Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][O:5][C:3]1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:18])[NH2:17])=[CH:12][C:11]=1[CH2:19][CH2:20][CH3:21]>C(O)C>[S:18]1[C:2]2[CH2:8][CH2:7][CH2:6][O:5][C:3]=2[N:17]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([CH2:19][CH2:20][CH3:21])[CH:12]=1
Reactant: CCCc1cc(C(N)=S)ccc1O
Reactant: O=C1OCCCC1Br
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1O
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A stirred mixture of α-bromo-δ-valerolactone (77% pure; 300 g, 1.3 mol), 4-hydroxy-3-propylbenzenecarbothioamide (229.09 g; 1.2 mol) (Example 504), and absolute ethanol (2.5 L) was gradually heated under nitrogen. A significant gas evolution occurred. When the latter had slowed, the mixture was brought to reflux. After 16 h at reflux, the mixture was cooled to rt, and then concentrated in vacuo. The residue was taken-up in 50% dichloromethane/hexanes, filtered, and the solid triturated and washed with more of the solvent mixture (700 mL total). After washing with hexanes and drying in vacuo, 207.1 g (58%) of the title compound were obtained as a yellow solid. The filtrate was concentrated in vacuo, and the residue chromatographed on silica gel to afford a thick oil containing impure product in which crystals formed. Filtration, trituration, and washing of the solid with ethanol afforded 27.6 g (234.7 g total; 66.1% yield) of opaque, pastel orange crystals, mp 152-154° C.; 1H NMR (DMSO-d6): δ 9.86 (broad exchangeable s, 1H), 7.5 (d, 1H), 7.4 (dd, 1H), 6.8 (d, 1H), 4.2 (t, 2H), 2.7 (t, 2H), 2.5 (t, 2H), 2.0 (m, 2H), 1.5 (m, 2H), 0.9 (t, 3H); LCMS: RT=3.0 min, (M+H)+ 276.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:15][CH:16]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
10.25 g of 2-amino-3-trifluoromethyl benzoic acid in 20 ml of toluene and 18.6 g of 2-chloro-3-methyl butanoyl chloride (prepared by J. Org. Chem., Vol. 40, p. 3420 (1975)) were mixed together, and the procedure of Example 10 of Belgian Patent No. 896,941 was followed for the preparation of 11.9 g of 2-(1-chloro-2-methylpropyl)-8-(trifuoromethy)-4H-3,1-benzoxazin-4-one melting at 78°-80° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C@H:35]1[CH2:40][O:39][CH2:38][CH2:37][NH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:30][C:28]([F:29])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][CH:7]2[CH2:6][N:36]2[CH2:37][CH2:38][O:39][CH2:40][C@@H:35]2[CH3:34])=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: C[C@H]1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1COCCN1CC1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 150 °C

Procedure:
A 20 mL vial was charged with (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (75 mg, 0.142 mmol), (S)-3-methylmorpholine (28.7 mg, 0.284 mmol Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (39.2 mg, 0.284 mmol), and acetonitrile (4 mL). The vial was sealed and heated at 150° C. for 90 min in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden). After this time, the mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory silica gel TLC (5% MeOH in CH2Cl2) to give 1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]([F:26])([F:25])[C:14]1([C:21]([Cl:24])([F:23])[F:22])[O:18][CH:17]([CH2:19]O)[CH2:16][O:15]1>O>[N+:1]([O-:4])([O:3][CH2:19][CH:17]1[CH2:16][O:15][C:14]([C:13]([Cl:12])([F:25])[F:26])([C:21]([Cl:24])([F:22])[F:23])[O:18]1)=[O:2]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reaction time: 0.5 h

Procedure:
34 ml nitric acid (96%) is added slowly to 43 ml chilled acetic anhydride. Then, 14.8 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane, is added dropwise with magnetic stirring over a 30 minute period to the chilled mixed acid (0° to -10° C.). An additional 25 minutes of stirring is allowed. The reaction mixture is drowned in 250 ml of cold tap water forming a small lower liquid layer. Ether extraction (3 × 75 ml) removed the lower layer and all of the yellow coloration. The ether solution is washed several times with water and then dried over Na2SO4, filtered and evaporated on a rotary evaporator. The cloudy residue is redissolved in ether, treated with Na2SO4, decanted and evaporated as before. The bright yellow liquid is redissolved in ether and treated with activated carbon (DARCO G-60), then filtered (colorless), and reevaporated to yield the above named product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16]([OH:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]3[CH2:24][CH2:25][NH:26][CH2:27][C:9]=3[C:8]=2[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:23])[C:10]3[CH2:24][CH2:25][NH:26][CH2:27][C:9]=3[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Reaction time: 2 h

Procedure:
To a solution of 5-(2-hydroxy-2-pyridin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid ethyl ester (200 mg, 0.547 mmol) in dry THF (10 mL) was added portionwise LAH (63 mg, 1.65 mmol) under nitrogen at RT. After stirring for 2 h, the reaction mixture was quenched with water (0.5 mL), NaOH (1 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to yield 2-(8-hydroxymethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, freebase) δ (ppm): 8.41 (d, 2H), 7.42 (s, 1H), 7.39 (d, 2H), 7.3 (d, 1H), 7.19 (d, 1H), 5.08 (t, 1H), 4.66 (s, 2H), 4.4 (s, 2H), 4.3 (m, 2H), 3.5 (m, 2H), 3.2 (m, 1H), 2.9 (m, 1H). Separation by chiral HPLC provides enantiomers II-81a-b.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH2:24])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of 2-amino-4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid ethyl ester (0.050 g) and triethylamine (0.046 g) in dichloromethane (2 mL) was added methane sulfonylchloride (0.043 g) under ice-cooling, and this mixture was stirred at room temperature for 3 days. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.015 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(=O)O)s2)cn1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 5-bromothiophene-2-carboxylic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and 10 molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) δ 13.10 (br s, 1H), 8.55 (d, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.50 (d, 1H), 6.90 (d, 1H). ESI MS (M+1)+: 236.
Reaction SMILES: [C:1]([C:4]1[C:8](=[O:9])[NH:7][C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][C:5]=12)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:7]1[C:8](=[O:9])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[C:6]12)[CH3:27]
Reactant: CC(=O)c1c2cccccc-2[nH]c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c2cccccc-2c(C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a warm suspension of 3-acetyl-1,2-dihydrocyclohepta[b]pyrrole-2-one [1.87 g, described by T. Nozoe et al., Bull. Chem. Soc. Japan, 38, 306 (1965)] in dimethyl formamide (DMF, 25 ml), potassium carbonate (1.66 g) and ethyl bromoacetate (2.84) were added successively. The mixture was stirred at 25° C. for 18 hr and then diluted with water. The precipitate was collected and dried to give 3-acetyl-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, mp 162°-165° C.; nmr (CDCl3) δ1.33 (t, J=7 Hz, 3H), 2.75 (s, 3H), 4.25 (q, J=7 Hz, 2H), 4.9 (s, 2H), 7.4 (m, 4H), 9.4 (d, J=10 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:21])[CH3:20].S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:21])[CH3:20]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The compound prepared in Example B1 (in the general formula (II), R3=H, R4=CH3, and R5=H) (50 mg, 0.20 mmol) was dissolved in pyridine (5 ml), acetyl chloride (80 mg, 0.70 mmol) was added thereto, and the mixture was stirred at 25° C. for one hr. A 15% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give the title compound (55 mg, 80%).
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccnc(F)c2)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (320 mg, 0.82 mmol) in methylene chloride (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed by rotary evaporation and 1N NaOH was added to the residue to make basic. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide 180 mg of 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74%). LCMS (M+1=298)
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>O>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:27][C:20]=1[F:19])#[N:23]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 100 °C
Yield: 66 %

Procedure:
A DMSO (25 mL, 0.1 M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 2,4-difluorobenzonitrile (348 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtOAc as the mobile phase. Isolated 530 mg (1.66 mmol, 66% yield).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][CH:9]=2)[N:4]=1)#[N:2].[H][H]>[Pd].C(O)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[CH:11]=[CH:12][C:3]=1[CH2:1][NH2:2]
Reactant: [H][H]
Reactant: N#Cc1ccc2ccc3ccccc3c2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: NCc1ccc2ccc3ccccc3c2n1
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 2-cyanobenzo[h]quinoline (2.04 g, 10.0 mmol) and 10% palladium on carbon (0.40 g) in acetic acid (120 ml) was hydrogenated at ambient temperature, in a Parr reactor, with hydrogen gas at a pressure of 2 atm. After 4 hours, during which time absorbance of two hydrogen equivalents was observed, the reaction mixture was filtered and the solvent evaporated under reduced pressure. The oily residue was taken up with ethyl ether and the mixture washed with a 10% NaOH solution until an alkaline pH was achieved. The organic phase was then separated and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography using MeOH as eluent. 1.87 g (90% yield) of 1-(benzo[h]quinolin-2-yl)methanamine in the form of a red solid was obtained.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Yield: 91 %

Procedure:
1.06 g of ethyl α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetate is suspended in a solution of 0.94 g of potassium hydroxide in a mixture of 40 ml of ethanol and 2 ml of water and the suspension is stirred at room temperature to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduced pressure and the residue is adjusted to pH 2.0 with 1 N hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried. The procedure yields 0.88 g of α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetic acid. Yield 91%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A mixture of N-(1-(3-bromophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (1.25 g, 3.7 mmol), tert-butyl piperazine-1-carboxylate (0.7 g, 3.7 mmol), diisopropylethylamine (1.0 mL, 5.7 mmol) and acetonitrile (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10%-15% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.45 g, 24%). 1H NMR (400 MHz, CDCl3): δ 8.72 (d, 1 H), 8.10 (d, 1 H), 7.51 (s, 1 H), 7.40 (m, 1 H), 7.24 (m, 2 H), 6.17 (dd, 1 H), 5.60 (d, 1 H), 4.52 (m, 1 H), 3.48 (m, 4 H), 3.26 (m, 2 H), 3.13 (m, 2 H), 1.63 (d, 3H), 1.44 (s, 9 H). MS (ESI) m/z: Calculated: 504; Observed: 505 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[H-].[Na+].[CH3:23]I.O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:23])([CH3:18])[CH2:13]1
Reactant: CI
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.1 g, 0.36 mmol) in THF (5 ml) was added to NaH (60% in oil, 79.0 mg, 1.79 mmol) which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h and then cooled to RT followed by dropwise addition of a solution of methyl iodide (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([OH:31])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure B, from #5 (1.62 g, 2.79 mmol, 1 eq.), dichloromethane (10 mL, 0.3 M) and trifluoroacetic acid (3 mL) was synthesized #@5 (1.42 g, 97%) as a solid which was used without further purification. LC-MS m/z 525.3 [M+H+] 1547.3 [M+Nal retention time=0.95 minute; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 7.89 (d, J=7.6 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (dd, J=7.6, 7.4 Hz, 2H), 7.28-7.34 (m, 2H), 4.14-4.32 (m, 4H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.51-2.57 (m, 1H, assumed; partially obscured by solvent peak), 2.20 (dd, J=15.9, 9.5 Hz, 1H), 1.95-2.06 (m, 1H), 1.70-1.83 (br m, 1H), 1.22-1.36 (br m, 1H), 0.84-0.93 (m, 9H), 0.70 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:14][C:15]3[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3Cl)nc12
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3ccc4c(Cl)ncnc43)c(-c3ccccc3Cl)nc12
Reaction time: 2 h

Procedure:
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (280 mg, 1.1 eq) in DMF (3 mL) was treated with NaH (1.2 eq, 80 mg, 60%) and the reaction mixture was stirred at rt for 30 min before addition of 3-(chloromethyl)-2-(2-chlorophenyl)-8-methylquinoline (500 mg, 1.7 mmol) in DMF (2 mL). After 2 h at rt, the mixture was partitioned between EtOAc (50 mL) and H2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (Na2SO4), concentrated and purified by flash chromatography (0% to 25% EtOAc/hexane) to provide 3-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-(2-chlorophenyl)-8-methylquinoline as a white foam. This material (60 mg, 0.14 mmol) was dissolved in EtOH (4 mL) and treated with NH3 gas for 3 min. The sealed tube was heated at 80° C. for 4 days. The reaction mixture was concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, 20/1) to provide a white solid [PI3Kδ IC50=1968 nM]. 1H-NMR (DMSO-d6) δ 7.94 (s, 1H), 7.89 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.37-7.62 (m, 6H), 6.96 (s, 2H), 6.86 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 5.30 (d, J=5.9 Hz, 2H), 2.64 (s, 3H). Mass Spectrum (ESI) m/e=400 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][C:5]([NH2:6])=[C:4]([F:15])[CH:3]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][C:5]([N:6]2[C:19](=[O:20])[C:18]3[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=3[C:16]2=[O:21])=[C:4]([F:15])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 4-chloro-5-cyclopentyloxy-2-fluoroaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acids solution (3.0 mL) was stirred under reflux for 3 h. After completion of the reaction, water (20 mL) was added to the resulting reaction mixture and extraction was conducted with ethyl acetate (20 mL×3). The organic layers were dried with anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting pale yellow oil was separated and purified by silica gel column chromatography (ethyl acetate/hexane=1/8), giving N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-3,4,5,6-tetrahydrophthalimide as a colorless clear oil (0.513 g, 1.41 mmol; yield=65%). This could be obtained as white solids upon addition of ethanol and subsequent recrystallization. MP: 69.0°-75.2° C. 1H-NMR(CDCl3,TMS,ppm): δ1.32-2.10(12H,m), 2.40(4H,m), 4.68(1H,m), 6.75(1H,d,JHF =7.0Hz), 7.20(1H, d,JHF =9.0Hz). IR (neat, cm-1): 1725, 1505, 1430, 1385, 1200.