Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)CCC.FC(F)(F)C(O)=O.[CH2:35]([NH:39]C1N=C2C(N=C(OC)N2)=C(N)N=1)[CH2:36][CH2:37][CH3:38].BrCCCBr>>[CH2:35]([NH:39][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Agent: BrCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, 1,3-dibromopropane, and 2-(tetrahydro-2H-pyran-4-ylethyl)amine.
Reaction SMILES: C1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]([OH:19])=[O:18])=[CH:12][CH:13]=3)[N:8]=2)C=CC=CC=1.COC(=O)[C:23]1[CH:28]=[CH:27][C:26](C=O)=[C:25](N)[CH:24]=1.C1(CC=O)C=CC=CC=1>>[C:23]1([C:16]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc2ccc(-c3ccccc3)nc2c1
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Agent: O=CCc1ccccc1
Product: O=C(O)c1ccc2cc(-c3ccccc3)cnc2c1
Yield: 87 %

Procedure:
Following the same reaction procedure and workup for Compound 405f, 500 mg (2.8 mmol) of Compound 53 was reacted with 340 mg (2.8 mmol) phenylacetaldehyde to produce 603 mg (87% yield) of the title intermediate.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[Se](=O)=[O:26]>O1CCOCC1.O>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:26])=[O:23])[CH:17]=[CH:16]3
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (500 mg, 1.66 mmol, described in Intermediate 6) and selenium dioxide (552 mg, 4.97 mmol) in dioxane (30 mL) and H2O (3 mL) was heated at reflux for 18 h. The reaction mixture was allowed to cool, then it was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=332 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=1.[C:12]([C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]([C@@H:16]1[CH2:17][CH2:18][C@H:19]([NH:22][C:2]2[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
32.3 g (0.15 mol) of 4,5-dichloro-6-(1-chloroethyl)pyrimidine(EP 543 402) were stirred in 200 ml of toluene with 23.3 g (0.15 mol) of cis-4-tert-butylcyclohexylamine and 20.2 g (0.20 mol) of triethylamine at from 80° to 90° C. for 6 hours. The mixture was extracted by stirring with water and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel, to give 36.3 g (73.2% of theory) of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[N:42]([Sn](CCCC)(CCCC)CCCC)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[N:42]=[N:43][NH:44][N:17]=2)[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC#N)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1nn[nH]n1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 100 °C

Procedure:
To a solution of (S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetonitrile (0.1 mmol) in toluene (6 mL), add azidotributyltin (0.1 mmol) and heat at 100° C. After heating for 14 h, cool to room temperature and dilute with ethyl acetate (20 mL). Wash the reaction with concentrated sodium fluoride (2×20 mL), dry the organic phase over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-5%), to afford the title compound as a colorless foam. MS (ES+): 633 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](=S)(OCC)[S-:20].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[SH:20][C:19]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: CCOC(=S)[S-]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NCCC1CCc2ccc3nc(S)oc3c21
Yield: 63.5 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) and potassium O-ethyl dithiocarbonate (65.1 mg, 0.406 mmol) were heated under reflux in pyridine (1 mL) for 2 hr. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (64.8 mg, yield 64%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:24]([CH2:23][Cl:22])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Br)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Br)c2C1=O
Yield: 82.6 %

Procedure:
16.9 g (48.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime were stirred with 9.5 g (55.5 mmol) of chloroacetic anhydride in 100 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 3 hours. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there were obtained 16.3 g (84%) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5, 6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 242°-244°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]#[C:16][C:17](=O)[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:28][N:27]=[C:17]([CH3:18])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 4-[1-phenyl-1-(3-oxo-1-butyn-1-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.365 g, 1.069 mmol) and hydrazine hydrate (0.065 mL, 1.14 mmol) in EtOH (5 mL) was allowed to stir at rt for 2 h and then it was heated at 80° C. for 14 h. The solvent was subsequently removed under reduced pressure and the residue was purified by preparative HPLC affording the title compound (0.151 g, 40%) as a colorless solid
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([NH:40][C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)NCC(C(=O)O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
3-(Acetylamino)-2-[4-(tert-butoxycarbonyl)phenyl]propanoic acid (222 mg, 0.72 mmol), EDCI (207 mg, 1.08 mmol), and HOBT (127 mg, 0.94 mmol) were dissolved in DMF (7 mL) and stirred for 5 minutes before adding aniline (99 μL, 1.08 mmol). After stirring at room temperature for 18 h, the solution was concentrated. The resulting residue was taken up in EtOAc, washed (water, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica (0-4% MeOH/DCM) afforded tert-butyl 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoate as an off-white solid. 1H NMR (DMSO-d6) δ10.18 (s, 1H), 8.08 (t, J=5.9 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.56 (d, J=7.6 Hz, 2H), 7.46 (d, j=8.2 Hz, 2H), 7.25 (t, J=7.9 Hz, 2H), 7.00 (t, J=7.5 Hz, 1H), 4.03 (dd, J=8.2, 6.3 Hz, 1H), 3.51 (ddd, J=13.2, 8.4, 5.0 Hz, 1H), 3.42 (dt, J=12.9, 6.5 Hz, 1H), 1.74 (s, 3H), 1.50 (s, 9H). MS (ESI) calcd [M+H]+ 383.2, found 383.1.
Reaction SMILES: S(OS([O-])=O)([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:23][C:24]=1[NH2:25].O>CN1CCCC1=O>[Cl:10][C:11]1[S:12][C:13]([C:16]2[NH:25][C:24]3[CH:23]=[CH:22][C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][C:19]=3[N:18]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Cl)s1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
3.1 3.89 g (20.5 mmol) of sodium disulfite are added to a solution of 3.00 g (20.5 mmol) of 2-chlorothiophene-5-carbaldehyde and 3.98 g (20.5 mmol) of ethyl 3,4-diaminophenylacetate in 30 ml of 1-methyl-pyrrolidone, and the mixture is stirred at 110° C. for 18 hours. Water is added to the reaction mixture, which is extracted with dichloromethane. The organic phase is dried using sodium sulfate and evaporated, giving ethyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate as a brown oil (ESI 321), which is employed without further purification for the next reaction.
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:43])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1>>[C:10]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:18]=[CH:19][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:43])=[O:42])=[CH:28][CH:29]=3)=[CH:3][C:4]1=2)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)CCCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Product: CN(C)CCCNC(=O)c1ccc(-c2cnc3c(c2)N(C(=O)c2ccccc2)CCN3)cc1
Yield: 44 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50 mg) was reacted with N-(3-dimethylamino-propyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (44% yield). M.p. 94° C., LCMS: m/z=444.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.72-1.80 (m, 2H), 2.27 (s, 6H), 2.48-2.53 (t, J=5.8 Hz, 2H), 3.48-3.54 (m, 2H), 3.67-3.73 (m, 2 h), 3.98-4.04 (m, 2H), 5.44 (bs, 1H), 7.10-7.18 (m, 2H), 7.36-7.48 (m, 6H), 7.69 (d, J=8.1 Hz, 2H), 8.07 (s, 1H), 8.42 (bs, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([OH:30])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:33]I>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([O:30][CH3:33])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:14][CH2:15]3)[C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
To trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide (20 mg, 48.1 μmol, Eq: 1.00) in THF (500 μl) was added NaH (3.37 mg, 84.2 μmol, Eq: 1.75) and methyl iodide (17.1 mg, 7.52 μl, 120 μmol, Eq: 2.5). After 2 hours the reaction mixture was diluted with water (300 ul). The crude reaction mixture was concentrated in vacuo. The residue was suspended with 5 mL sat NaHCO3 and extracted with dichloromethane (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as an off-white solid (12.1 mg, 58.5%), MS (ISP) m/z=430.2 [(M+H)+].
Reaction SMILES: C(O[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)C(C)=C.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl.Cl.N(C(C(=N)N)(C)C)=N[C:23](C(=N)N)(C)C>O>[C:12]([O:17][CH2:18][CH2:23][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11])(=[O:16])[C:13]([CH3:15])=[CH2:14].[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)ON(CC)CC
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: C=C(C)C(=O)OC
Agent: Cl
Solvent: O
Product: C=C(C)C(=O)OCCN(CC)CC
Temperature: 60 °C

Procedure:
In a flask equipped with a stirring blade and a tube for nitrogen introduction were charged 1,500 parts of ion-exchanged water and heated to 60° C. Twenty parts of diethylamino methacrylate and 60 parts of methyl methacrylate were added thereto while stirring. To the mixture were further added 20 parts 2,2'-azobis(2-amidinopropane) dihydrochloride ("V-50" produced by Wako Pure Chemical Ind. Ltd.) and 10 parts of 2,2'-azobis(2-methyl-N-(1,1'-bis(hydroxymethyl)-2-hydroxyethyl)propionamide) ("V-080" produced by Wako Pure Chemical Ind. Ltd.), followed by heating to 65° C., at which the mixture was subjected to soap-free polymerization for 24 hours. After completion of the reaction, the fine particles thus produced were washed with 5000 parts of ion-exchanged water by means of a centrifugal separator to obtain fine particles of a diethylaminoethyl methacrylate/methyl methacrylate copolymer having an amidino hydrochloride group and a hydroxyl group on the surface thereof and having an average particle size of 0.5 μm.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A mixture of 1.11 g of 2-fluoro-4-(trifluoromethyl)benzaldehyde, 739 mg of methyl thioglycolate, 1.3 g of potassium carbonate and 20 ml of DMF was stirred at 140° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 848 mg of methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 2).
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=O)[CH3:4].[CH3:16]/[C:17](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:18]\CCI.O>C(O)C>[CH3:18]/[C:17](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:4][CH2:3][S:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(CSC(C)=O)OCC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CSCC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Solid sodium hydroxide (0.14 g, 3.5 mmol) was added to a stirred solution of diethyl acetylthiomethylphosphonate (0.59 g, 2.5 mmol) in ethanol (10 mL). The resulting mixture was stirred at room temperature under nitrogen until all the sodium hydroxide dissolved, then added a solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl iodide (0.84 g, 2.4 mmol) in ethanol (2 mL). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was poured into cold water and extracted with ether. The ethereal extract was washed with water, dried, filtered and evaporated to give a residue, which was purified by flash chromatography on a silica gel column. Elution of the column with methylene:acetate (10:1, v:v) afforded the title compound (0.91 g, 2.26 mmol, 94%) as a colorless oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)O)(C(C)(C)C)(C)C.S(Cl)(Cl)=O.[CH3:34][C@H:35]1[CH2:40][NH:39][C@H:38]([CH3:41])[CH2:37][NH:36]1.O.[F-].C([N+](CC)(CC)CC)C>>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:36]2[CH2:37][C@H:38]([CH3:41])[NH:39][CH2:40][C@H:35]2[CH3:34])[C:11]2[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=2)=[CH:26][CH:25]=1)[CH3:24]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@H](C)NC[C@H]2C)cc1

Procedure:
4-(3-(tert-Butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, infra) was treated with thionyl chloride and trans-2,5-dimethylpiperazine as described in Example 5. The crude mixture of diastereomers was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.25:0.1). The less mobile isomer (1.28 g, 2.5 mmol) was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give 0.46 g of (±)-N,N-diethyl-4-((αR*)-3-hydroxy-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a white solid, mp 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cc(F)ccc2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc(-c3ccccc3Cl)c(CNc3ncnc4[nH]cnc34)cc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=1683 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.44 (s, 1 H), 8.14 (s, 1H), 8.07-8.11 (m, 2H), 7.66-7.71 (m, 1H), 7.59-7.66 (m, 1H), 7.49-7.55 (m, 2H), 7.40-7.46 (m, 1H), 7.34-7.40 (m, 1H), 4.05-4.17 (m, 2H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1.[NH2:14][OH:15]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]([NH:14][OH:15])=[NH:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(C#N)cnc1N
Reactant: NO
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nc(C(=N)NO)cnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
3-Amino-6-cyano-N-methylpyrazine-2-carboxamide (839 mg, 4.7 mmol) was suspended in ethanol (25 mL) followed by addition of 50% aqueous hydroxylamine (2 mL, 31.3 mmol) and the mixture was stirred at room temperature for one hour. The suspension obtained was diluted with water (2 5mL) and the insoluble solid collected by filtration and washed with water. The solid was dried in vacuo to give 3-amino-6-[(hydroxyamino)(imino)methyl]-N-methylpyrazine-2-carboxamide (664 mg, 67% yield) as a white solid: MS (EI) for C7H10N6O2: 211 (MH+).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[C:19]([CH:22]=O)[S:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[C:19]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[S:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: C1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3csc(C=O)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3csc(CN4CCCCC4)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(2-formyl-1,3-thiazol-4-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 39) (21 mg, 0.052 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (7.77 μL, 0.078 mmol) and acetic acid (7.49 μL, 0.131 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (16.63 mg, 0.078 mmol) was added and the mixture was allowed to stir under nitrogen. The mixture was loaded onto a 2 g SCX-column, eluting with MeOH (25 mL) followed by 2M MeOH/NH3 (25 mL). Product-containing fractions were evaporated to dryness to give a solid (18 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 4% 2N methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg).