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Yield: 16.1 %

Procedure:
In an analogous manner to example 6, the title compound (0.56 g) as a white solid, mp 263°-266° C. dec. is prepared from ethyl-4-(1-piperazinyl)benzo[b]thiophene-2-carboxylate monohydrochloride (4.63 g, 14.2 mmol, prepared in example 5), 4-chlorophenethyl bromide (3.27 g, 14.9 mmol), sodium bicarbonate (2.44 g, 29.1 mmol) and anhydrous dimethyl sulfoxide (75 mL). The title compound is recrystallized from methanol (35 mL) and acetonitrile (35 mL); 1H NMR (DMSO-d6) δ 10.76 (1H, s), 8.10 (1H, s), 7.77 (1H, d, J=8.0 Hz), 7.44 (5H, m), 7.08 (1H, d, J=7.8 Hz), 4.37 (2H, q, J=7.0 Hz), 3.64 (4H, m), 3.56 (8H, m), 3.13 (2H, m), 1.34 (3 H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 162.42, 151.71, 143.15, 132.82, 130.94, 128.95, 128.86, 128.63, 128.34, 117.59, 113.66, 113.59, 61.97, 52.66, 51.40, 31.20, 24.06, 14.47; IR (KBr) 1714, 1448, 1282, 1246, 754 cm-1 ; CI/MS (CH4) 429(100%). IC50 =53 nM (5HT1ABinding Affinity) IC50 =411 nM (5HT1DBinding Affinity) pA2 =6.51 (blocking of 5-HTl-like-mediated contraction in canine saphenous vein)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][C:3]=1[Cl:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:24][C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)[CH:22]=[CH:23][C:2]=1[NH:1][C:39]([C:34]1[C:33](=[O:42])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[C:37]([CH3:38])=[CH:36][CH:35]=1)=[O:40]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1Cl
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2Cl)c(=O)n1-c1ccc(F)cc1
Yield: 93.6 %

Procedure:
Using N-[6-(4-amino-3-chlorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (160 mg, 0.467 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg, 0.607 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (161 μL, 0.934 mmol) and HATU (230.8 mg, 0.607 mmol) and in the same manner as in Example 60, the title compound (250 mg, 94%) was obtained as a white solid.
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[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22]Cl)=[CH:7]2.[H-].[Na+].[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1>CN(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[C:18]([F:19])([F:21])[F:20])[C:8]([CH2:22][N:29]1[C:30]3=[N:31][CH:32]=[N:33][C:34]([NH2:36])=[C:35]3[C:27]([I:26])=[N:28]1)=[CH:7]2
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure I using 8-chloro-3-(chloromethyl)-2-(2-trifluoromethylphenyl)quinoline (0.356 g, 1.0 mmol), NaH (0.044 g 60% in oil, 1.1 mmol, 1.1 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.287 g, 1.1 mmol, 1.1 eq) in 5 mL DMF. 1-((8-Chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=7 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (1 H, s), 8.08 (1 H, d, J=8.2 Hz), 7.96-8.03 (2 H, m), 7.74-7.84 (1 H, m), 7.56-7.70 (3 H, m), 7.26-7.37 (1 H, m), 5.47 (2 H, s) Mass Spectrum (ESI) m/e=580.9 and 583.0 (M+1)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=O.[C:19]([O:26][CH3:27])(=[O:25])[CH2:20][CH2:21][C:22]([CH3:24])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:27][O:26][C:19](=[O:25])[CH2:20][C:21]1[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:22]=1[CH3:24]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cccnc1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Yield: 39.1 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(pyridin-3-yl)methanone (0.362 g; 1.4 mmol), methyl levulinate (0.198 mL; 1.54 mmol), chlorotrimethylsilane (0.717 mL; 5.6 mmol) in DMF (5.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.193 g (39%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[O:24][C:23]([Si](C(C)C)(C(C)C)C(C)C)=[N:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.Cl[Pd]Cl>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2cnco2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-3-fluoro-benzoic acid (1.00 g), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (1.90 g), PdCl2 [1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (400 mg), and aqueous Na2CO3 solution (2 M; 5.70 mL) in N,N-dimethylformamide (6 mL) is stirred overnight at 80° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated in vacuo and water is added. The resulting mixture is acidified with hydrochloric acid (4 M; 6 mL) and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether, filtered off and dried to give the title product. LC (method 1): tR=0.87 min; Mass spectrum (ESI+): m/z=208 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:18])[CH2:12][CH:13](O)[C:14]([OH:16])=[O:15].Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:18])[CH:12]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc(OC)c(C(=O)CC(O)C(=O)O)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(OC)c(C(=O)C=CC(=O)O)c1

Procedure:
There is heated under reflux a mixture containing 13 g of the acid obtained in Stage A, 15 cm3 of acetic acid, and 1.5 cm3 of concentrated hydrochloric acid.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:1]([C:5]1[CH:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2ncc(C#C[Si](C)(C)C)cn2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butyl-6-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 1) (2.4 g, 8.85 mmol) was dissolved in dichloromethane (10 ml) and tetrabutylammoniumfluoride on silica gel (7.1 g, 10.6 mmol, 1.5 mmol/g) was added at room temperature. The mixture was stirred for 2 hours at room temperature and purified by flash chromatography by directly loading the mixture onto a 70 g silica gel column and eluting with heptane:ethyl acetate 100:0->40:60. The desired compound was obtained as a light yellow solid (1.45 g, 83% yield), MS: m/e=200.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])[CH:13]=[C:12]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(CCCN)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCCCc1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
The title compound is prepared by the reaction of the compound of Example 58 with methacryloyl chloride in the presence of triethylamine in toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.[OH-].[K+].[NH2:25]OS(O)(=O)=O.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[N:10]([NH2:25])[C:9]2=[O:21])[CH:7]=1
Reactant: NOS(=O)(=O)O
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1c(=O)n(-c2cc(Cl)ccc2O)c2ccc(C(F)(F)F)cc21

Procedure:
To a solution of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (0.2 g, 0.6 mmol) in absolute N,N-dimethylformamide (5 ml) was at room temperature added potassium hydroxide (2 pellets) and hydroxylamine-o-sulfonic acid (0.16 g, 1.3 mmol) The reaction was stirred over night, water was added (20 ml) and the mixture was acidified with 4 M hydrochloric acid. The crude crystalline product was collected by filtration and subjected to column chromatography using methylene chloride:methanol (19 1) as eluent. The fractions containing the product were concentrated in vacuo yielding the title compound as white crystals, M.p. 228°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:6].C(N(C(C)C)CC)(C)C.[CH2:36]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:50][CH:49]=2)Cl)=[CH:42][CH:41]=1)[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:54]([C:51]1[CH:52]=[CH:53][C:48]([CH:46]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)=[O:6])[C:43]2[CH:44]=[CH:45][C:40]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=2)=[CH:49][CH:50]=1)[CH:55]([CH3:57])[CH3:56]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccn12
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (320 mg) in methylene chloride (10 ml) was added diisopropylethylamine (0.22 ml) and bis(4-isobutylphenyl)chloromethane (340 mg) in methylene chloride (5 ml) at room temperature. After stirring for 18 hours, the reaction mixture was evaporated and extracted with ether. The organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (methylene chloride:ethyl acetate=20:1) to give ethyl 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyrate (279 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)[CH:20]=1>>[CH3:36][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[CH:20][C:19]=1[NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOCCOc1ccc(C(=O)Nc2cc(N)ccc2C)cc1
Product: CCOCCOc1ccc(C(=O)Nc2cc(NC(=O)c3ccc4ccccc4c3)ccc2C)cc1
Yield: 23 %

Procedure:
Using an analogous procedure to that described in Example 22, 2-naphthoyl chloride was reacted with N-(5-amino-2-methylphenyl)-4-(2-ethoxyethoxy)benzamide to give the title compound in 23% yield; Mass Spectrum: M+H 470.