Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17]([OH:19])=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C(C)=CC=CC=1C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17](=[O:19])[NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)NCc1ccccc1)OC2
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (101 mg, 0.34 mmol, prepared in Example 31) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol) in distilled dichloromethane (4 ml) under nitrogen was added benzylamine (40 μl, 0.37 mmol) followed by 2,6-lutidine (0.12 ml, 1.02 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4) over sodium sulfate, filtered, and the solvent evaporated in vacuo to give 72 mg (56%) of 2-amino-5-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [I-].[CH:2]([O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[O:22][CH3:23])=[C:10]([C:24]2[O:25]CC(C)(C)[N+]=2C)[CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[OH-:32].[Na+]>CO>[CH:2]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:24]([OH:25])=[O:32])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:14][C:13]=1[O:22][CH3:23])([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C1=[N+](C)C(C)(C)CO1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C(=O)O
Yield: 84 %

Procedure:
Prepare a solution of 2-(6,4'-diisopropyloxy-2 '-methoxy-biphenyl-2-yl)-3,4,4-trimethyl-oxazolinium iodide (13.20 g, 0.0245 mole) in 20% NaOH (140 mL) and methanol (140 mL) and stir at reflux overnight. Concentrate the resulting colorless solution on the rotovap until precipitation begins. Dilute the resulting suspension to 300 mL with water and acidify with concentrated HCl to pH=1. Extract the precipitate into CH2Cl2 (400 mL), wash with brine, separate and dry over MgSO4. Filter, concentrate and recrystallize from cyclohexane (~175 mL) to obtain the title compound (7.10 g, 84%). m.p. 117-119° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)(O)=[O:2].[ClH:18].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[Cl:18][C:1]([CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)=[O:2]
Reactant: CCOC(=O)CN1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.46 g of 4-(2-carboxyethyl)-1-[(ethoxycarbonyl)methyl]-piperidine in 10 ml of methylene chloride is added 1 ml of saturated ethereal hydrochloric acid. 1.2 g of thionyl chloride are added and the mixture is stirred for 3 hours at ambient temperature. The reaction mixture is concentrated by evaporation and the residue is mixed twice with toluene and again concentrated by evaporation. The crude product is reacted further in Example 1 without purification.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH3:13][O:14][C:15]([C:17]#[C:18][C:19]([O:21][CH3:22])=[O:20])=[O:16]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([C:15]([O:14][CH3:13])=[O:16])=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: COC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C(=O)OC
Reaction time: 6 h

Procedure:
A solution of 4.8 g (0.03 mole) of 3-diazooxindole in 150 ml of warm (45°) benzene is treated with 5.10 g (0.036 mole) of dimethylacetylene dicarboxylate. After stirring for 6 hours at 45°, an additional 0.426 g (0.003 mole) of ester is added and reaction continued overnight.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:38]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:39])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(C3CCN(C(=O)N4CCOCC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was dissolved in tetrahydrofuran (2 mL). Morpholine-4-carbonyl chloride (27 mg, 0.183 mmol) was added to the reaction mixture followed by triethylamine (51 uL, 0.366 mmol). The suspension was stirred at rt overnight. The reaction was concentrated under vacuum. The compound was triturated with 1:1 ether-hexanes to yield desired product (70 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.92 (s, 1 H), 7.79 (d, 1 H), 7.58 (m, 3 H), 7.35-7.32 (m, 4 H), 7.13 (d, 1 H), 6.67 (s, 1 H), 5.64 (s, 2 H), 3.90-2.50 (m, 13 H), 2.50-2.10 (m, 2 H); ES-MS m/z 523.3 [M+H]+, HPLC RT (min) 2.47.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[F:49][C:50]1[C:55]([F:56])=[CH:54][C:53]([F:57])=[C:52]([F:58])[C:51]=1O>C1COCC1>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][C:51]1[C:50]([F:49])=[C:55]([F:56])[CH:54]=[C:53]([F:57])[C:52]=1[F:58])=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCC[Sn](C=CCCC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Reaction time: 8 h

Procedure:
To a solution of tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid (1.0 equiv.) in anhydrous THF at room temperature is added dicyclohexyl carbodiimide (1.2 equiv) (Aldrich) and 2,3,5,6-tetrafluorophenol (1.2 equiv) (Aldrich). The resulting solution is stirred overnight. The mixture is filtered, the filtrate is concentrated, and the residue is chromatographed to provide 2,3,5,6-tetrafluorophenyl 5-(tri-n-butylstannyl)-4-pentenoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:14][C:15](=[O:28])[NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:14][C:15](=[O:28])[NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1ccc(NC(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)cc1)N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Temperature: 25 °C

Procedure:
To a solution of (S)-ethyl 4-(3-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)ureido)benzoate (109 mg, 0.220 mmol) in THF (3 mL) and MeOH (1 mL) was added 1 M aqueous LiOH (4 mL, 4.00 mmol). The resulting mixture was then stirred at rt. After stirring for 24 h, the reaction was acidified with 1 N HCl to ˜pH 7. The aqueous solution was extracted with DCM (3×10 mL). The combined DCM layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as an off-white solid. 1H-NMR (300 MHz, MeOH-d4): δ ppm 8.48 (d, J=4.7 Hz, 1H), 7.83-7.98 (m, 2H), 7.62 (ddd, J=9.8, 8.5, 1.3 Hz, 1H), 7.27-7.51 (m, 6H), 6.40 (d, J=1.5 Hz, 1H). MS (ESI pos. ion) m/z: 445.9 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)c1cccc2c1C(=O)C(=O)N2
Agent: Cl
Product: CC(C)c1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 73 %

Procedure:
The title compound was prepared from 4-isopropyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 73% yield: 1H NMR (DMSO-d6): δ 1.30 (d, J=6.7 Hz, 6H), 3.82 (septet, J=6.7 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H 7.24 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 11.10 (s, 1H), 13.05 (s, 1H); APCI−MS m/z 357 (M−1)−. Anal. Calcd for C17H18N4O3S: C, 56.97, H. 5.06; N, 15.63; S. 8.95. Found C, 56.88, H, 5.12; N, 15.73; S, 8.91.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[CH2:28]([C:30]1[C:38]2[C:37]([NH2:39])=[CH:36][CH:35]=[CH:34][C:33]=2[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]>CC(N(C)C)=O>[CH2:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[NH:39][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:22])[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Reactant: CCc1nn(Cc2nc(C)cs2)c2cccc(N)c12
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nn(Cc2nc(C)cs2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.346 g, 0.997 mmol) in DMA (5 mL) was cooled to 0° C. and treated with phosphorous oxychloride (0.182 mL, 1.99 mmol). The mixture was warmed up to ambient temperature and after stirring for an hour, the mixture was cooled to 0° C. again and treated with a solution of 3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine (0.181 g, 0.665 mmol) in DMA (2 mL). The mixture was allowed to warm up to ambient temperature and stirring continued overnight. The mixture was concentrated and then quenched with saturated aqueous lithium hydroxide, stirred at ambient temperature for 30 minutes and then diluted with DCM. The organic layer was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (2-10% 7N NH3/MeOH in DCM) to provide N-(3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.133 g, 36% yield) as beige solids. MS (APCI) m/z=559 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)cnc1C1=CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carbamic acid-tert-butyl ester (11.2 g) in N,N-dimethylformamide (90 ml) was added sodium hydride (1.46 g) under ice-cooling, and stirred at the same temperature for 0.5 hours. Then methyl iodide (5.7 ml) was added thereto, and stirred at the same temperature for 2 hours. After completion of the reaction, water was added thereto, and the precipitated solid was collected by filtration to give N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid-tert-butyl ester.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[CH3:10][OH:11].C[O-].[Na+]>O>[F:8][C:7]1[C:2]([O:11][CH3:10])=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(F)ccc1F
Reaction time: 0.17 h
Yield: 69 %

Procedure:
step 1—To a flask containing 2,3,6-trifluoropyridine (2 g, 15 mmol) was added MeOH (5 mL) followed by methanolic NaOMe (5 mL, 25% NaOMe in MeOH). An exothermic reaction occurred and some solid formed. The reaction was stirred for 10 min and diluted with H2O. The solid was filtered and washed with H2O. The solid was dissolved in EtOAc, washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 1.5 g (69%) of 3,6-difluoro-2-methoxy-pyridine (140). The recovered material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH:27]=[CH:26][N:25]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(Br)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (950 mg, 3 mmol), (prepared as described for the starting material in Example 24), 2-bromo-4-bromomethylpyridine (765 mg, 3 mmol) and potassium carbonate (2.38 g 17 mmol) in DMF (10 ml) was heated at 80° C. for 2 hours. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane and the solid product collected by filtration, washed with ethyl acetate/hexane and dried to give 7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (647 mg, 44%).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:36](=[O:37])[CH2:35][O:34][CH3:33])=[CH:25][CH:24]=1
Reactant: COCC(=O)Cl
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (144 mg, 0.35 mmol) and Et3N (200 μL, 1.4 mmol) in CH2Cl2 (15 mL) at rt was added methoxyacetyl chloride (50 μL, 0.53 mmol). After 18 h at rt, the reaction mixture was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (127 mg, 89%). MS (ESI): mass calcd. for C22H23N3O3S, 409.15; m/z found, 410.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.74 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.40 (m, 3H), 7.30 (m, 3H), 4.83 (br m, 0.5H), 4.46 (br m, 0.5H), 4.06 (m, 1H), 4.01 (s, 1H), 3.76 (m, 2.5H), 3.63 (br d, J=9.3 Hz, 0.5H), 3.58 (br s, 1H), 3.45 (s, 1.5H), 3.43 (s, 1.5H), 3.35 (br d, J=2.1 Hz, 0.5H), 3.33 (m, 0.5H), 3.01 (dd, J=9.9, 2.3 Hz, 0.5H), 2.87 (dd, J=9.8, 2.2 Hz, 0.5H), 2.78 (br d, J=9.9 Hz, 0.5H), 2.58 (d, J=9.5 Hz, 0.5H), 1.99 (br d, J=9.3 Hz, 0.5H), 1.96 (br d, J=9.8 Hz, 0.5H), 1.76 (br d, J=10.0 Hz, 0.5H), 1.66 (br d, J=10.0 Hz, 0.5H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C1COCC1.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>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C

Procedure:
To 3.30 g (16.4 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) in 40 mL THF are added 2.44 g (16.4 mmol) 2,4-dichloropyrimidine, 57.5 mg (82.0 μmol) bis(triphenyphosphine)dichloropalladium and 9.10 mL (65.7 mmol) TEA. The reaction mixture is stirred under reflux for 4 h and at r.t. over night. The reaction mixture is filtrated and the solvent is removed in vacuo. The residue is triturated with water and afterwards with diethylether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:13][CH2:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccccc1[N+](=O)[O-]
Yield: 42.2 %

Procedure:
2-Nitrophenol (91.0 g. 0.65 mole), 2-bromoethyl ethyl ether (100.0 g. 0.65 mole), anhydrous potassium carbonate (9.0 g, 0.72 mole) and acetone (1 liter) were refluxed for 65 hours. The reaction mixture was filtered, and the acetone removed by rotary evaporation. The residue was partitioned between 200 ml. of dichloromethane and 100 ml water. The organic phase was further washed with 200 ml. of 10% sodium hydroxide followed by 100 cc of water. The product (58.0 g) was obtained in 42% yield by a vacuum distillation (100°-120° C./0.5 mm).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[CH3:9][O:10][C:11](=[O:26])[C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:13]([CH3:15])=O>C(O)C>[CH3:9][O:10][C:11]([C:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:13]=1[CH3:15])=[O:26]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: Cc1cc(N)n(C)n1
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2c(c(C)nn2C)C1c1cccc([N+](=O)[O-])c1

Procedure:
1,3-Dimethyl-5-pyrazolamine (3.33 g; 0.030 mol) is dissolved in ethanol (35 ml) and methyl-2-(3-nitrobenzyliden)acetoacetate (6.75 g; 0.27 mol) is added thereto. The mixture is refluxed for about 5 hours, then the solvent is evaporated under reduced pressure and the residue is taken up in methylene chloride, washed with 2% hydrochloric acid and then with saturated aqueous sodium bicarbonate, the organic phase is dried over sodium sulphate and then the solvent is evaporated. The solid compound of the title is recovered by filtration, after taking up in ethyl ether. M.p. 163°-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:44][CH2:45][CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:44][CH2:45][CH2:46][CH2:47][S:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:50])=[O:49]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CCCCl)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.1 g, 1.2 mmole) in methylene chloride (15 ml) at 0° was added, dropwise, a solution of 3-chloropropanesulphonyl chloride (0.072 g, 0.4 mmole) in methylene chloride (1 ml). The resulting mixture was stirred at 0° for 2 hours, an additional portion of 3-chloropropanesulphonyl chloride (0.036 g, 0.2 mmole) was added and stirring was continued overnight at room temperature, the reaction mixture was quenched by the addition of aqueous citric acid, the organic phase separated and washed with water. After drying over magnesium sulphate, the organic phase was concentrated under reduced pressure and the resulting gum purified by flash chromatography on silica gel eluting with ethyl acetate to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 80°- 81° (0.24 g, 96%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH:36]([OH:40])[CH2:37][CH:38]=[CH2:39])=[CH:34][C:33]2[C:28](=[C:29]([CH3:41])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([O:40][CH:36]([C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:41])[CH2:37][CH:38]=[CH2:39])=[N:7][CH:6]=1
Reactant: C=CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2[nH]ccc12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(Oc1ncnc2[nH]ccc12)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared according to procedure L. A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (474 mg, 3.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (694 mg, 6.2 mmol) in anhydrous DMSO (4.5 mL) was stirred at rt for 5 h and then added via cannula to a mixture of 1-(2-(2-chlorophenyl)-8-methylquinolin-3-yl)but-3-en-1-ol (500 mg, 1.5 mmol) and sodium hydride, 60% dispersion in mineral oil (180 mg, 4.5 mmol) in DMSO (3 mL) that had been stirred for 30 min at rt and 30 min at 50° C. prior to the addition. The mixture was stirred at rt for 6 h before addition of water (10 mL), and the mixture was extracted with EtOAc (4×20 mL). The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH, 50/1) to provide 3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)but-3-enyl)-2-(2-chlorophenyl)-8-methyl-quinoline [PI3Kδ IC50=28 nM] as a white solid. 1H-NMR (CDCl3) δ 10.20 (s, br, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.15-7.64 (m, 8H), 6.59-6.62 (m, 1H), 6.34-6.37 (m, 1H), 5.64-5.79 (m, 1H), 4.93-5.01 (m, 2H), 2.74 (t, J=8.7 Hz, 2H), 2.70 (s, 3H). Mass Spectrum (ESI) m/e=441 (M+1).