Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C:19](=O)[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>C(O)C>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][CH:19]([NH2:28])[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: NC1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A reaction mixture was prepared from 2.7 g. of 1-benzoyl-4-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 7.7 g. of ammonium acetate and 125 ml. of ethanol. 590 mg. of sodium cyanoborohydride were added and the resulting suspension stirred at ambient temperature for 22 hours. The reaction mixture was then poured over an ice-1N hydrochloric acid mixture and the acidic aqueous layer extracted with chloroform. The aqueous layer was then made basic with 14N aqueous ammonium hydroxide and the alkaline layer extracted several times with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded a residue which was shown to be essentially one spot material by TLC. The residue was recrystallized from a mixture of methylene dichloride and ether to yield crystals of 1-benzoyl-4-amino-1,2,2a,3,4,5-hexahydrobenz-[cd]indole melting at 118°-120° C.; yield 825 mg.
Reaction SMILES: [CH3:1][O:2][P:3]([O-:6])[O:4][CH3:5].[H-].[Na+].[O:9]([CH2:16][CH2:17][CH2:18]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:18][CH2:17][CH2:16][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[O:4][CH3:5]
Reactant: BrCCCOc1ccccc1
Reactant: COP([O-])OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(CCCOc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Dimethylphosphite (5.0 g, 45 mmol) was cautiously added to a suspension of NaH (60% dispersion, 2.0 g, 50 mmol) in DMF (45 mL) at 0°. After 2 h, 3-phenoxy propylbromide (10.75 g, 50 mmol) was added, and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure, the residue dissolved in water (100 mL), extracted with Et2O, and the combined extracts washed with water, brine and dried (MgSO4). The solution was concentrated at reduced pressure to give 10.28 g of crude product. A portion of the crude material (5 g) was distilled to afford 52 (3.4 g, 63%) as a colourless oil. 13C NMR (CDCl3) δ 21.4 (d, J=141.8 Hz), 22.7 (d, J=4.5 Hz), 52.5 (d, J=6.8 Hz), 67.2 (d, J=15 Hz), 114.6, 121.0, 129.6, 158.8. ESMS 245 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Nc1cc(F)c(F)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(F)c(F)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (144 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (297 mg, 1.0 mmol) in xylene (6 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as an off-white solid (224 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:20][CH2:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[N:23]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 2,6-dichloropurine (0.062 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (5 mL). 2-Chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=615 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1 H, s), 8.15 (1 H, s), 8.04 (1 H, dd, J=8.5, 1.2 Hz), 7.96 (1 H, d, J=6.7 Hz), 7.60 (1 H, d, J=7.3 Hz), 7.61 (1 H, t, J=7.9 Hz), 7.54 (1 H, d, J=6.7 Hz), 7.50 (1 H, t, J=6.7 Hz), 7.44 (1 H, t, J=7.3 Hz), 4.62 (2 H, d, J=26.9 Hz) Mass Spectrum (ESI) m/e=455.0 and 457.0 (M+1)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[CH3:6])[N:15]=[CH:16][C:17]=12
Reactant: Cc1ccc(C)c(-n2ncc3c(O)ncnc32)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C)c(-n2ncc3c(Cl)ncnc32)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Phosphorus oxychloride (7.76 mL, 83.24 mmol) was added to 1-(2,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (1 g, 4.16 mmol). The resulting solution was stirred at 100° C. for 2 hours. LCMS showed reaction was complete. The reaction mixture was evaporated. Ice/water and then EtOAc were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with water, dried (MgSO4) and concentrated to give crude product (1.077 g, 100%) which was used without purification. 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 2.35 (3H, s), 7.26-7.37 (3H, m), 8.72 (1H, s), 8.86 (1H, s); m/z (ES+) (M+H)+=259; HPLC tR=2.48 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[C:33]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)#[N:34]>>[C:33]([C:35]1[CH:36]=[C:37]([O:41][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1)#[N:34]
Reactant: N#Cc1cccc(O)c1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(C#N)c4)cn3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 3-cyanophenol using a method similar to that described for D73 in Description 73 although the reaction was worked up after the first night of heating. MS (ES): MH+ 542.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1-(3-chlorophenyl)-2-nitro-ethanol (26 g, 0.14 mol) in DMF (50 mL) were added imidazole (28.6 g, 0.42 mol) and chlorotriethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude product was purified by flash chromatography (2% EtOAc/hexane) to yield the title compound (37 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (1H, s), 7.27–7.32 (3H, m), 5.40 (1H, dd, J=3.2, 9.5 Hz), 4.51 (1H, dd, J=9.5, 12.1 Hz), 4.36 (1H, dd, J=3.3, 12.1 Hz), 0.85 (9H, t, J=7.5 Hz), 0.54 (6H, q, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-chlorophenyl)piperazine (1.62 g, 8.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.06 g, 8.6 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound L, 2.11 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([O:18]CC)=[O:17])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
Ethyl 1-(4-chlorobenzyl)-1H-indole-2-carboxylate (2.00 g, 6.37 mmol) and lithium hydroxide (1.53 g, 63.7 mmol) were dissolved in THF:water (10 mL: 20 mL). The reaction was heated at 60° C. overnight. The reaction was cooled and further diluted with water. The reaction was transferred into a separatory funnel and was washed with diethyl ether. The aqueous layer was acidified using 2N HCl to pH 2 where a white solid formed. The suspension was returned to the separatory funnel and was washed with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain pure product as a white solid. Yield: 1.47 g, (White solid).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>C(O)(C)(C)C.ClCCl>[Cl:16][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)nc1NCC1CC1
Temperature: 170 °C
Yield: 107.1 %

Procedure:
In a sealable tube, 3 g (42 mmol) of cyclopropylmethylamine is added to 3 g (14 mmol) of 2,6-dichloronicotinic acid in solution in tert-butanol (14 ml), the tube is sealed and heated at 170° C. for 30 minutes in a Biotage Initiator microwave. The reaction mixture is cooled to room temperature, diluted in dichloromethane (100 ml) and washed with a 10% aqueous solution of acetic acid (12 ml). The organic phase is dried over Na2SO4, filtered, concentrated and dried under vacuum. 3.4 g of product is obtained in the form of an orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1CCCCN1c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), 2-methylpiperidine (1.76 mL), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 22 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.85 g, 87%) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:11]=1>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: Oc1ccc2c(c1)C=CCO2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Oc1ccc2c(c1)CCCO2
Reaction time: 0.67 h
Yield: 92.1 %

Procedure:
The 6-hydroxybenzopyran (1.5 g; 10 mM) was dissolved in 100 ml of anhydrous benzene along with Wilkinson's catalyst (280 mgs; 0.30 mM). This hydrogenation bottle containing this reaction mixture was first flushed with nitrogen and then with hydrogen. The bottle was pressurized to 40 psi in a Paar shaker and agitated for 40 minutes at which time the pressure in the bottle (400 ml dead volume) had dropeed to 30 psi and was dropping no further. The bottle was then flushed with nitrogen and the solvent was removed in vacuo. The residue was taken up in ether and filtered through a pad of celite. The solvent was removed and the oil was purified by flash chromatography on a 30 mm×6" column of silica gel eluted with 600 ml of 20% ethyl acetate in hexane. This purification produced 1.40 g (93%) of 2,3-dihydro-6-hydroxybenzopyran as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:68]=[CH:67][C:5]([CH2:6][CH:7]2[C:30](=[O:31])[N:29]([CH3:32])[CH:28]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:27](=[O:37])[O:26][CH:25]([CH3:38])[CH2:24][N:23]([CH3:39])[CH:22]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:21](=[O:44])[O:20][CH:19]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=3)[C:18](=[O:53])[N:17]([CH3:54])[CH:16]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:15](=[O:59])[O:14][CH:13]([CH3:60])[CH2:12][N:11]([CH3:61])[CH:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:9](=[O:66])[O:8]2)=[CH:4][CH:3]=1.[C:69]1(=[O:79])O[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12>C(O)(=O)C>[C:69]1(=[O:79])[N:52]([C:49]2[CH:50]=[CH:51][C:46]([CH2:45][CH:19]3[C:18](=[O:53])[N:17]([CH3:54])[CH:16]([CH2:55][CH:56]([CH3:57])[CH3:58])[C:15](=[O:59])[O:14][CH:13]([CH3:60])[CH2:12][N:11]([CH3:61])[CH:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:9](=[O:66])[O:8][CH:7]([CH2:6][C:5]4[CH:67]=[CH:68][C:2]([N:1]5[C:69](=[O:79])[C:70]6=[CH:78][CH:77]=[CH:76][CH:75]=[C:71]6[C:72]5=[O:73])=[CH:3][CH:4]=4)[C:30](=[O:31])[N:29]([CH3:32])[CH:28]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:27](=[O:37])[O:26][CH:25]([CH3:38])[CH2:24][N:23]([CH3:39])[CH:22]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:21](=[O:44])[O:20]3)=[CH:47][CH:48]=2)[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12
Reactant: CC(C)CC1C(=O)OC(Cc2ccc(N)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccc(N)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CC(C)CC1C(=O)OC(Cc2ccc(N3C(=O)c4ccccc4C3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccc(N3C(=O)c4ccccc4C3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C

Procedure:
475.6 mg (0.50 mmol) of 8,20-bis-(4-aminobenzyl)-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (for example from Example 4) were initially charged in 1.5 ml of glacial acetic acid and heated under reflux with 162.9 mg (1.1 mmol) of phthalic anhydride for 5 h. The mixture was concentrated, the residue was taken up in tertbutyl methyl ether (MTBE) and washed with sodium bicarbonate solution and saturated sodium chloride solution. The solution was dried with sodium sulfate, reconcentrated and subsequently filtered over a short silica gel column (Ø=3 cm, l=5 cm) using cyclohexane/ethyl acetate 2:1. Evaporation of the filtrate gave 0.55 g of slightly contaminated 8,20-bis-(4-phthalimidobenzyl)-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2N(C)C(=O)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[H-].[Na+].C(O[C:26](=[O:30])[O:27][CH2:28][CH3:29])C.[Cl-].[Na+]>CN(C)C=O>[CH2:28]([O:27][C:26]([C:9]1[NH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20]2)=[O:30])[CH3:29]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reaction time: 0.25 h

Procedure:
A solution of 28.5 g. of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 400 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.25 mol. of sodium hydride (11.0 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. The suspension is then treated at -10° C. to -5° C. with a solution of 35.5 g. of diethylcarbonate in 50 ml. of dimethylformamide. The mixture is stirred firstly for 1 hour at 20° C., then for an additional 4 hours at 60° C. and finally poured onto a mixture of 100 g. of sodium chloride and 2.5 kg. of ice. The precipitate is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The crystalline residue is heated to reflux with 500 ml. of ethanol for 10 minutes and then cooled in an ice-bath. After filtering and washing with ethanol and ether, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in the form of greenish crystals; melting point 208°-210° C. (decomposition). Crystallization from acetonitrile does not increase the melting point.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:61]1([CH2:67][SH:68])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O1CCOCC1.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]>[CH2:67]([S:68][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)cccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(Br)cccc1SCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2,6-dibromotoluene (20 g, 100 mmol) in dioxane (160 ml) was stirred under argon. Then, DIPEA (30.9 ml, 160 mmol), xantphos (2.77 g, 4.8 mmol) and Pd2(dba)3 (2.4 g, 2.4 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (9.4 ml, 80 mmol) was slowly added and the reaction stirred for 6 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction (three times) with ethyl acetate, the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.CCOC(C)=O>[C:11]([C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[N:12]
Reactant: COc1ncc(Br)cc1C
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc(C#N)cc1C
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 5-bromo-2-methoxy-3-methyl-pyridine (1.0 g, 5.0 mmol) in DMF (10 ml) was added CuCN (0.534 g, 6.0 mmol) and the resulting mixture is heated at reflux for 28 h. After cooling to room temperature the mixture is diluted with EtOAc and washed with 10% ammonia solution followed by water and brine solution. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/Hexane) to give 5-cyano-2-methoxy-3-methyl-pyridine (36) (0.68 g, 93%).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)(Cl)Cl>[CH2:6]([O:10][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOP(=O)(Cl)Cl

Procedure:
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 8A, using 1.25 ml (13.5 mmol) of phosphorous oxychloride, 1 g (13.5 mmol) of butanol in 5 ml of carbon tetrachloride to provide a colorless oil.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].Cl[CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 4-(n-hexadecylamino)benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The soluion which forms after one hour is treated with 11.0 g of 1-chloro-2,3-propanediol and is then stirred at 60° C for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate melting at 112°-113° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=1>[Pd].C(O)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2]1
Reactant: CCOC(=O)c1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNc2ccccc2C1
Temperature: 50 °C
Reaction time: 52 h

Procedure:
Ethyl quinoline-3-carboxylate (Aldrich, 15.44 g, 76.7 mmol) was added to a mixture of ethanol (150 mL) and 10% palladium on carbon (3.0 g) in a Parr shaker. The glass reactor was sealed and flushed with nitrogen, and pressurized with hydrogen (60 psi). The mixture was shaken at 50° C. for 52 hours. The solids were filtered, rinsed with methanol, concentrate under reduced pressure, and chromatographed on silica gel eluting with 5-40% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.12 Hz, 3H), 2.83 (m, 3H), 3.17 (m, 1H), 3.39 (m, 1H), 4.09 (q, J=7.12 Hz, 2H), 5.74 (s, 1H), 6.44 (m, 2H), 6.86 (m, 2H). MS (DCI) m/z 206.10 (M+H)+.