Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:29])[O-:28])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1.[ClH:31].[CH3:32][CH2:33][O:34][CH2:35]C>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:28])[O:29][CH2:32][CH2:33][O:34][CH3:35])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)[O-])C3)nc(-c3c(O)cccc3F)nc2c1
Agent: Cl
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Reaction time: 0.04 h

Procedure:
To a solution of ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (352 mg, 0.75 mmol) in CH2Cl2 (3 mL) was added dropwise a 2.0 M HCl solution in ether (0.375 mL, 0.75 mmol) under an N2 atmosphere. It was followed by the addition of 20 mL ether which lead to the precipitation of 2-methoxyethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (350 mg, 92%) which was then filtered and dried. LC/MS: m/z 469.5 (M+H)+ at 2.29 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.45 (m, 3H), 6.89 (d, J=8.3 Hz, 1H), 6.82 (t, J=9.5 Hz, 1H), 4.54 (s, 1H), 4.03 (d, J=2.7 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.24 (s, 3H), 2.99 (m, 2H), 2.54 (s, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.38 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O=[C:6]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH:7]=O.[BH4-].[Na+]>C(O)C>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:6]1[CH2:7][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: O=CC(=O)c1ccco1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1coc(C2CNCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
A solution of 10.25 g of ethylene diamine in 250 ml of ethanol was added to a solution of 19.53 g of the above aldehyde in 250 ml of ethanol at 0° C. The mixture was stirred at room temperature for 1.5 hours, then recooled to 0° C. and 9.6 g of sodium borohydride added. This mixture was stirred overnight, quenched with water and the ethanol removed. The residue was extracted with dichloromethane, washed with water, dried and the solvent evaporated. The residue was crystallized from hexaneether, giving 13.8 g of 2-(2-furanyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1ccccn1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and 2-pyridinemethanamine (CAN 3731-51-9) as starting materials; LC-MS (UV peak area/ESI) 99.0%, 394.1 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([O:15]C)[C:8]([O:13]C)=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].B(Br)(Br)Br.C(=O)([O-])O.[Na+].C(O)(=O)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4]
Reactant: COc1cc(C(=O)CBr)cc(C#N)c1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)CBr)cc(O)c1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4.2 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile dissolved in 150 ml of methylene chloride are treated with 8.9 ml of boron tribromide. The reaction mixture is stirred at 20° for 18 hours. It is subsequently poured into 220 ml of saturated sodium hydrogen carbonate solution and 100 g of ice, adjusted to pH 6 with glacial acetic acid and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. There is obtained 5-(bromoacetyl)-2,3- dihydroxybenzonitrile as an amorphous solid.
Reaction SMILES: CC(C)([O-])C.[K+].CC(C)([O-])C.[CH3:12][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:22]([O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:23]>C(O)(C)(C)C>[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:13]([CH3:12])([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:24][CH2:22][CH3:23])=[O:32]
Reactant: CCOC(=O)CCCCCBr
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC
Temperature: 50 °C
Yield: 485 %

Procedure:
A mixture of 1.34 g (12 mmol) potassium t-butoxide and 10 g t-butanol was stirred and heated until the t-butoxide had been dissolved. The solution was cooled to about 50° C. and 1.7 g (1 1.8 mmol) of ethyl 2-methylacetoacetate (I) was added dropwise. Ethyl-6-bromohexanoate (3 g, 13.5 mmol) was then added dropwise and the reaction mixture was stirred and refluxed for 5 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was partitioned between 1 M HCl and chloroform. The organic layer Was dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexane as the eluent to yield 2.5 g (75%) of ethyl 2-(5-carboethoxypentyl)-2-methylacetoacetate (IIa) as yellow liquid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Yield: 69.2 %

Procedure:
Diethyl malonate (10.4 g, 65 mmol) was added to a solution of sodium ethoxide (4.42 g, 65 mmol) in ethanol (75 mL). 1-(tert-Butoxycarbonyl)-4-[(p-toluenesulfonyloxy)methyl]piperidine (25 g, 68 mmol), prepared as in Example 1, Step (a), was added and the mixture was heated at reflux for 4 hours. The mixture was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (25% ethyl acetate-hexane) gave 1-(tert-butoxycarbonyl)-4-[2,2-di(ethoxycarbonyl)ethyl]piperidine (16 g, 45 mmol) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]2)=[N:2]1.[OH-].[Na+]>OS(O)(=O)=O>[N:10]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#CN1CCN(c2n[nH]c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Yield: 73 %

Procedure:
A mixture of 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g, 40 mmol) and 25% H2SO4 (100 ml) was stirred at reflux for 4.5 hours. The reaction was cooled in an ice bath and made basic by the dropwise addition of 50% NaOH. The basic solution was extracted with ethyl acetate. The ethyl acetate was washed with H2O, dried with MgSO4, and concentrated to afford 5.2 g (73% of the desired compound, as a solid. The solid was recrystallized twice from toluene to afford 3.0 g of 3-(1-piperazinyl)-1H-indazole, m.p.=153°-155° C.
Reaction SMILES: O.[CH2:2]([O:4][C:5](=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].CC[O-].[Na+].[C:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3]
Reactant: CCOC(=O)CCCCC(=O)OCC
Reactant: BrCc1ccccc1-c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCC(Cc1ccccc1-c1ccccc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Into a 3 neck flask, equipped with water cooler, were added 43.8 mL (0.22 mol) of diethyladipate and 220 mL THF. 16.3 g (0.24 mol, 1.1 equivalents) of NaOEt were added in small portions, at 20° C., and the reaction mixture was stirred at 60° C. for 16 hours. After cooling to 20° C., 48.6 g (0.20 mol) of 2-phenyl-benzyl bromide was added dropwise. The reaction mixture was stirred at 60° C., for 16 hours, to give 2-(2-phenyl-benzyl) adipic acid diethylester as a viscous oil, in a yield of 92%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:9][CH3:10])=[O:8].[N:11]1([CH2:20][CH2:21][C:22](OC)=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>C1COCC1>[OH:23]/[CH:22]=[C:21](/[CH2:20][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)\[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CCn1ccc2ccccc21
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C\O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.3 %

Procedure:
To the suspension of potassium tert-butoxide (1.0 g, 8.91 mmol) in dry THF (10 mL) was added dropwise solution of methyl formate (1.0 ml, 16.22 mmol) and methyl 3-(1H-indol-1-yl)propanoate (1.0 g, 4.92 mmol) in dry THF over 30 min. The mixture was stirred at room temperature for 1 h. Concentration in vacuo then afforded the crude title compound (1.3 g). LCMS: rt=2.59 min, [M+H+]=232
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1.P(Cl)(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:23][C:13]1[C:12]2[S:11][C:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=3[Cl:9])=[N:18][C:17]=2[C:16]([F:19])=[CH:15][N:14]=1
Reactant: [O-][n+]1cc(F)c2nc(-c3c(Cl)cc(I)cc3Cl)sc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cnc(Cl)c2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Yield: 34 %

Procedure:
To a suspension of 2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine-5-oxide (2.8 g, 6.4 mmol) in 1,2-dichloroethane (80 mL) was added phosphorus oxychloride (1.8 mL, 19.1 mmol). The reaction mixture was heated under reflux for 16 hours. Upon cooling, the resultant mixture was treated cautiously with aqueous sodium bicarbonate to achieve pH 6-7, and then extracted with dichloromethane (×2). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 0-50% diethyl ether in petroleum ether to afford the title compound as a white solid (1.0 g, 34% yield). 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J=1.5 Hz, 1H), 7.82 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([NH:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=[CH:30][CH:31]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}aniline (70 mg) in dichloromethane (10 ml) were added pyridine (1 ml) and MsCl (0.032 ml). After stirred for 2 hours at the room temperature, the mixture was partitioned between ethyl acetate and water and the organic layer was washed with 1N-HCl, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with ether to afford (S)-N-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}phenyl}-methanesulfonamide (0.05 g).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])[CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1cccc(CCl)c1
Reactant: CCNCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1cccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)c1
Temperature: 55 °C
Yield: 55 %

Procedure:
Diethylamine hydrochloride (0.33 g) was added to a stirred mixture of N-[5-(4-cyanobenzamido)-2-methylphenyl]-3-chloromethylbenzamide (0.4 g), potassium carbonate (0.5 g) and acetone (6 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. The reaction mixture was evaporated and the residue was triturated under water. The solid was isolated and dried under vacuum at 55° C. to give the title compound (0.24 g); NMR spectrum: (DMSOd6) 0.95 (t, 6H), 2.19 (s, 3H), 3.58 (s, 2H), 7.22 (d, 1H), 7.5 (m, 3H), 7.85 (m, 3H), 7.99 (d, 2H), 8.12 (d, 2H); Mass Spectrum: M−H− 439.
Reaction SMILES: C[O:2][CH:3]1[CH:8]([CH:9](OC)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5](OC)[O:4]1.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>O>[CH:9](=[C:8]([CH2:7][CH2:6][CH:5]=[O:4])[CH:3]=[O:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1CCC(C(OC)c2ccccc2)C(OC)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCCC(C=O)=Cc1ccccc1

Procedure:
A mixture of 100 g. 2,6-dimethoxy-3-(α-methoxybenzyl)tetrahydropyran, 300 g. dioxane, 200 ml. water and 40 g. concentrated hydrochloric acid was stirred for 2 hours at 60°-70° C. The solution, which eventually became homogeneous and brown colored, was cooled, neutralized with sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted twice with ether and the combined organic phase was washed until neutral. The solvent was removed and the residue was distilled in vacuo to give 51 g. of the title compound; b.p. 132° C. (1 mm). Yield: 51 g. (73%) (distillation was accompanied by partial decomposition).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: OCCCl
Reactant: CC(C)(O)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Yield: 63.8 %

Procedure:
(Navalokina, R. Et al J. Org. Chem. USSR (Engl. Trans.), 1980, 16, 1382–1386.2) Ramalingam, K. U.S. Pat. No. 4,864,051, 1989.). A 250 mL round bottom flask was charged with ZnCl2 (68.14 g, 0.5 mole) which was then fused by heating under vacuum. After returning to room temperature the material was placed under an atmosphere of N2. To this was added acetone cyanohydrin (45.66 mL, 0.5 mole) followed by 2-chloroethanol (50.24 mL, 0.75 mole) and the mixture placed in a preheated oil bath (60° C.). After stirring for 18–20 h at 60° C., the reaction mixture was cooled, diluted with water (300 mL) and washed with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. Purification was accomplished by vacuum distillation (10 mm Hg) using a vigreux column. The fraction boiling between 65–75° C. was collected to afford the desired product as a colorless oil (47.1 g, 63.8% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 3.85 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.60 (6H, s).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:22][N:21]([S:28]([CH2:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:35])=O)(=[O:30])=[O:29])[CH2:20][CH2:19][C:18]2=1.[Si]([O:46][NH2:47])(C(C)(C)C)(C)C.O>ClCCl>[OH:46][NH:47][C:33](=[O:35])[CH:32]([CH2:31][S:28]([N:21]1[CH2:20][CH2:19][C:18]2[C:17]3[C:25](=[CH:26][CH:27]=[C:15]([O:14][CH3:13])[CH:16]=3)[NH:24][C:23]=2[CH2:22]1)(=[O:29])=[O:30])[CH:36]([CH3:38])[CH3:37]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)O)C(C)C)C3
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)NO)C(C)C)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (104 mg) was added to a slurry of 2-(6-methoxy-1,3,4,9-tetrahydro-β-carboline-2-sulfonylmethyl)-3-methylbutyric acid (172 mg) in dichloromethane (10 ml). The mixture was stirred for 5 minutes before addition of O-(t-butyldimethylsilyl)hydroxylamine (80 mg), then for 1.5 h. The mixture was poured into water (10 ml) and extracted with dichloromethane (3×15 ml). The combined organics were washed with water (2×50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and 1.0N hydrogen chloride in ether (2.5 ml) was added. The mixture was stirred at room temperature for 2 h. It was evaporated under reduced pressure and the residue chromatographed (SiO2, 5% methanol in dichloromethane) to give the title compound (37 mg, 21%) as a pale orange solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[C:34]([S:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)=[O:9])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](NC(=O)N(CCS)CCc1ccccc1)C(=O)N1CCN(C)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)N(CCSC(=O)c1ccccc1)CCc1ccccc1)C(=O)N1CCN(C)CC1

Procedure:
1-[(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]propionyl]-4-methylpiperazine (Compound No. 30-1, 32.9 g)is dissolved in chloroform (87 ml) under a nitrogen atmosphere, and the solution is stirred. To the solution are added triethylamine (13.3 ml) and then benzoyl chloride (10.1 ml )dropwise under ice cooling, and the mixture is stirred for 25 minutes. The reaction mixture is concentrated under reduced pressure, a 10% aqueous sodium hydrogencarbonate solution is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 32-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:20])=[CH:7]2.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:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cccc2cc(CNc3ncnc4[nH]cnc34)c(Oc3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenoxyquinolin-3-yl)-methanamine (0.110 g, 0.360 mmol), 6-chloropurine (0.072 g, 0.46 mmol, 1.2 eq) and DIEA (0.72 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenoxyquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=125 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.18-8.24 (s, 1H), 8.14-8.20 (s, 1H), 7.85-7.91 (d, J=7.58, 1H), 7.72-7.79 (d, J=7.34, 1H), 7.47-7.55 (m, 3H), 7.42-7.47 (m, 3H), 7.35-7.42 (m, 1H), 4.01-4.14 (m, 2H), Mass Spectrum (ESI) m/e=403 (M+1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[CH:7]=[CH:6][S:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: BrCc1ccsc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccsc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
A mixture of 3-(bromomethyl)thiophene (360 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature for 2 days. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in water (20 mL). The solid material was recovered by filtration, washed with water (2×15 mL) and hexanes (3×15 mL), and dried in vacuo, affording the title compound (80 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.02 (s (br), 1H), 7.12 (dd, 1H, J=1.3 Hz, 3.5 Hz), 7.47 (m, 2H); M+239; HPLC purity: 96.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Yield: 56.6 %

Procedure:
2.1 g of 3-(3-[N-(2-(4-nitrophenyl)-ethyl)-N-methylamino]-propyloxy)-5-phenyl-1,2,4-thiadiazole (for) preparation, see Example 8)), were dissolved in a mixture of 75 ml ethanol and 75 ml methanol and reacted with a catalytic quantity of Raney nickel. The reaction mixture was then hydrogenated for 2.5 hours at room temperature with hydrogen at a hydrogen pressure of 5 bars. The catalyst was filtered off and the filtrate concentrated to dryness. The oily crude title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 1.1 g of the title compound were obtained as an oil.