Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.05 h
Yield: 65.3 %

Procedure:
40% Methanolic Triton B (0.054 mL, 0.12 mM) was added to a solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (39.5 mg, 0.10 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (54.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 33.0 mg (65%) of the {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 15H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 3450, 1748, 1670, 1582, 1486, 1246, 1225, and 1151. MS (ES) m/e 523.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Yield: 90 %

Procedure:
A mixture of benzoic acid 4-hydroxy-3-nitro-phenyl ester (Tapia, R.; Torres, G. and Valderrama, J. A. Synth. Commun. 1986, 16, 681) (20.7 g, 80 mmol), benzyl bromide (42.75 g, 250 mmol), potassium carbonate (48.3 g, 350 mmol) and DMF (300 mL) was stirred at room temperature for 2 days. After removing the solvent the residue was dissolved in water and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with CH2Cl2 to give the title compound as a pale yellowish solid (25.1 g, 90%); 1H NMR (300 MHz, CDCl3) δ 5.27(s, 2H), 7.17 (d, J=9.1 Hz, 1H), 7.30-7.55 (m, 8H), 7.60-7.70 (m, 1H), 7.80 (d, J=2.9 Hz, 1H), 8.15-8.25 (m, 2H); MS (ES) m/z: 345.0 (MH+, 100%); HRMS Calcd. for C20H15NO5 (M+): 349.0951. Found: 349.0952.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17]C(=O)C)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1.Cl>CCO>[CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C3(C)CC3)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)c1
Temperature: 25 °C

Procedure:
A mixture of N-{4-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-yl}-acetamide (Step 1.3) (34.8 mmol), a 6N aqueous solution of HCl (53 mL) and EtOH (265 mL) was stirred for 5 h at 85° C., cooled to rt and then concentrated. The residue was slowly diluted with a saturated solution of NaHCO3 and then extracted with EtOAc (3×). The combined organic phases were successively washed with a saturated solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated with CH2Cl2 and then filtered to afford the title compound as a yellow-green solid. HPLC: t=3.55 min (method B); LC-MS: tR=1.03 min, [M+H]+ 246; TLC: Rf=0.26 (1:2 Hex/EtOAc).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:39]([O:43][C:44](=[O:46])[CH3:45])([CH3:42])([CH3:41])[CH3:40].Cl[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH2:49]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:39]([O:43][C:44](=[O:46])[CH2:45][C:52]1[CH:53]=[N:48][CH:49]=[C:50]([Cl:54])[CH:51]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)OC(C)(C)C
Reactant: ClC1=CC=CN(Cl)C1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Pd2(dba)3 (928 mg, 1.01 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (838 mg, 2.13 mmol) are added at RT under an atmosphere of argon to a solution of lithium hexamethyl disilazide in toluene (prepared by addition of n-BuLi (1.6 M in hexane, 24.3 ml, 38.85 mmol) to hexamethyl disilazane (6.27 g, 38.85 mmol) in toluene (100 ml) at −78° C.). The mixture is stirred at RT for 10 minutes, then it is cooled to −10° C. Acetic acid tert-butyl ester (4.12 g, 35.48 mmol) is added during 10 minutes. This mixture is canulated into a cold (−10° C.) solution of 1,3-dichloropyridine (5.00 g, 33.79 mmol) in toluene (40 ml). The mixture is warmed to RT and stirred for 2 h. TLC analysis indicated substantial conversion of starting material. Water was added, the resulting slurry is filtered, and the filtrate is extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 100:0 to 92:8 to 85:15) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.39 (s, 9H), 3.47 (s, 2H), 7.58-7.60 (m, 1H), 8.31 (s,1H), 8.41-8.42 (m, 1H). ES+−MS: 228.3 [M+H]+.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li].C([Mg]Cl)C=C.[CH3:14][C:15]1[CH:16]([C:25](OCC)=[O:26])[C:17]2([CH2:22][CH2:23][CH:24]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2.[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[CH3:14][C:15]1[CH2:24][CH2:23][CH2:22][C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16]=1[C:25](=[O:26])/[CH:7]=[CH:5]/[CH3:6]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1C(C)=CCCC12CCCC2
Agent: C=CC[Mg]Cl
Agent: [Cl-]
Agent: [Li]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C/C=C/C(=O)C1=C(C)CCCC12CCCC2
Temperature: 33 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
At 20° C., a solution of lithium diisopropylamine (9.3 ml, 2M in THF/heptane) was treated dropwise within 10 min. with a solution of allylmagnesium chloride (15 ml, 2 M in THF). The resulting mixture was heated at 33° C., treated dropwise with a solution of ethyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (6 g, 27 mmol) in THF (7 ml), stirred at 20° C. for 1 h and at 40° C. for 24 h, treated with a mixture of allylmagnesium chloride (15 ml, 2 M in THF) and lithium diisopropylamine (9.3 ml, 2M in THF/heptane), stirred at 30° C. for 2 h, poured into a mixture of a saturated aqueous solution of NH4Cl (100 ml) and ice (115 g), and diluted with MTBE (200 ml). The organic phase was washed with 10% aqueous HCl (80 ml), with a saturated aqueous solution of NaHCO3 (80 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 100:1 to 90:10) of the crude product (8.3 g) gave (E)-1-(7-methylspiro[4.5]dec-7-en-6-yl)but-2-en-1-one and (E)-1-(7-methylspiro[4.5]dec-6-en-6-yl)but-2-en-1-one (1 g, 17%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH:31]=[CH2:32])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH2:42]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH2:31][CH2:32][NH:42][CH3:41])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN
Reactant: C=Cc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1
Product: CNCCc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1

Procedure:
Example 162 was prepared from N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide (Example 151) and methylamine in the same manner as Example 151. ESI MS m/z 592 [C30H37N7O4S+H]+.
Reaction SMILES: [Cl-].[C:2]1([S:8][C:9]2([C:12]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1>[C:2]1([S:8][C:9]2([C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH2:10][CH2:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 50 °C
Yield: 89.6 %

Procedure:
460 mg (0.5 mmol) of tris-triphenylphosphinerhodium chloride (=1 mol-%, with respect to the reaction component) are added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 15.7 g (0.05 mol) of 4-chlorophenyl-ethenyl 1-phenylmercapto-cyclopropyl ketone in 40 ml of toluene is added and the mixture is heated to 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is held between 40 and 50 bar until gas uptake has ended. The mixture is then reacted for a further hour. For working up, the solvent is stripped off under reduced pressure and the residue remaining is purified on silica gel using dichloromethane as eluant. 14.2 g (90% of theory) of 4-chlorophenylethyl 1-phenylmercaptocyclopropyl ketone are obtained in the form of an oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3[CH2:35]COC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(CCC(NN)=O)#[N:37].O1CCC(CC(NN)=O)C1>>[C:35]([CH2:31][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)=[O:5])=[N:26][N:27]=1)#[N:37]
Reactant: N#CCCC(=O)NN
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CCC#N)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 3-cyanopropanehydrazide (compound 140.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 439 (M+H)+. 1H-NMR (300 Hz, CD3OD): δ 7.68 (d, 2H), 7.58-4.47 (m, 3H), 7.30 (s, 1H), 4.89-4.80 (m, 1H), 3.65-3.62 (m, 1H), 3.32-3.30 (m, 1H), 3.15 (t, 2H), 3.03-2.95 (m, 4H), 2.50 (s, 3H), 2.42 and 2.32 (2 singlets, amide rotamers, ArCH3, 3H), 2.03-2.00 (m, 1H), 1.83-1.78 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([OH:28])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC=CC=1CCC1C=CC(C(OC)=O)=CC=1N)C1C=CC=CC=1.C(OC1C=CC=CC=1C=CC1C=CC(C(OC)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([OH:28])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=CCc2ccccc2OCc2ccccc2)cc1O
Agent: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c([N+](=O)[O-])c1
Agent: COC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)c(N)c1
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1O

Procedure:
Methyl 4-[3-(2-benzyloxyphenyl)propyl]-2-hydroxybenzoate was prepared from methyl 4-[3-(2-benzyloxyphenyl)propenyl]-2-hydroxybenzoate by the method described in Example 9 for the synthesis of methyl 4-[2-(2-benzyloxyphenyl)ethyl]-3-aminobenzoate from methyl 4-[2-(2-benzyloxyphenyl)ethenyl]-3-nitrobenzoate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C.[Na]>[CH2:15]([O:14][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)[CH3:16]
Reactant: CC[O-]
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=S)c1cnc(C)nc1OCC
Temperature: 0 °C
Yield: 283 %

Procedure:
An ice-cooled suspension of 50 g (215 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 300 ml of ethanol was treated dropwise with a solution of sodium ethoxide (prepared from 5.1 g (222 mg.atom) of sodium and 300 ml of ethanol). After 1 hour the mixture was evaporated and the residue partitioned between 400 ml of dichloromethane and 400 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 48 g (92%) of ethyl 4-ethoxy-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH+ =243].
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:26](O)[CH3:27]>>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: CCO
Reactant: O=C(O)C1CCC(N2CCCC2=O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCC(N2CCCC2=O)CC1
Temperature: 10 °C
Yield: 102 %

Procedure:
To 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid are added ethanol (30 mL, 10V/W) and conc. sulfuric acid (0.4 g, 0.2 W/W), and the mixture is heated to reflux for 3.5 hours. After cooling the reaction solution to 10° C., sodium bicarbonate (powder) is thereto added. After foaming is stopped, ethanol is evaporated under reduced pressure. The residue is extracted with ethyl acetate and saturated brine. The resultant solution is dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure to give ethyl 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylate (oil, 2.3 g, 102%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)N
Reactant: c1cc(OCC2CO2)ccc1OCCOCC1CC1
Product: CC(C)(C)NCC(O)COc1ccc(OCCOCC2CC2)cc1
Yield: 74 %

Procedure:
Following the procedure of Example I, 1-{4-[2-(cyclopropylmethoxy)-ethoxy]-phenoxy}-2,3-epoxy-propane is prepared and then treated with t-butylamine. 7.6 g (yield=74%) of crude 1{4-[2-(cyclopropylmethoxy)-ethoxy]phenoxy}-3-t-butylamino-propan-2-ol are thus obtained, and this material is converted to the fumarate by mixing stoichiometric amounts of the base and of the acid in solution in isopropanol. The neutral fumarate which has precipitated is filtered off and recrystallised from ethanol (yield=80%), M.p.=158°-160° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O>CO.[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCO/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 20 h
Yield: 89 %

Procedure:
8.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetate are dissolved in 150 ml of methanol and 45 ml of 2N aqueous sodium hydroxide solution. After 20 hours, 50 ml of water are added thereto. The methanol is then removed in vacuo. The aqueous solution is treated with 90 ml of 1N aqueous hydrochloric acid and concentrated to dryness. The residue is taken up in 200 ml of dimethylformamide. The sodium chloride is removed by filtration and the solution is concentrated to 50 ml. The acid is precipitated by the addition of acetonitrile. There are obtained 6.5 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetic acid. Yield: 6.5 g of melting point 180° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:31]C1C=CC(N=C=O)=CC=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][C:25]([OH:31])=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C=Nc1ccc(O)cc1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccc(O)cc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 4-hydroxyphenyl isocyanate in Step 1 of the synthesis. The expected product melts at 190°-194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](Cl)=[N:22][CH:21]=1)[CH3:17]>C[N-]C.O.[NH4+].[Cl-]>[OH:13][C:8]1[NH:9][C:10]2[C:6]([C:7]=1[C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:27])=[CH:21][N:22]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: C[N-]C
Agent: [Cl-]
Agent: [H-]
Solvent: O
Product: CCOC(=O)c1ccc(-c2c(O)[nH]c3ccc([N+](=O)[O-])cc23)nc1
Temperature: 135 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
To a cooled solution of 5-nitrooxindol (5.27 g, 29.6 mmol) in N,N-dimethylamide (50 mL) was added sodium hydride (1.4 g, 35 mmol) during 5 min at 0° C. After 10 min at 0° C., 6-chloronicotinic acid ethyl ester (5.0 g, 26.9 mmol) was added dropwise and the reaction was heated to 135° C. for 45 min. The mixture was diluted with water (200 mL) and saturated NH4Cl(aq) (100 mL). The formed precipitate was filtrated and washed with water, methanol, ethyl acetate and diethyl ether. The residual green yellow solid was dried to give 4.1 g (47% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 14.57 (s, 1 H), 11.24 (s, 1 H), 8.73 (s, 1 H), 8.26 (s, 1 H), 8.10 (d, J=9 Hz, 1 H), 7.92 (d, J=8 Hz, 1 H), 7.67 (d, J=9 Hz, 1 H), 7.03 (d, J=9 Hz, 1 H), 4.31 (q, J=7 Hz, 2 H), 1.32 (t, J=7 Hz, 3 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCOCC>[Si:1]([O:8][CH2:9][CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCC=O
Reaction time: 1.5 h

Procedure:
To a 500 ml round bottom flask was introduced 5.23 g (27.5 mmol) of 3-t-butyldimethylsilyloxypropanol (prepared according to the method of McDougal et al, J. Org. Chem. 1986, 51, 3388), to which was added 175 ml CH2Cl2, and 8.13 g (36.4 mmol, 1.3 eq) of pyridinium chlorochromate. The reaction was stirred 90 minutes, diluted with ether, and filtered through Florisil™. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using 10% ether in hexane. This afforded 2.63 g (50%) of the product, 3-t-butyldimethylsilyloxypropanal.
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: NCc1cc2cc(F)ccc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
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, 1 H), 8.07-8.11 (m, 2 H), 7.66-7.71 (m, 1 H), 7.59-7.66 (m, 1 H), 7.49-7.55 (m, 2 H), 7.40-7.46 (m, 1 H), 7.34-7.40 (m, 1 H), 4.05-4.17 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cncc(NC(=O)c3ccccc3)c2)cc1C
Solvent: CC(=O)O
Product: Cc1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1C

Procedure:
A solution of 1.0 g (3.7 mmol) of N-[5-(3,4-dimethylphenyl)pyridin-3-yl]benzamide in 120 ml of acetic acid was reacted according to General Method 6A. The solution was concentrated under reduced pressure. Yield: 1.85 g
Reaction SMILES: C([O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C@@H:19]([C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[F:27][C:26]([F:28])([F:29])[C@H:19]([O:18][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:30])=[O:8])=[CH:11][CH:12]=1)=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [H][H]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(C(=O)O)cc1)C(F)(F)F
Yield: 98.9 %

Procedure:
Then, 0.07 g of 5% palladium/carbon and 10 ml of a tetrahydrofuran solution containing 0.63 g of 4-((R)-1-trifluoromethylheptyloxycarbonyl)benzoic acid benzyl ester were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.49 g of 4-((R)-1-trifluoromethylheptyloxycarbonyl)benzoic acid as a colorless liquid (gradually crystallized) (isolated yield: 98%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[C:1]([NH:5][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 77 %

Procedure:
The preparation of Example 1 was repeated with the changes that tert-butyl amine (14.6 g, 0.200 mole) and 4-nitrobenzoyl chloride (18.6 g, 0.100 mole) were the starting reactants. This reaction produced 17.13 g of crystals of the desired product (77% yield), mp 162°-163° C. proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.257 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 6.097 ppm (bs, 1H; N-H); 1,500 ppm (s, 9H; tert-butyl H).