Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18]([N:20](C)[C:21](=[O:38])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:24]=2)=[O:19])=[CH:9]1)=O)(C)(C)C.C(OC(N1C2C(=CC=CC=2)C(C2C(N(C)C(=O)C=2C2C3C(=CC=CC=3)NC=2)=O)=C1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C)CCCCl>CC(C)=O.O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18]([NH:20][C:21](=[O:38])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:24]=2)=[O:19])=[CH:9]1
Reactant: CN(C)CCCn1cc(C2=C(c3cn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(C)C2=O)c2ccccc21
Agent: CN(C)CCCCl
Agent: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CCCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-(1-tert. -butoxycarbonyl-1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-N-methylmaleinimide used as starting material is prepared as follows: A mixture of 0.9 g (2.03 mmol) 2-(1-tert.-butoxycarbonyl-1H-indol-3-yl)-3-(1H-indol-3-yl)-N-methylmaleinimide (Tetrahedron, 44, 2887/1988), 0,3 g potassium carbonate and 0.3 g (2.4 mmol) 3-dimethylaminopropyl chloride in 10 ml acetone is stirred for 12 hours at ambient temperature and for 8 hours under reflux. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The red extract is evaporated and the residue flash chromatographed on silica gel (Merck Type 7734) using, as elution agent, a mixture of toluene/ethanol (10+1.5 v/v). The desired product is obtained in the form of a red oil and used as such in the above reaction. Yield 0.8 g (74% of theory); RF=0,20 (toluene/ethanol 1:2 v/v).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[CH2:34](I)[CH3:35].[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:34][CH3:35])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[(4-Dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and ethyl iodide (0.14 mL) were dissolved in dimethylformamide (5 mL), and sodium hydride (0.07 g) was added under ice-cooling. The mixture was stirred at room temperature for 24 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g).
Reaction SMILES: [C:1]([O:4][CH:5]([C:18]1[CH:22]([OH:23])[O:21][C:20](=[O:24])[CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]>CO.[Rh]>[C:1]([O:4][CH:5]([CH:18]1[CH:22]([OH:23])[O:21][C:20](=[O:24])[CH2:19]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1O
Agent: [Rh]
Solvent: CO
Product: CCCCCCCCCCCCC(OC(C)=O)C1CC(=O)OC1O

Procedure:
A solution of 4-(1-acetoxytridecyl)-5-hydroxy-2(5H)-furanone (0.11 g, 0.32 mmol) and 5% rhodium on alumina (24 mg) in 6 ml of methanol was stirred rapidly under a hydrogen atmosphere for two hours. The mixture was concentrated, taken up in ethyl acetate, filtered through celite, and concentrated to give the tetrahydrofuranone as a colorless glass.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of sodium carbonate (7.18 g), tetrakis(triphenylphosphine)palladium(0) (1.957 g), 4-(benzyloxy)-3-fluorophenylboronic acid (10 g), and 3-bromopyridin-2-amine (5.86 g) in DME (120 ml) and water (24 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (9.97 g) as a pale yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[OH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C(Cl)Cl>[CH3:3][O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CO)cccc32)cc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COCc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h

Procedure:
3rd stage: In sequence, 27 g of pulverulent potassium hydroxide, 27 ml of methyl iodide and 2.7 g of tetrabutyl-ammonium-hydrogen-sulfate are added to a solution of 13.5 g of 4-hydroxymethyl-1-tosylindole in 400 ml of methylene chloride. The substance is strongly agitated for 24 h. Then, it is filtered off of the potassium hydroxide, washed neutral with water, and the solvent is distilled off. The raw product (16.46 g) is crystallized out of diisopropylether. 12.2 g of 4-methoxymethyl-1-tosylindole with a m.p. of 85.5°-89° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20]([OH:22])=O)[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)[CH2:31][CH2:30]1>>[ClH:25].[ClH:25].[OH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:22])[CH2:34][CH2:33]2)[CH2:42][CH2:41]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 21 analogously to the method described in example 1.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[C:13]4[N:14]=[C:15]([C:21]5[N:22]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:23]=[CH:24][N:25]=5)[S:16][C:17]=4[CH2:18][CH2:19][O:20][C:11]=3[CH:10]=2)[CH:6]=[N:5]1.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:33]1[CH2:36][CH:35]([NH:37][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([C:9]3[CH:32]=[CH:31][C:12]4[C:13]5[N:14]=[C:15]([C:21]6[N:22]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:23]=[CH:24][N:25]=6)[S:16][C:17]=5[CH2:18][CH2:19][O:20][C:11]=4[CH:10]=3)[CH:6]=[N:5]2)[CH2:34]1
Reactant: NC1COC1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCCl)c3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCNC4COC4)c3)ccc1-2
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.416 mmol) and 3-oxetanamine (0.608 g, 2.08 mmol) in 5 mL of DMF was added potassium carbonate (0.287 g, 2.08 mmol) and potassium iodide (0.069 g, 0.416 mmol). The reaction mixture was heated at 50° C. for approximately 4 hours. The heated was increased to 70 C and the reaction was continued another 15 hours to give the desired product as determined by LCMS. The crude material was purified by RP-HPLC to cleanly give 461. MS: (ESI+)=518.3
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#N.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH2:21][CH2:20][N:19]([C:4]2[C:3]([CH3:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH:18]([CH3:22])[CH2:17]1)[CH3:15]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: CCN1CCNC(C)C1
Product: CCN1CCN(c2cc(N)c([N+](=O)[O-])cc2C)C(C)C1

Procedure:
A reaction was conducted by the method similar to Example 143-1) except that the compound of 1) above was used in place of 4-cyano-3-fluoro-6-nitroaniline and 1-ethyl-3-methylpiperazine was used in place of 1-tert-butoxycarbonyl-3-methylpiperazine, to provide the title compound as an orange-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:21]([O-])=O)[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>CO.[Zn+2].[Br-].[Br-].[Pd]>[NH2:21][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cncc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(N)cncc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate (900 mg, 2.626 mmol) and ZnBr2 (118.3 mg, 28.16 μL, 0.5252 mmol) in methanol (27.00 mL) was added Pd on C (10%, wet, Degussa) (300 mg). The reaction mixture was stirred at RT for 4 h under an atmosphere of hydrogen (balloon). The catalyst was filtered off and the filtrate was concentrated in vacuo to yield tert-butyl 4-(3-amino-5-chloropyridin-4-yl)piperazine-1-carboxylate which was used without further purification (820 mg, 99%). MS (ES+) 313.2.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[O:11][C:12]([C:15]([O:21][Si](C(C)C)(C(C)C)C(C)C)([CH3:20])[C:16]([F:19])([F:18])[F:17])=[N:13][N:14]=3)[C:7]([NH2:32])=[CH:6][C:5]=2[C:33]([F:36])([F:35])[F:34])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:32][C:7]1[C:8]([C:10]2[O:11][C:12]([C:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[N:13][N:14]=2)=[N:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:5]([C:33]([F:34])([F:36])[F:35])[CH:6]=1
Reactant: CC(C)[Si](OC(C)(c1nnc(-c2nc(C3CC3)c(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(c1nnc(-c2nc(C3CC3)c(C(F)(F)F)cc2N)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 6-cyclopropyl-2-(5-(1,1,1-trifluoro-2-(triisopropylsilyloxy)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (step 4) (200 mg, 0.371 mmol) in dry THF (10 ml) was treated with silica supported tetra-n-butylammonium fluoride (500 mg, 0.750 mmol). The resulting red suspension was stirred at RT for 5 minutes and filtered through Celite® (filter material). The mixture was washed through with THF (10 ml) and the filtrate was concentrated in vacuo to give an orange oil. Purification of the oil by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (E)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (0.728 g, 2.2 mmol), dimethyl-prop-2-ynyl-amine (0.56 ml, 6.58 mmol), bis(triphenylphosphine) palladium(II) chloride (0.061 g, 0.088 mmol), copper(I) iodide (1.25 mg, 0.0065 mmol) in dry triethyllamine (7 ml) were heated to 100° C. by microwave irradiation for 20 min. To the cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (5 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH2:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[CH2:16]([O:15][C:13]([C:4]1[N:3]=[C:2]([NH:32][C@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]2[NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1)=[O:14])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)c1nc(Cl)c2cc(C)ccc2n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Yield: 108.4 %

Procedure:
To a suspension of 8.47 g of 4-chloro-2-ethoxycarbonyl-6-methylquinazoline and 7.60 g of (1S,2R)-2-(t-butoxycarbonylamino)cyclohexylamine in 350 ml of toluene, 11.8 ml of triethylamine and a catalytic amount of 4-dimethylaminopyridine were added, and then the mixture was heated at reflux for 16 hours. After the reaction solution was mixed with a saturated sodium hydrogencarbonate solution and extracted with chloroform, the organic layer was washed with a 10% citric acid solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off to obtain 15.7 g of the desirable compound as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 85.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and tert-butylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-tert-butyl-2-(trifluoromethoxy)benzenesulfonamide (0.33 g, 85%) was provided after purification. MS (ESI) m/z 376. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
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][N:13]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[C:33]([NH2:38])[N:32]=1>C(O)CCC>[Cl:37][C:36]1[C:31]([NH:20][C@H:18]([C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:19])=[N:32][C:33]([NH2:38])=[N:34][CH:35]=1
Reactant: Nc1ncc(Cl)c(Cl)n1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1ccccn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)ncc1Cl)c1cc2cccc(Cl)c2nc1-c1ccccn1

Procedure:
A mixture of (1S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (0.090 g, 0.32 mmol) in n-butanol (3 mL) was treated with DIEA (0.11 mL, 0.64 mmol, 2.0 eq), followed with 4,5-dichloropyrimidin-2-amine (0.062 g, 0.38 mmol, 1.2 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide 5-chloro-N4-((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)pyrimidine-2,4-diamine [PI3Kδ IC50=105 nM] as a white solid. 1H-NMR (DMSO-d6) δ ppm 8.65-8.76 (m, 1H), 8.53 (s, 1H), 8.11-8.20 (m, 1H), 8.07 (d, J=1.96 Hz, 1H), 7.91-8.00 (m, 2H), 7.86 (s, 1H), 7.62 (t, J=8.02 Hz, 1H), 7.51-7.58 (m, 1H), 6.03-6.25 (m, 1H), 1.38-1.63 (d, J=7.04, 3H), Mass Spectrum (ESI) m/e=412 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[CH:13]=2)O1.Br[C:29]1[CH:30]=[C:31]([C:36]2[N:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[N:39]=[N:38][N:37]=2)[C:32]([NH2:35])=[N:33][CH:34]=1.[F-].[Cs+]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:9]2[CH:10]=[N:11][N:12]([C@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]3)[CH:13]=2)=[CH:30][C:31]=1[C:36]1[N:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=2[F:50])[N:39]=[N:38][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: COc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nnnc2-c2cc(-c3cnn([C@H]4CCCN(C(=O)OC(C)(C)C)C4)c3)cnc2N)c(F)c1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A solution of (S)-tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1099, 642 mg, 1.70 mmol), 5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1100, 543 mg, 1.418 mmol), and CsF (1.5 M, 2.84 mL, 4.26 mmol) in 7 mL DMF was degassed with nitrogen for 30 minutes, at which point 1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride (174 mg, 0.212 mmol) was added and the mixture was degassed an additional 15 minutes before heating to 120° C. under an atmosphere of nitrogen. After 1 hour, LCMS analysis indicated that the reaction was complete. Methylene chloride (10 mL) and satd' aqueous sodium bicarbonate (10 mL) were added, and the reaction mixture extracted with methylene chloride (2×10 mL), the combined organics concentrated under reduced pressure, and the residue purified via silica gel chromatography (50-100% ethyl acetate in hexanes) to give (S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1101) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.25-7.16 (m, 2H), 6.94-6.88 (m, 2H), 6.31 (s, 2H), 4.15-4.01 (m, 1H), 3.96 (s, 3H), 3.28 (d, J=11.5 Hz, 1H), 2.98-2.81 (m, 2H), 2.62 (dd, J=2.7, 22.8 Hz, 1H), 2.62 (s, 1H), 2.14-2.10 (m, 1H), 1.97-1.73 (m, 1H), 1.62 (s, 9H) and 1.57-1.47 (m, 1H) ppm.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:23])[F:24])[C:18]([F:21])([F:19])[F:20])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]4[CH3:33])=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH:43]=[CH2:44].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:44][CH2:43][C:42]([N:41]([CH3:46])[CH3:40])=[O:45])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 47.1 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (200 mg, 0.36 mmol), N,N-dimethylacrylamide (107 mg, 1.08 mmol), sodium hydride (60% in oil, 23 mg, 0.56 mmol) and tetrahydrofuran (4 ml) were subjected to reaction using a procedure similar to that of Example 25(1) (17 hours at room temperature), worked up and purified by preparative thin layer chromatography (4 sheets (each 1.0 mm thickness), ethyl acetate) to give the titled compound (114 mg, 47.1%) as white powder.