Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[N:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)NS(=O)(=O)/C=C/c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1ccncc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
(E)-N-tert-Butyl-2-(4-pyridyl)ethenesulfonamide (3.8 g) was dissolved in trifluoroacetic acid (38 ml) and the mixture was stirred in an oil bath at 50° C. for 4 hr. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in trifluoroacetic acid (19 ml) and stirred in an oil bath at 50° C. for 45 min. The reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between chloroform:methanol(9:1) and a saturated aqueous solution of sodium hydrogen carbonate. The aqueous layer was extracted twice with chloroform:methanol(9:1) and once with ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted 4 times with ethyl acetate. All extracts with ethyl acetate were combined, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give (E)-2-(4-pyridyl)ethene-sulfonamide(2.34 g) as a pale-brown powder.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>O>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCCC(NC(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCCC(N)C1)C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{1-[2-(6-Chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (160 mg, 0.30 mmol) was added into a 4N solution of HCl in dioxane (2 mL, 8 mmol), followed by water (0.5 mL). The resulting mixture was stirred at RT for 2 hours, then concentrated under vacuum. The residue was taken up with water (5 mL) and a 1N aqueous solution of NaOH (15 mL), then extracted with DCM (2×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by crystallization from ACN, the title compound was obtained as a white powder (46 mg, 35%). 1H NMR (DMSO-d6) δ 7.47-7.31 (m, 4H), 4.83 (s, 1H), 4.81 (s, 1H), 4.52 (s, 1H), 4.47 (s, 1H), 3.42 (br s, 2H), 2.85 (s, 1.5H), 2.80 (s, 1.5H), 2.70-2.43 (m, 5H), 2.23-2.09 (m, 1H), 1.88-1.74 (m, 1H), 1.65-1.52 (m, 1H), 1.46-1.31 (m, 2H), 1.25 (s, 2H), 1.02-0.83 (m, 1H), 0.83-0.65 (m, 1H). HPLC (max plot) 99.4%, Rt 2.21 min. UPLC/MS: (MS+) 439.3 ([M+H]+). Melting point: 165-170° C. (ACN).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)([OH:3])=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](OC(=O)C2CCCN2C(OCC2C=CC=CC=2)=O)=[CH:24][CH:23]=1)([O-])=O>>[CH2:22]([NH:19][C:1]([CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)=[O:3])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCN1C(=O)OCc1ccccc1
Product: CCCCCCNC(=O)C1CCNC1

Procedure:
By substituting the 3-carboxy-1-phenylmethyloxycarbonylpyrrolidine obtained in Example 10 for the N-carbobenzoxy-DL-proline p-nitrophenyl ester in the procedure of Example 2, 3-[(hexylamino)carbonyl]pyrrolidine is obtained.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccc(N2CCN3CCC2CC3)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine (0.43 g, 2.0 mmol), phenylisocyanate (0.29 ml, 2.5 mmol) and methanol (60 ml) was stirred at room temperature for hours. The mixture was evaporated and diethylether (30 ml) was added, the precipitate was filtered. The product was isolated. Yield 0.23 g (34%). Mp. 145° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([NH:21]C(=O)C)([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)([NH2:21])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(N)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Yield: 55.7 %

Procedure:
A stirred solution of N-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (Example 69) (0.04 g, 0.12 mmol) in concentrated HCl (0.07 mL, 3.03 mmol) was heated at 100° C. for 24 hrs in a sealed glass tube. The reaction mixture was then cooled to room temperature and neutralized with 10% NaOH solution (2 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were concentrated under vacuum. The crude product residue obtained was purified by preparative TLC using eluting solvent as MeOH:CH2Cl2 (3:7) to afford 20 mg (38%) of 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(Pyridin-4-yl)ethanamine as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, 2H, J=5.6 Hz), 7.91-7.88 (m, 2H), 7.70 (s, 1H), 7.51 (d, 2H, J=6.4 Hz), 7.28 (t, 2H, J=8.8 Hz), 2.81 (s, 2H); 1.85 (s, 3H); LC-MS m/z calculated for [M+H]+ 300.09. found 300.1.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=2)[S:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[CH2:14][C:13]([CH3:12])([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=2)[S:16]1
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CC(C#C[Si](C)(C)C)Sc2ccc(CO)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3 ml (21.3 mmol) of trimethylsilylacetylene and 50 ml of THF were introduced into a three-necked flask. A solution of 8.6 ml (21.3 mmol) of n-butyllithium (2.5M in hexane) was added dropwise at −78° C. under a stream of nitrogen and the reaction mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 4 g (19.4 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde in 50 ml of THF at −78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 5.9 g (100%) of the expected alcohol were obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([O:15]C)=[O:14])=[N:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)c1cc(-c2ccccc2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(C(=O)O)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Methyl 1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (20 ml) and sodium hydroxide (0.8 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (2.2 g), melting point: 149–150° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[OH:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:21])[CH:7]([C:27]1[CH:26]=[C:25]([CH3:29])[C:24]([OH:30])=[C:23]([CH3:22])[CH:28]=1)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1O
Reactant: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)c1cc(C)c(O)c(C)c1

Procedure:
A solution of 1.8 g. (6 mmol.) of N-(β,β,β-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl ester and 1.2 g. (10 mmol.) of 2,6-dimethylphenol in 20 ml. of methylene chloride containing three drops of boron trifluoride etherate was stirred at 25° for 3 hours. The reaction mixture was concentrated in vacuo, 5 ml. of 2:1 hexanemethylene chloride was added and the resulting solution was chromatographed on silica gel. Elution with 2:1 hexanemethylene chloride then with methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:16][C:17]1[N:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21](=[O:29])[C:20]([Cl:30])=[N:19][CH:18]=1>C(Cl)Cl>[Cl:30][C:20]1[C:21](=[O:29])[N:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:17]([CH2:16][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][N:19]=1
Reactant: CCOC(=O)Cn1c(CBr)cnc(Cl)c1=O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(CSc2ccccc2)cnc(Cl)c1=O

Procedure:
THIOPHENOL (1.28 ML, 12.5 MMOL) WAS ADDED DROPWISE TO A STIRRED SOLUTION OF TRIETHYLAMINE (3.0 ML, 21.5 MMOL) AND 6-BROMOMETHYL-3-CHLORO-1-ETHOXYCARBONYLMETHYLPYRAZINONE (3.86 G, 12.5 MMOL) IN METHYLENE CHLORIDE (20 ML). AFTER 15 MIN THE MIXTURE WAS PARTITIONED BETWEEN METHYLENE CHLORIDE AND WATER. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID WHICH WAS CARRIED FORWARD TO THE NEXT STEP:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cncnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cncnc2)CC1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
5-Bromo pyrimidine (1.0 g, 6.29 mmol) and 1-Boc-piperazine (1.17 g, 6.28 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 10 min. Sodium tert-butoxide (816 mg, 8.49 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 80% EtOAc in petroleum ether) to get tert-butyl 4-(pyrimidin-5-yl)piperazine-1-carboxylate (700 mg, yield 42%). 1H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 8.48 (m, 2H), 3.61-3.58 (m, 4H), 3.30-3.27 (m, 4H), 1.47 (s, 9H). MS (ESI) m/z: Calculated for C13H20N4O2: 264.16. found: 265.0 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2c1nc(Cc1cc3c(cc1I)OCO3)n2CCCNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (100 mg, 0.21 mmol) in DMF (3 mL) was added cyclopropanecarbonyl chloride (29 μL, 0.32 mmol) and triethylamine (90 μL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS71 as a white solid (75 mg, 65%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.32 (s, 1H), 6.77 (s, 1H), 6.02 (s, 2H), 4.24 (s, 2H), 4.16 (t, J=7.3 Hz, 2H), 3.26 (t, J=6.2 Hz, 2H), 1.91-2.01 (m, 2H), 1.50-1.57 (m, 1H), 0.90-0.95 (m, 2H), 0.76-0.82 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H21FIN6O3, 539.0704. found 539.0705.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[OH-].[K+].O.C(Cl)Cl.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CN(C)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCOc1ccc2ccc(N)nc2n1
Temperature: 60 °C

Procedure:
A suspension of 2-amino-7-chloro-1,8-naphthyridine (89.75 g) in 3-dimethylamino-1-propanol (236 cc) is preheated to approximately 30° C. Potassium hydroxide pellets (85% pure; 65.8 g) are then introduced gradually. The reaction is exothermic, and the temperature rises to 80° C. at the end of the addition. The reaction mixture is then heated for a further 30 minutes to 90° C., allowed to cool to 60° C. and then poured into water (1500 cc) in the presence of methylene chloride (500 cc). The decanted organic extracts are washed with water (2×200 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The product obtained in the form of an oil is crystallized by stirring in hexane (300 cc). The crystallized solid is then separated by filtration, washed with hexane and dried at 20° C. at reduced pressure (0.07 kPa). 2-Amino-7-(3-dimethylaminopropoxy)-1,8-naphthyridine (109 g), m.p. 88° C., is obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]([OH:42])([CH2:40][CH3:41])[CH3:39]>>[CH:38]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)([CH2:40][CH3:41])[CH3:39]
Reactant: CCC(C)O
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CCC(C)Oc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) was reacted with 2 equivalents each of n-butyl lithium and sec-butanol by the procedure described in Reference Examples 6 and 7 to afford 2-(sec-butyloxy)-4-(3-pyridyloxy)-5-(4-chloro-phenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=500 (M++1); Rt=4.26 min. 1H-NMR 500 MHz (CDCl3): δ 0.91 (t, 3H), 1.29 (d, J=6 Hz, 3H), 1.56-1.64 (m, 1H), 1.71-1.80(m, 1H), 4.81-4.88 (m, 1H), 7.18-7.30 (m, 6H), 7.36-7.38 (t, 1H), 7.40-7.43 (m, 1H), 7.60 (m, 1H), 8.52-8.56 (m, 2H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[C:16]([C:26]#[N:27])=[C:15]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:14]=1>CN(C=O)C>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:32]2[S:33][CH:34]=[C:30]([CH2:29][S:28][C:15]3[C:16]([C:26]#[N:27])=[C:17]([C:21]4[S:25][CH:24]=[N:23][CH:22]=4)[C:18]([C:19]#[N:20])=[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:14]=3)[N:31]=2)=[CH:36][CH:37]=1
Reactant: OCCCO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reaction time: 0.25 h

Procedure:
30 μl (0.419 mmol) of 1,3-propanediol are initially charged in 2 ml of DMF, 18 mg (0.154 mmol) of potassium tert-butoxide are added and the mixture is stirred for 15 minutes, after which 75 mg (0.14 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, dissolved in 2 ml of DMF, are added. The reaction mixture is stirred at room temperature for 30 minutes and then purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 11 mg (15% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.94-7.88 (2H, m), 7.47-7.15 (11H, m), 6.24 (1H, br.s), 3.48-3.42 (2H, m), 2.84 (2H, t, J=7.0 Hz), 2.32 (3H, s), 2.23 (3H, s).
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]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]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]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH3:21])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(2-chloro-5-fluoro-phenyl)quinolin-3-yl)ethanamine (0.072 g, 0.215 mmol), 6-chloropurine (0.040 g, 0.26 mmol, 1.2 eq) and DIEA (0.42 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.68 (s, 1 H), 8.60 (s, 1 H), 8.02-8.10 (m, 2 H), 7.92-7.99 (m, 1 H), 7.85-7.93 (m, 1 H), 7.54-7.63 (m, 1 H), 7.50 (dd, J=8.80, 4.89 Hz, 1 H), 7.07 (td, J=8.61, 3.13 Hz, 1 H), 5.48-5.65 (m, 1H), 1.71 (d, J=7.04 Hz, 3H), Mass Spectrum (ESI) m/e=454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1>C(=O)(O)[O-].[Na+]>[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 230 °C
Yield: 56.9 %

Procedure:
A stirrable paste prepared by mixing 2-aminothiophenol (9.39 g, 0.075 mol) and 4-aminobenzoic acid (10.29 g, 0.075 mol) with PPA (120 g) was heated to 230° C. for 4 hours, cooled and poured into a large volume of 10% sodium bicarbonate solution (about 1000 ml). The solid was collected by filtration, washed with water and dried. Recrystallisation from methanol gave pale yellow needed crystals (9.65 g, 57%), m.p. 155-157° C.
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:24][O:23][C:19](=[O:22])[CH2:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH:4]([N+:15]([O-:17])=[O:16])[CH2:3][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(C(C)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.IC.[CH2:32]([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:18]1[CH:17]=[C:16]2[C:21]([N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C@@H:13]([CH2:24][CH3:25])[C:14](=[O:23])[N:15]2[CH3:32])=[CH:20][CH:19]=1
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccc(Br)cc3NC(=O)[C@@H]2CC)cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-6-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-7-bromo-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−121° (c=0.0052 G/ML, DMSO); MS (ESI) m/z 425/427 ([M+H]+); MS (ESI) m/z 423/425 ([M−H]−); Anal. Calcd for C17H17BrN2O4S: C, 48.01; H, 4.03; N, 6.59. Found: C, 47.74; H, 4.17; N, 6.22.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.164 g, 0.8 mmol) and 2,4-dichlorobenzenethiol (0.143 g, 0.8 mmol). The title compound was obtained as an orange solid (132 mg, 47.3% yield). 1H NMR (300 MHz, CDCl3) δ: 8.09 (1H, s), 7.68 (2H, m), 7.42 (1H, d), 2.50 (3H, s).