Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.C>CS(O)(=O)=O.C(O)CC>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A solution of 10.3 gm. of N-isopropyl-(3,4-methylenedioxyphenyl)urea, 7.1 ml. of benzaldehyde, and 3 drops of methanesulphonic acid in 250 ml. of toluene is refluxed under a water separator for 21 hours. The cooled solution is then washed with 200 ml. of water, dried and evaporated to yield a powder. This product is decolorized in hot propanol with a small amount of activated charcoal and recrystallized from propanol to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 169°-172°C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9](=O)[CH3:10])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].Cl.[CH3:18][NH:19][OH:20]>O1CCOCC1.O>[C:5]([N:4]1[CH2:1][C:2]2([CH3:3])[CH:9]([CH2:10][O:20][N:19]2[CH3:18])[CH2:8]1)(=[O:7])[CH3:6]
Reactant: CNO
Reactant: C=CCN(CC(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CC2CON(C)C2(C)C1

Procedure:
15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acetamide are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[CH2:32][S:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([NH:41][S:42]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[O:40])[CH2:35][CH2:34]2)=[N:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:32]3[S:31][C:30]([N:33]4[CH2:34][CH2:35][CH:36]([C:39]([NH:41][S:42]([N:45]5[CH2:49][CH2:48][CH2:47][CH2:46]5)(=[O:44])=[O:43])=[O:40])[CH2:37][CH2:38]4)=[N:29][C:28]3=[O:27])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C1CSC(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)=N1
Product: O=C1N=C(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
Pyrrolidine-1-sulfonic acid (1-{5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and Pyrrolidine-1-sulfonic acid [1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amide following General Procedure E.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:9][N:8]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1>C(Cl)Cl>[Cl:3][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:10]4[C:6]([CH3:5])=[N:7][N:8]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:9]=4)[CH2:13][CH2:14]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:25][CH:26]=1
Reactant: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(CCl)cc2)CC1
Reaction time: 3 h

Procedure:
Add thionyl chloride (0.4 mL, 5.49 mmol) to a solution of {4-[4-(3-Methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-methanol (474 mg, 1.08 mmol) in DCM (20 mL). Maintain stirring for 3 hr. Concentrate to dryness to give the title compound as a yellow material (545 mg) MS (ES): m/z=459/460/461[M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:4]2[CH:3]=[CH:2][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(Nc2cc(Cl)n(-c3ccccc3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 3 h

Procedure:
A solution of 5-chloro-N-(4-methoxyphenyl)-1-phenyl -1H-pyrazol-3-amine (0.2 g) in ethanol (10 ml) and triethylamine (0.2 g) was reduced at atmospheric pressure of hydrogen over 10% palladium/charcoal (0.2 g), with stirring, over 3 hours. The solution was filtered and evaporated to leave the title compound as a colourless solid, mp 96°-98°, the NMR and mass spectra of which were identical to those for the title compound of Example 2.
Reaction SMILES: [OH:1][C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][C:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: O=C1c2ccccc2C(=O)N1CCCCC(O)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCC(O)(c1ccccc1)c1ccccc1

Procedure:
Batch size: 5.0 g (13.0 mmol) 2-(5-hydroxy-5,5-diphenyl-pentyl)-isoindol-1,3-dione and 1.3 g (26.0 mmol) hydrazine hydrate in 50 ml ethanol.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([NH2:41])[N:3]=1.[H+].[B-](F)(F)(F)[F:44].N([O-])=O.[Na+].NC1N=C2C(NC=N2)=C(N)N=1.[OH-].[Na+]>O1CCCC1>[CH2:14]([O:13][C@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([F:44])=[N:3][C:4]=2[NH2:41])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: F[B-](F)(F)F
Agent: Nc1nc(N)c2[nH]cnc2n1
Agent: O=N[O-]
Agent: [H+]
Solvent: C1CCOC1
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 96 h

Procedure:
To a solution of 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)adenine (5, 15.0 g., 27.1 mmoles) in a mixture of 500 ml. tetrahydrofuran and 1 l. of 48% fluoboric acid at -10° in a 4-l. beaker equipped with a mechanical stirrer was added dropwise in 20 minutes a saturated aqueous solution of sodium nitrite (7.5 g., 108 mmoles). The addition of sodium nitrite was repeated three times after which none of the 2-aminoadenine remained (tlc). The fluorboric acid was neutralized to pH 6 with 505% sodium hydroxide keeping the temperature between -40° and 0°. The solution was extracted four times with chloroform (300 ml., 250 ml., and two 200-ml. portions). The chloroform extract was washed with saturated sodium chloride solution and then dried over magnesium sulfate before it was evaporated to dryness in vacuo. The residual oil was dissolved in a liter of ethanolic ammonia (saturated at 0°), and the solution was allowed to stand for 4 days at 4° before it was evaporated to dryness. The residue was recrystallized from ethanol; yield 5.5 g. Additional material was recovered from the filtrate by recrystallization and the final filtrate was evaporated to dryness, diluted with 50 ml. of 1 N hydrochloric acid, stirred on a steam bath for 30 minutes, cooled, and the aqueous portion decanted. A chloroform solution of the residue was washed with saturated sodium bicarbonate, then water, and dried over magnesium sulfate before evaporation in vacuo. The residue was recrystallized from ethanol; total yield of 6, 7.2 g. (48%); m.p. 155°-157°. This material was essentially homogeneous according to tlc (19:1) and hplc [2 aqueous pentanesulfonic acid (0.005 M):3 acetonitrile-3% acetic acid].
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:30])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH:30][C:4](=[O:5])[CH2:3][C:2]([CH3:7])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:1])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[CH:17][CH:16]=1
Reactant: CC(C)(CC(=O)Cl)c1ccccc1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(CC(=O)Nc1nn2cccnc2c1-c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product from Example 117A (82 mg, 0.42 mmol) was added a solution of the product from Example 99A (59 mg, 0.2 mmol) in pyridine (2.0 mL). The mixture was stirred at ambient temperature for 1 hour and then at 40° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13-10.16 (bs, 1H), 9.09 (dd, J=7.0, 1.7 Hz, 1H), 8.60 (dd, J=4.1, 1.7 Hz, 1H), 7.68-7.72 (m, 2H), 7.40-7.45 (m, 4H), 7.27-7.35 (m, 2H), 7.15-7.22 (m, 1H), 7.12 (dd, J=7.0, 4.1 Hz, 1H), 2.70 (s, 2H), 1.41 (s, 6H); MS (ESI) m/z 405 (M+H)+; Anal. calculated for C23H21ClN4O.0.1H2O: C, 67.93; H, 5.25; N, 13.78. Found C, 67.65; H, 5.08; N, 13.61.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][CH2:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([N:17]([CH3:27])[C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.C(N=C=O)C1C=CC=CC=1>>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([N:17]([CH3:27])[C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)=[O:4]
Reactant: CN=C=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CO)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: O=C=NCc1ccccc1
Product: CNC(=O)OCC1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 202, but substituting methyl isocyanate and 17-(hydroxymethyl)-4-methyl-5α-4-azaandrostan-3-one for the benzyl isocyanate and steroid alcohol, respectively, used therein, the title compound was obtained. MS M+2 calculated for C22H36 N2O3, mw=376.54; observed m/e 378.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:27].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([CH2:12][C:13]5[CH:14]=[C:15]([NH:19][C:20]([C:22]6[S:23][CH:24]=[CH:25][CH:26]=6)=[O:21])[CH:16]=[CH:17][CH:18]=5)=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:27])=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: O=C1Nc2cc(Cc3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(Cc5cccc(NC(=O)c6cccs6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 30.8 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (prepared below, 50 mg, 0.133 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (25.4 mg, 0.133 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜3 mL of i-prOH yielding 31% (22.6 mg, 0.041 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.[OH-].[K+].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=1.Cl>C(O)C>[OH:10][C:9]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[CH:2]=[CH:1][C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccc(O)cc2O)cc1
Temperature: 0 °C

Procedure:
A mixture of 3.04 g (0.02 mole) of 2,4-dihydroxyacetophenone, 10 ml of 60% strength aqueous potassium hydroxide and 10 ml of ethanol is cooled to 0° C. 2.72 g (0.02 mole) of anisaldehyde are added with stirring and the reaction mixture is heated to 50° C. for 4 hours. The mixture is then poured into a 10% solution of hydrochloric acid. The precipitate formed is filtered off, washed three times with water and is dried. It is then taken up with ethyl acetate, is treated with animal charcoal and is filtered rapidly through silica with a 9/1 mixture of pentane and ethyl acetate. A yellow product is obtained.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:4]3[C:3]([CH3:8])=[C:2]([I:1])[C:6]([CH3:7])=[N:5]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1n[nH]c(C)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C)c1I

Procedure:
Protocol T was followed using 4-Iodo-3,5-dimethyl-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3); 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 5.00 (s, 2H), 3.62-3.82 (m, 4H), 3.02-3.12 (m, 4H), 2.22-2.32 (d, 6H). 13C NMR (400 MHz, CDCl3): 165, 158.2, 156.2, 150.2, 146.8, 141.8, 118.8, 115.4, 115.2, 52.8, 51.6, 50.2, 45.2, 42, 14.8, 12.6.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33].C(N(CC)CC)C>C1C=CC=CC=1>[C:32]([C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:12])=[CH:4][CH:3]=2)=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc(N)ccc2CC1c1ccc(C#N)cc1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2ccc(C#N)cc2)C3)cc1
Temperature: 100 °C

Procedure:
To a solution of Intermediate 13 (100 mg, 0.24 mmol) and 10 mL of anhydrous benzene under argon at 25° C. was added 4-acetylphenyl isocyanate (43 mg, 0.26 mmol) and triethylamine (50 mg, 0.48 mmol). The resulting mixture was heated to 100° C. for 12 hours and the reaction was quenched with water. The product was extracted with EtOAc, the layers were separated, and the organic layer was washed with brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (85:15) to yield Intermediate 23 as a light yellow 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]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]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:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)cc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)cc(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(3,5-difluorophenyl)-quinolin-3-yl)methanamine (0.105 g, 0.345 mmol), 6-chloropurine (0.064 g, 0.41 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(3,5-difluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=76 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.48 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.86-7.94 (m, 2H), 7.52-7.61 (m, 1H), 7.27-7.35 (m, 2H), 6.96-7.06 (m, 1H), 4.73 (d, J=5.71, 2H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:21]([O:30][CH3:31])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]([O:30][CH3:31])=[O:29]
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Reactant: COC(=O)c1ccccc1S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCC(C)C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 115-116° C.). 1H NMR (DMSO-d6) δ 0.80 (m, 6 H), 1.0 (m, 1 H), 1.17 (m, 1 H), 1.43 (m, 1 H), 1.96 (m, 2 H), 3.4 (2 H+H2O), 3.81 (s, 3 H), 6.02 (bd, 1 H), 6.88 (t, 1 H), 7.05 (t, 1 H), 7.42 (m, 5 H), 7.80 (dd, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:40][C:41]1[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1[C:51](O)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:51]([C:42]2[C:43]([C:47]([F:50])([F:48])[F:49])=[N:44][N:45]([CH3:46])[C:41]=2[Cl:40])[O:16][N:15]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C(F)(F)F)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.023 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 4.99 (s, 2H), 3.95 (s, 3H), 2.87 (t, 2H), 1.80-1.58 (m, 2H), 1.01 (t, 3H); MS (ES) m/z 484 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:12][C:3]1[C:4]([O:8][CH2:9][O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COCOc1cccc(Br)c1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COCOc1cccc(-c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 1-bromo-2-fluoro-3-(methoxymethoxy)benzene (17.9 g), (4-fluorophenyl)boronic acid (16.0 g), tris(dibenzylideneacetone)dipalladium(0) (3.49 g), a 2 M aqueous sodium carbonate solution (114 mL), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.13 g), and toluene (180 mL) was stirred at 100 C for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then passed through celite. The organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure to obtain the title compound (19.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]([O:23]C)=O)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([NH2:27])[CH3:26]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]([NH:27][CH2:25][CH3:26])=[O:23])[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN
Reactant: COC(=O)c1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Product: CCNC(=O)c1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-chloro-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine-9-carboxylate (11-2) (80 mg, 0.235 mmol) and ethylamine (2M in THF, 5 mL, 10 mmol) was stirred at room temperature for overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with 0-20% EtOH in EtOAc to give 3-chloro-N-ethyl-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine-9-carboxamide (11-3).
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>CCO.[O-2].[Mn+4].[O-2]>[N:1]1[C:2]([CH:10]=[O:11])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCc1nc2ccccn2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Product: O=Cc1nc2ccccn2n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a solution of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (0.35 g, 2.3 mmol) in EtOH (50 mL) was added manganese (IV) oxide (1.02 g, 11.5 mmol). The mixture was refluxed for 2 days. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was concentrated, and the residue was purified by reverse phase column chromatography (eluting with 10% v/v acetonitrile in water, with 0.01% NH3.H2O) to afford the title compound (0.15 g, 43% yield) as a white solid. ESI MS: m/z 148 [M+H]+.