Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=O.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:22]
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cccc(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cccc(F)c1
Yield: 91.2 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.83 g, 17.5 mmol), 2-(3-fluoro-anilino)-4,5-difluorobenzoic acid (Example S, 4.24 g, 15.9 mmol), O-benzylhydroxylamine hydrochloride (2.5 g, 15.9 mmol), and triethylamine (2.4 mL, 17.5 mmol) provided 5.4 g of the crude title compound.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[N:33][CH:34]=2)[CH:12]=[CH:11][C:10]=1[C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=1.Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:27])([F:26])[F:28])=[CH:19][C:18]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[N:33][CH:34]=2)[CH:12]=[CH:11][C:10]=1[C:45]1[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)O)nc2)c1CNc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.16 mL, 0.49 mmol) was added to a THF (1.0 mL) and MeOH (1.5 mL) solution of ethyl 3-(5-(2-(((2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-methoxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate (56 mg, 0.08 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1.C(N(C(C)C)CC)(C)C>CO.[Pd]>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=2)[CH:2]=[N:3]1
Reactant: COCCCn1nc(Br)c2ccc(C(=O)OC)cc21
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1ncc2ccc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 105.4 %

Procedure:
To a solution of methyl 3-bromo-1-(3-methoxypropyl)-1H-indazole-6-carboxylate (3.0 g) and diisopropylethylamine (2.4 mL) in methanol (60 mL) was added 10% palladium on carbon catalyst (600 mg), and the mixture was stirred under hydrogen for 1 hour. An insoluble was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, sequentially washed with 10% hydrochloric acid water and saturated saline, and then concentrated under reduced pressure to give methyl 1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-1)] (2.40 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14]([NH2:16])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14]([NH:16][S:40]([CH3:39])(=[O:42])=[O:41])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: NC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
To a mixture of 2-(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetamide (73.3 mg) and THF (dry) (10 mL) was added sodium bis(trimethylsilyl)amide (0.158 ml, 1.9 M in toluene) at −78° C. The mixture was stirred at −40° C. under argon atmosphere for 30 min. And then methanesulfonyl chloride (34.4 mg) was added thereto. The resulting mixture was stirred at room temperature under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (11.00 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[N:11]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(/C=C/C2=NS(=O)(=O)c3ccccc3N2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
2-Aminobenzenesulfonamide (0.25 g, 1.4 mmol) was added to a suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.25 g, 1.2 mmol), HBTU (0.55 g, 1.4 mmol) and NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) and the reaction was stirred at rt for 16 h. Extra NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) was added and the reaction was stirred at rt for 64 h. The solution was acidified and the precipitate was collected by filtration. Hot EtOH (15 mL) was added to the crude product and the undissolved solid was collected by hot filtration, providing (E)-3-[2-(3,4-dimethoxyphenyl)ethenyl]-4H-1,2,4-benzothiadiazine-1,1-dioxide (58 mg, 14%) as a colourless crystalline solid; mp 276-279° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.29 (d, J5′,6=8.0 Hz, 1H, H6′), 7.31 (s, 1H, H2′), 7.38 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.68 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.80 (d, J7,8=8.0 Hz, 1H, H8), 7.82 (d, J=15.6 Hz, 1H, CH═CHCO), 12.13 (s, 1H, NH); δC (125 MHz, DMSO-d6) 55.4, 55.6, 110.3, 111.8, 116.6, 117.6, 122.0, 122.7, 123.3, 126.3, 126.9, 133.0, 135.2, 142.2, 149.0, 151.1, 153.5; HRMS (ESI) calculated for C17H16N2O4S [M+H]+ 345.0904, found 345.0900; νmax 756, 1134, 1263, 1513, 1568, 1600, 3024, 3117, 3163, 3200 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH3:35][S:36]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Reaction time: 5 h
Yield: 12.5 %

Procedure:
To a solution containing 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in pyridine (0.4 ml) was added methyl sulfonyl chloride (25 μl, 0.32 mmol). After stirring for five hours, solvent was removed and the reaction was basified with aqueous sodium bicarbonate solution. The reaction was extracted with dichloromethane and concentrated. The product was purified by semipreparative HLPC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid). The acetonitrile was removed from the HPLC fractions containing the desired product. Ethyl acetate was added and the solution neutralized using saturated sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (0.0135 g, 13% yield): 1H NMR (CDCl3) 6.7-7.1 (m, 11H), 4.78 (t, 1H), 4.1 (t, 3H), 3.45-3.62 (m, 2H), 2.62-3.18 (m, 8H), 2.58 (m, 4H), 1.63 (m, 4H), 1.43 (m, 2H); ES-MS (m/z) 539 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[N:29][N:28]=[C:27]1[SH:31]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:27]3[N:26]([CH3:25])[CH:30]=[N:29][N:28]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Cn1cnnc1S
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nncn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (125 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 4-methyl-4H-[1,2,4]triazole-3-thiol (230 mg, 2 mmol) following the general procedure Y
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:26]1=2.O1CCOCC1>CO.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].Cl[Pd]Cl>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:32]=[CH:33][C:26]1=2
Reactant: OB(O)c1ccc2sccc2c1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4sccc4c3)n2n1
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), benzo[b]thiophen-5-ylboronic acid (40 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (28 mg, 36%). 1HNMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 443.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[C:4]=2[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (450 mg, 1.45 mmol) in DMF (20 mL) was added potassium carbonate (0.4 g, 2.90 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 3.96 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 16 h. The mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give crude product. This material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (3:1 to 1:1) to give 8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (250 mg, 39.2% yield) as yellow oil. LCMS retention time 1.886; LCMS MH+-28 413.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]3[NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[C:23]=2[F:30])[CH2:2]1.N1CC([O:35][C:36]2C=C3C(=[CH:44][C:45]=2O)N=CN=C3NC2C=CC(F)=C(Cl)C=2F)C1>>[Cl:29][C:24]1[C:23]([F:30])=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH:3]4[CH2:2][N:1]([C:36](=[O:35])[CH:45]=[CH2:44])[CH2:4]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Product: C=CC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OCCOC)C1
Yield: 50 %

Procedure:
The procedure of step 3) of Example 115 was repeated except for using the compound obtained in step 2) instead of 6-(azetidin-3-yloxy)-4-(3-chloro-2,4-difluorophenylamino)quinazolin-7-ol to obtain the title compound (21 mg, 50%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][N:8]([CH3:36])[C:9]([C:11]1[N:12]([CH3:35])[C:13]([C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:14]([CH3:16])[CH:15]=1)=[O:10]>C(OCC)(=O)C>[CH3:1][N:2]([CH:4]=[N:32][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:19]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:17]([C:13]3[N:12]([CH3:35])[C:11]([C:9]([N:8]([O:7][CH3:6])[CH3:36])=[O:10])=[CH:15][C:14]=3[CH3:16])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:34])[CH3:3]
Reactant: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
DMF (0.65 ml) and DMF acetal (0.19 g, 0.21 ml, 1.61 mmol) were added to a solution of N-methoxy-5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-N,1,4-trimethyl-1H-pyrrole-2-carboxamide (10d, 0.65 g, 1.46 mmol) in ethyl acetate (13 ml) under stirring at room temperature. The mixture was stirred at room temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 ml) and the mixture so obtained was washed with water (2×20 ml). The organic layer separated was dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by flash column chromatography using 4% methanol in DCM as an eluent to obtain the title compound 10e (0.62 g, 84.9%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([NH:10][CH:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dextro amphetamine (200 g) and triethylamine (164 g) were dissolved in 1500 ml. of benzene. A solution of p-toluene sulfonyl chloride (310g) in 500 ml. of benzene was added dropwise to the cooled solution during one hour. The reaction mixture was stirred for three hours at room temperature, then allowed to stand for approximately 16 hours (over night) at room temperature (approximately 20° C.). The salts were filtered off and the benzene solution was washed with dilute HCl, water and brine. Evaporation of the solvent afforded an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([O:14][C:15]([C:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([CH:28]=O)[NH:19][C:18]=1[CH3:30])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:30])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 59.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (60 mg, 0.29 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (75 mg) to give 78 mg (60%) of the title compound as an orange 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[S:18]([CH3:21])(=[O:20])=[O:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:19])=[O:20])[C:8]([CH2:22][NH:23][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[CH:7]2
Reactant: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-(methylsulfonyl)phenyl) quinolin-3-yl)methanamine (0.060 g, 0.173 mmol), 6-chloropurine (0.032 g, 0.21 mmol, 1.2 eq) and DIEA (0.34 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=222 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.29 (s, 1H), 8.13 (s, 1H), 8.01-8.09 (m, 2H), 7.78-7.81 (m, 1H), 7.66-7.76 (m, 1H), 7.57-7.65 (m, 1H), 7.46 (d, J=7.83 Hz, 2H), 4.87-4.98 (m, 2 H), 3.28 (s, 3H), Mass Spectrum (ESI) m/e=465 (M+1).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:25][CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][CH2:19][N:18](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCCNCCCNCCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
A mixture of 1,5,9,13-tetra(p-toluenesulfonyl)-1,5,9,13-tetraazacyclohexadecane prepared as in Example 10E (33.7 g, 0.0399 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (200 mL) was added dropwise with stirring at 0° C, followed by ethyl ether (500 ml). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (50 ml), the pH was adjusted to 11 with solid NaOH, and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (4×100 ml) and the extracts were filtered. The filtrates were combined and filtered to remove cloudiness. The solvent was removed in vacuo and the crude product was purified by recrystallization from CHCl3 -ethyl ether to give 4.29 g (47% yield) of the product as colorless prisms: mp 84-6° C.; 1H NMR (CDCl3) δ 1.54 (br s, 4 H), 1.70 (quint, J=6.0 Hz,8 H), 2.72 (t, J=6.1 Hz, 16 H); Exact mass (M+H)+ : calcd., 229.2391; Found, 229.2417 (C12H29N4).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.[OH-:23].[Na+:24]>O>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[OH2:23].[OH2:3].[OH2:3].[Na+:24]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1
Temperature: 60 °C

Procedure:
0.97 g (2.9 mmols) of topiramate (Cheminor Ltd.), 10 mL distilled water, and 2.8 mL IN NaOH (2.8 mmol) were added to a glass beaker, warmed on a hotplate to 60° C. and stirred with a TEFLON-coated stir bar on a magnetic stirplate. The solid topiramate dissolved in about 25 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Br
Product: Nc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1

Procedure:
Prepared as described in Example 1, starting from 1.0 g of 2 -bromo-6-chlorophenylacetonitrile and 0.57 g of 2,4 -diamino-5-pyrimidine-carboxaldehyde, mp 264-280° C.; MS(CI).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(C)N1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
1-Isopropyl-4-(5-nitro-pyridin-2-yl)-piperazine (0.9 g, 3.6 mmol) is dissolved in MeOH (20 mL) and tin (II) dichloride dihydrate (4 g, 18 mmol) is added. The mixture is cooled using a water bath and conc. HCl is added (4 mL). The reaction is stirred at room temperature overnight. After removing the methanol, the resultant light yellow solution is basified using conc. NaOH (pH 11) and a white precipitate is formed. The solid is collected by filtration and the water is extracted with diethyl ether (5×). The organic layers are combined, dried over MgSO4, filtered, concentrated under vacuum to afford an orange oil which crystallizes on standing to afford an orange solid (0.68 g, 86%).