Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH2:27])=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH:27][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc(OCc2ccccc2)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methanamine (0.021 g, 0.053 mmol), 6-chloropurine (0.012 g, 0.06 mmol, 1.5 eq) and DIEA (0.1 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=31 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.38 (s, 1 H), 8.12 (s, 1 H), 8.07 (s, 1 H), 7.90 (s, 1 H), 7.88 (s, 1 H), 7.52-7.59 (t, 1 H), 7.21-7.25 (m, 2 H), 7.19 (m, 4 H), 7.06-7.12 (m, 2 H), 5.05-5.10 (m, 2H), 4.90-4.96 (s, 2H), Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([O:31][CH3:32])([CH3:30])[CH3:29])[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:32][O:31][C:28]([CH3:30])([CH3:29])[C:27]#[C:26][C:17]1[CH:18]=[C:19]2[C@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:9]3[C:10](=[CH:11][CH:12]=[C:7]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 70 °C

Procedure:
A vial was charged with (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (104 mg, 0.210 mmol), pyridin-3-ylboronic acid (77 mg, 0.629 mmol), and tetrakis(triphenylphosphine)palladium (24.22 mg, 0.021 mmol). The vial was purged with Ar (g), then DMF (1048 μL) and potassium carbonate (524 μL, 1.048 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 70° C. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(F)(F)(F)F>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: FC(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(=O)OCCCCCCS(=O)(=O)c1ccc(CBr)cc1
Yield: 71 %

Procedure:
2.0 g of 4-[(6-acetoxyhexyl)sulfonyl]toluene, 1.3 g of N-bromo-succinimide (NBS), 0.015 g of benzoyl peroxide (BPO) , and 20 mL of carbon tetrafluoride were added to a 250 mL round bottomed flask and heated with reflux for 12 hours in nitrogen. The mixture was allowed to cool down and then filtered. The filtrate was washed by deionized water repeatedly. The organic fraction was dried over anhydrous magnesium sulfate and then concentrated by a rotary evaporator. The concentrate was further purified by re-crystallization to produce a white solid. The yield was 71% with the following structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:21]1([C:24]2[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1.[S].C(O)(=O)C>C(O)C>[CH:21]1([C:24]2[N:29]=[C:28]([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.722 mmol) in ethanol (10 mL) was added 2-cyclopropylpyrimidine-4-carbaldehyde (106 mg, 0.722 mmol), sulfur powder (69 mg, 2.16 mmol), and acetic acid (0.2 mL). The reaction mixture was heated to 80° C. for 18 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative HPLC to afford the title compound (40 mg, 13.5%). 1H NMR (300 MHz, CDCl3) δ 1.09-1.18 (m, 3H), 1.19-1.31 (m, 4H), 1.65-1.73 (m, 1H), 1.84 (d, 1H), 1.88-1.98 (m, 2H), 2.31 (d, 1H), 2.69-2.87 (m, 1H), 2.99 (br s, 1H), 3.03 (br s, 1H), 3.11 (br s, 1H), 3.14-3.27 (m, 1H), 3.37-3.57 (m, 2H), 4.37 (d, 1H), 4.45-4.59 (m, 1H), 6.76 (d, 1H), 7.79-7.96 (m, 1H), 8.67 (d, 1H), 10.25 (br s, 1H). MS (ES+APCI) (M+H) 406.3; LCMS retention time 3.055 min (Method U1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[CH:53]([OH:56])[CH2:52][CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:53]([OH:56])[CH2:52][CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCC(O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and piperidin-4-ol and isolated as light-yellow gum (12.6 mg, 67%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:3][CH2:2][F:1])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:15]
Reactant: COCCN
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Yield: 43.4 %

Procedure:
1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 499.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(Cl)cc2c1=O
Yield: 84.1 %

Procedure:
12 g (40 mmol) of the product from Example A in 100 ml of pyridine are heated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours. The mixture is concentrated in vacuo, the residue is stirred with 120 ml of water and the pH is adjusted to 5 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, boiled in 80 ml of methanol and dried. 12.3 g (84% of theory) 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of melting point 295°-298° (with decomposition) are obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].CS([Cl:16])(=O)=O.N1C=CC=CC=1>CN(C)C=O>[Cl:16][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CCOC(CC)CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(CC)CCCCCl

Procedure:
As shown in Reaction 4, Compound III may be reacted with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to produce 5-ethoxyheptanol (Compound IV). Compound IV may be produced at a yield of from approximately 90% to approximately 99%. The reaction may be conducted at a temperature of from approximately −50° C. to approximately room temperature (from approximately 20° C. to approximately 25° C.). To control the reaction, in some embodiments, the reaction is conducted at room temperature. As shown in Reaction 5, Compound IV may be reacted with methanesulfonyl chloride (MSCl) and pyridine in dimethylformamide (DMF) to produce 1-chloro-5-ethoxyheptane (Compound V) at a yield of from approximately 75% to approximately 95%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([OH:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([O:17][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)s1

Procedure:
To a mixture of ethyl 6-(5-chloro-2-thienyl)-5-hydroxy-6-oxohexanoate (21.6 g), pyridine (6.4 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (12.7 g) with stirring under ice-cooling. After the resulting mixture was stirred at room temperature for 16 hours, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(5-chloro-2-thienyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (30.5 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:13]([O:12][C:10](=[O:11])[NH:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccnc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
3-Amino-2-bromopyridine described in Preparation Example S-1 (1.4 g, 8.1 mmol) was dissolved in pyridine (10 mL), ethyl chloroformate (0.93 mL, 9.7 mmol) was added dropwise on an ice bath, and the solution was stirred for 2 hours at room temperature. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the title compound (0.56 g, 2.3 mmol, 28%) was obtained.
Reaction SMILES: Br[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[O:4][Si](C)(C)C.[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[OH:4])=[N+:17]=[N-:18]
Reactant: C[Si](C)(C)OC(CBr)c1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
[2-Bromo-1-(3-bromo-phenyl)-ethoxy]-trimethyl-silane (5.85 g, 16.6 mmol and tetrabutyl sodium iodide (613 mg, 1.66 mmol) were dissolved in DMSO and sodium azide (2.16 g, 33.2 mmol) was slowly added. The mixture stirred at 80° C. for 4 hours and then at room temperature for 18 hours. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were washed with water brine and 1M HCl, then again with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5-10% ethyl acetate in hexanes. The title compound was isolated as a yellow oil (3.38 g, 83%). 1H NMR (300 MHz, CDCl3): 7.57 (s, 1H), 7.48 (d, 1H), 7.31-7.29 (m, 2H), 4.87 (m, 1H), 3.49 (d, 2H), 2.45 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=O.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>[Cl-].[Na+].O>[CH3:13][O:12][C:11]1[C:10]([N+:22]([O-:24])=[O:23])=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:14](=[O:15])[O:16][C:7]2=[O:9]
Reactant: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c([N+](=O)[O-])c1OC)C(=O)OC2=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4,5-Dimethoxy-phthalic acid (1.0 g) was cooled in ice-water bath. A cooled mixture of sulfuric acid (3.0 ml) and fuming nitric acid (3.0 ml) was added dropwise. The mixture was stirred for 10 minutes and left standing for 10 minutes. A mixture of brine and ice was added (1:1). The solid was filtered off, washed with water and recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:42]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro-6-methylbenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH3:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH3:14])[N:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1CCCN1c1nc(Cl)cc(Cl)n1
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: C1COCCO1
Product: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
Heat a mixture of 4,6-dichloro-2-(2-methylpyrrolidin-1-yl)pyrimidine (2.25 g, 9.74 mmol), 4-fluorophenylboronic acid (10.23 mmol), Pd(PPh3)4 (562 mg, 0.487 mmol), and a 2M potassium phosphate solution (9.74 mL) in dioxane (35 mL) under nitrogen at 80° C. for 16 h. Evaporate the mixture and add water (50 mL). Extract with EtOAc (3×50 mL), dry (Na2SO4), and evaporate. Purify by SiO2 flash chromatography, eluting with 9:1 hexanes:EtOAc to provide the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:1]([C:4]1[C:5]([C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=2)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2[C@H]2COC[C@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2[C@H]2COC[C@H]21
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a stirred solution of Intermediate 352F (0.370 g, 0.852 mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.297 g, 1.704 mmol) in dioxane (2 mL) was added a solution of K3PO4 (0.543 g, 2.56 mmol) in water (0.5 mL) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)CH2Cl2 (0.052 g, 0.064 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 4% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 352G (0.270 g, 54%) as an off-white solid. MS(ES): m/z=437 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Nc2ccc3[nH]ccc3c2)nc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (42 mg, 0.162 mmol), 1H-5-indolylamine (31 mg, 235 mmol) and potassium carbonate (25 mg, 0.180 mmol) was heated overnight in 1 mL of DMF at 100° C. in a sealed tube. The reaction mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed with water (20 mL×3) and saturated NaCl. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by flash column chromatography (30% ethyl acetate/hexanes) to obtain the title compound as a white solid (mp 142–143° C., 45 mg, 0.127 mmol, 78%). 1H NMR (CDCl3): 9.56 (d, J=1.5 Hz, 1H), 8.74 (dt, J=1.8, 8.1 Hz, 1H), 8.63 (dd, J=3, 5.1 Hz, 1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.30 (d, J=3 Hz, 1H), 7.19 (m, 1H), 6.82 (s, 1H), 6.55 (d, J=3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([O:17][CH2:18][CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:20][CH2:19][CH2:18][O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCOc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccccc2)cc1
Yield: 87 %

Procedure:
1-Chloro-4-nitrobenzene is reacted in dimethylsulphoxide, in the presence of a base, with ethylene glycol monophenyl ether: 1-nitro-4-(2-phenoxy-ethoxy)-benzene is obtained in 87% yield.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][OH:10].Cl>>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][Br:7]
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cl
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
3,4-Dihydro-2H-pyran (92.5 g, 1.1 mol) was added dropwise to 2-bromoethanol (125 g, 1.0 mol) on an ice-bath. The temperature was kept between 25°-30° C. during addition. When addition was complete a concentrated hydrochloric acid solution (1 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was fractionated in vacuo to give 147 g (70%) of 2-bromoethyl tetrahydropyran-2-yl ether.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1.[CH3:19]O>>[CH3:19][O:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1
Reactant: CO
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Agent: Cl
Product: COc1c2c(cc3ccc(=O)oc13)CC(OC)O2
Reaction time: 1 h

Procedure:
Dry methanol was saturated at 0° with gaseous hydrogen chloride. A sample of 0.576 g. (2.46 mmoles) of 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one was dissolved in the resultant solution, and the dark reaction was allowed to proceed at room temperature for one hour. The solvent was evaporated and the residue was taken up in ethyl acetate/benzene. 1:4 and filtered through 50 g. silica, eluting with the same solvent system. Fractions containing the product, which is first eluted, were combined and evaporated to give pure 2,9-dimethoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one as a white solid. Recrystallization from methanol afforded an analytical sample of this product, mp 131°-132°.