Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:37][N:38]([CH3:43])[S:39]([N:9]1[CH2:8][C:7]2[CH:29]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=2[N:15]2[C:11](=[N:12][N:13]=[C:14]2[C@H:16]2[CH2:17][CH2:18][C@H:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:10]1)(=[O:41])=[O:40]
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 72 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.062 g, 0.14 mmol) and triethylamine (0.030 ml, 0.22 mmol) in dichloromethane (2.5 ml) was added N,N-dimethylsulfamoyl chloride (0.023 ml, 0.22 mmol) at room temperature. After stirring for 72 h the reaction mixture was transferred directly onto a silica gel chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.042 g, 58%) as white solid. MS m/e: 502 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:20](O)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:20]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CCNCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCCC1
Yield: 80 %

Procedure:
In substantially the same manner as Working Example 2, piperidine (0.86 g, manufactured by Wako Pure Chemical Industries, Ltd.).was condensed with Boc-L-leucine (2.74 g, manufactured by Peptide Institute, Inc.) to give N-(Boc-L-leucyl)piperidine (3.34 g) as white needles (yield 80%). The Boc group of the product was deprotected by using TFA, and 1.20 g of thus-deprotected compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.93 g) to give the above-titled compound (Compound 23; 1.10 g) as a pale yellow oily product (yield 39%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH:23]=[CH2:24])[C:17]=4O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:29]>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]5[O:29][CH:23]([CH3:24])[CH2:22][C:18]=5[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CC(C)O4)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-cyclopentyl-3-ethyl-6-[2-hydroxy-3-(2-propenyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.0 g) in acetic acid (15 ml) was added sulfuric acid (15 ml) while cooling in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, a precipitate formed which was collected by filtration and washed with water. The product was purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc/hexane to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-methyl-2,3-dihydrobenzo[b]furan-5-yl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 164-165° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:6](=[CH:5][CH2:4][CH2:3][N:2]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:1])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 2.61 g of 5-[3-(methylamino)propylidene]-5H-dibenzo[a,d]cycloheptene, 2.00 g of ethyl bromoacetate, 1.38 g of potassium carbonate, and 13 ml of N,N-dimethylformamide was stirred at 70° C. for 4 hours. After the reaction was completed, water was added to the reaction mixture and the mixture was then extracted with diethyl ether. The ether layer was washed with water and dried, and then the solvent was removed by distillation. The residue was purified by column chromatography on aluminum oxide [n-hexane-diethyl ether (1:1)] to give 1.88 g of slightly yellow viscous liquid.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH2:19]Cl)([CH3:13])[CH3:12].Cl>C1COCC1.CCCCCC>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH2:19][CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])[CH:21]=1)([CH3:13])[CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(C(C)C)cc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCc1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
To a stirred suspension of sodium hydride (60% oil suspension, 0.44 g,11 mmol) in THF (25 ml) was added methyl acetoacetate (1.08 ml, 10 mmol) dropwise at 0° C. After 10 min stirring at 0° C., n-buthyllithium (1.31M in hexane, 8 ml, 10.5 mmol) was added to the reaction mixture at 0° C. To this orange color solution was added a solution of 5-isopropyl-2-methoxybenzyl chloride (1.99 9, 10 mmol) in THF (5 ml) at 0° C. After 40 min stirring at 0° C. to room temperature, the reaction mixture was poured into 1N HCl (20 ml) and extracted with ethyl acetate. The extract combined was dried (MgSO4) and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography on silica gel (hexane/ethyl acetate: 10/1 as eluent) to afford 1.55 g (55.8%) of title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a mixture of 1.7 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.8 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.1 g of 2-amino-3-bromo-5-chlorobenzoic acid of the formula:
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[C:21]([Cl:26])[C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14].C1C[O:36]CC1>>[ClH:26].[F:2][C:3]([F:32])([F:31])[C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[C:21]([OH:36])[C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14]
Reactant: C1CCOC1
Reactant: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(Cl)nccc12
Agent: Cl
Product: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(O)nccc12
Yield: 33 %

Procedure:
A 0.6 mL 5N HCl solution is added to a stirred solution of 1-chloro-isoquinoline-5-sulfonic acid {2-[2-(2-trifluoromethyl-phenoxy)-ethylamino]-ethyl}-amide (70 mg, 0.15 mmol) in THF (1 mL) at ambient temperature under nitrogen. The resultant mixture is heated at 65° C. for 16 hours. At ambient temperature, the mixture is concentrated. The crude product is dissolved in a small amount of MeOH/CH2Cl2 before it is treated with Et2O to form a white suspension. After filtration and vacuum drying, 24 mg (0.49 mmol, 33% yield) of the title compound is obtained as a white powder. ESIMS: m/z 456 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][CH:28]4[CH2:29][CH2:30][C:25]([F:32])([F:24])[CH2:26][CH2:27]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(F)(F)CC1
Temperature: 110 °C
Yield: 82.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.433 g, 1.28 mmol), 4,4-difluorocyclohexyl amine hydrochloride (0.242 g, 1.41 mmol), diisopropylethylamine (0.491 ml, 2.82 mmol) in propan-2-ol (10 ml) was heated at 110° C. in a microwave reactor for 20 min. The mixture was then cooled to 25° C. and was partitioned between water (50 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the resulting yellow solid by column chromatography on silica gel (gradient: 0 to 60% EtOAc in heptanes) afforded (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,4-di fluoro-cyclohexyl)-amine (0.46 g, 82%) as a yellow solid. LCMS (Method G, ESI): RT=1.21 min, m+H=437; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 7.17 (d, J=4.3 Hz, 1H), 4.39-4.26 (m, 1H), 2.29-1.98 (m, 6H), 1.83-1.68 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O[C:15]1(O[Si](C)(C)C)[CH2:17][CH2:16]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH:15]2[CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)ccc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 500 mg of 2-amino-5-chloro-benzoic acid (2.91 mmol) in methanol were added 3 Å molecular sieves, 2.34 ml of [(1-ethoxycyclopropyl)oxy]trimethylsilane (11.66 mmol) and 1.67 ml of acetic acid and the mixture was stirred for 30 min at RT. Then 916 mg of sodium cyanoborohydride (14.57 mmol) were added and the reaction mixture was heated to reflux for 16 h. The reaction mixture was allowed to cool to RT, filtered and the filtrate was concentrated in vacuo. The remaining solid was dissolved in ethyl acetate and the solution was washed with 1N HCl and brine, dried (MgSO4), filtered and concentrated to give 312 mg of the crude title compound that was used in the following step without further purification. 1HNMR (DMSO-d6, 300 MHz): δ 0.46 (m, 2H), 0.79 (m, 2H), 3.44 (m, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.70 (s, 1H), 7.89 (br s, 1H), 13.09 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]2[CH:37]=[C:38]([N:42]3[C:47](=[O:48])[C:46]([CH2:49][C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)=[N:45][C:44]4[CH:56]=[CH:57][CH:58]=[N:59][C:43]3=4)[CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([NH:29][C:30]3[CH:31]=[C:32]([C:36]4[CH:37]=[C:38]([N:42]5[C:47](=[O:48])[C:46]([CH2:49][C:50]6[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=6)=[N:45][C:44]6[CH:56]=[CH:57][CH:58]=[N:59][C:43]5=6)[CH:39]=[CH:40][CH:41]=4)[CH:33]=[CH:34][CH:35]=3)=[O:14])[N:11]=2)[CH:2]=1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1)c1csc(-c2cccnc2)n1
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a stirred suspension of 2-(3-pyridyl)thiazole-4-carboxylic acid (0.56 g) and triethylamine (0.55 g) in methylene chloride (25 ml) was added pivaloyl chloride (0.33 g) in methylene chloride (5 ml) and the mixture was stirred for 2 hours. After the reaction mixture was cleared, 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.0 g) was added thereto and the mixture was stirred under reflux for 2 hours. The reaction mixture was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. Crude residue was chromatographed on silica gel (70 g, chloroform-methanol 100:1 as eluent) to give 4-[3-[3-[2-(3-pyridyl)thiazol-4-ylcarbonylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine as colorless crystals (0.48 g).
Reaction SMILES: CO.[NH:3](C(OCC1C=CC=CC=1)=O)[C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H][H]>[Pd].C(O)(=O)C>[NH2:3][C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
300 ml of absolute methanol, 2 ml of acetic acid, and palladium black were added to 9.68 g (20.26 mmol) of Z-Lys(Boc)-Pro-OH, and hydrogenation was performed in the stream of dry hydrogen at room temperature under 1 atm for 8 hours. Then, the catalyst was filtered off and washed on the filter with methanol. Pooled filtrate was evaporated to dryness. The residue was precipitated with ether from the absolute methanol. Then, it was dried under vacuum, while desiccant was changed several times.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.[NH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:23][CH2:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: COC(=O)COc1ccc(CN)cc1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde, methyl [4-(aminomethyl)phenoxy]acetate, acetate salt and DIEA (1 eq.) (purification by flash chromatography on SiO2, DCM/MeOH 95:5) as a pale yellow oil (63%). M+ (ESI): 422.2. HPLC, Rt: 4.3 min (purity: 96.4%). 1H NMR (CDCl3) δ: 7.37 (d, J=8.3 Hz, 2H), 7.28 (m, 4H), 6.88 (d, J=8.6 Hz, 2H), 4.63 (s, 2H), 3.78 (m, 7H), 2.40 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.30 (brs, 8H), 0.90 (t, J=6.8 Hz, 3H).
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: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1ccccn1
Reactant: Nc1ncc(Cl)c(Cl)n1
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: [NH2:1][CH:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][CH:3]1[NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.Cl[C:27]1[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>CS(C)=O>[F:8][C:5]1([F:7])[CH2:4][CH:3]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:2]([NH:1][C:27]2[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)[CH2:6]1
Reactant: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1
Temperature: 120 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-methylpropane-2-sulfonamide (66 mg, 0.26 mmol) in DMSO (650 μl) was added DIPEA (135 μl, 0.77 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 47 mg, 0.26 mmol). The reaction mixture was sealed and heated at 120° C. for 18 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 10-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1)[NH:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH2:36])[C:34]=2[N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[F:1][C:2]1[CH:15]=[C:14]([C:26]2[CH:27]=[CH:28][C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:36])[C:34]=3[N:35]=2)[CH:13]=[C:4]([NH:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(F)cc(NCCN3CCCC3)c2)OC1(C)C
Reactant: Nc1ncnc2ccc(Cl)nc12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2ccc(-c3cc(F)cc(NCCN4CCCC4)c3)nc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of crude 31-B (300 mg, 1.0 mmol), 3-A (150 mg, 0.80 mmol), Pd(PPh3)4 (30 mg) and Cs2CO3 (600 mg, 1.8 mmol) in dioxane/H2O (10 mL/1.0 mL) was stirred at 90° C. for 2 h. The reaction solution was partitioned between EtOAc (100 mL) and brine (35 mL). The combined organic layer was washed with water (3×30 mL), concentrated and purified by prep-HPLC (25 mg, 8.9%). LCMS (0-60AB), RT=0.904 min, M+H 352.9 1H-NMR (Methanol-d4, 400 MHz): δ 8.53 (s, 1H), 8.35 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H)), 7.33 (s, 1H), 7.24 (d, J=10.4 Hz, 1H), 6.49 (d, J=11.2 Hz, 1H), 3.60-3.57 (m, 2H), 3.37-3.28 (m, 6H), 2.07-2.04 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26]([C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:5][N:6]=2)[CH:27]=1
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)s2)c1OC
Temperature: 120 °C
Yield: 33.9 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (393 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (495 mg) and tripotassium phosphate (568 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (61.8 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D34) (170 mg) as a yellow solid. MS (ES): C22H20F4N2O3S requires 468. found 469.1 (M+H+).