Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.C1(=O)[N:8]([O:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:25][CH:26]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCON3C(=O)c4ccccc4C3=O)cc2)S1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
0.32 ml of hydrazine monohydrate was added to a suspension of 2.64 g of 5-[4-(2-phthalimidooxyethoxy)-benzyl]thiazolidine-2,4-dione [prepared as described in step (d) above] in 30 ml of ethanol, and the resulting mixture was stirred at 80° C. for 2 hours. At the end of this time, the reaction mixture was cooled and the precipitated phthalhydrazide was filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:20 by volume mixture of methanol and methylene chloride as the eluent, to give 1.93 g of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Na+].Cl[O-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)Cc1ccccc1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of the objective compound of step (9) (87.8 g, 0.308 mol), 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (480 mg 3.07 mmol) and sodium bromide (31.7 g, 0.308 mol) in ethyl acetate (900 mL)-toluene (900 mL) were added 6% sodium hypochlorite aqueous solution (PURELOX, 410 mL, 0.34 mol) and a solution of sodium hydrogencarbonate (75 g, 0.89 mol) in water (540 mL) with dropwise over 1.5 hours under ice-cooling, and the mixture was stirred for 1 hour. This reaction mixture was extracted with ethyl acetate and the extract was washed successively with potassium iodide (2.5 g, 15 mmol)-containing 10% potassium hydrogensulfate aqueous solution (400 mL), 10% sodium thiosulfate aqueous solution (2×200 mL), 0.2 M phosphate buffer (pH 7, 500 mL) and saturated brine and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. To the residue were added ethyl acetate (150 mL) and hexane (500 mL), and the mixture was stirred at room temperature ˜0° C. for 5 hours. The resulting crystal crop was collected by filtration, washed with hexane-ethyl acetate (3:1, 300 mL) and dried in vacuo to give 63.28 g (73%) of N-benzyloxycarbonyl-DL-phenylalaninal as white crystals.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:21]=1)[CH2:10][N:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:21]=1)[CH2:10][N:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydroxylamine (50% in water) (539.42 μL; 8.98 mmol; 5 eq.) was added to a solution of tert-butyl N-(5-cyano-2-fluorobenzyl)-N-methylglycinate, obtained in step 1 (500 mg; 1.80 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at RT for 24 hours. Solvent was evaporated in vacuo and the resulting oily residue was freeze-dried to afford the title compound as a colourless oil (602 mg; quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.73 (dd, J=7.3, 2.3 Hz, 1H), 7.62-7.56 (m, 1H), 7.20-7.12 (m, 1H), 5.81 (s, 2H), 3.71 (s, 2H), 3.20 (s, 2H), 2.28 (s, 3H), 1.43 (s, 9H). LC/MS (Method B): 310.1 (M−H)−, 312.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=2[N:10]=[CH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1

Procedure:
18 g (0.1 mol) of 3-ethylxanthine were stirred at 60° C. for 2 hours with 19.2 g (0.11 mol) of benzyl bromide and 15.2 g (0.11 mol) of potassium carbonate. The reaction solution was transferred to an Edenmeyer flask and treated with 1000 ml of water. The precipitate was filtered off with suction, washed several times with warm water and dried at 50° C. under reduced pressure.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([NH:31][CH2:32][CH2:33][CH3:34])=[C:7]([O:12][CH2:13][CH:14]([OH:30])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:8]=[CH:9][C:10]=1[CH3:11].[C:35](Cl)(Cl)=[O:36]>>[OH:30][CH:14]([CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:21]1)[CH2:13][O:12][C:7]1[C:6]2[N:31]([CH2:32][CH2:33][CH3:34])[C:35](=[O:36])[NH:4][C:5]=2[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCCNc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)ccc(C)c1N
Agent: Cl
Product: CCCn1c(=O)[nH]c2c(C)ccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c21
Yield: 54 %

Procedure:
In a manner analogous to that described in Example 1, from 3-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylaminobenzene trihydrochloride and phosgene, there is obtained, in a yield of 54% of theory, 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-7-methyl-3-propyl-2-benzimidazolinone; m.p. 234°-235° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[NH:15]([C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH3:14])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COC(=O)Cc1c(Cl)nc(C)nc1Nc1ccccc1
Temperature: 50 °C
Yield: 37.2 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine-5-acetic acid, methyl ester (8.5g, 36mM) and aniline (4.7g, 49mM) was heated at 50° C. for 13 hours. Methylene chloride (300ml) was added to the cooled mixture and the mixture filtered. The liltrate was washed with 2M hydrochloric acid (1×170ml, 1×85ml) and water. The organic layer was separated, stirred with 2M sodium hydroxide (110ml) and then separated. The aqueous layer was extracted with methylene chloride (2×85ml). The organic layers were combined, washed with water, over anhydrous magnesium sulphate and the solvent evaporated to afford a solid. This solid was purified by flash column chromatography on silica (Merck 9385), eluting with ethyl acetate/hexane (20:80 v/v) to give 4-anilino-6-chloro-2-methylpyrimidine-5-acetic acid, methyl ester (3.92g, 48.6%), m.p. 115°-116° C.; microanalysis, found; C,57.7; H, 4.5; N, 14.2%; C14H14N302. requires C, 57.6; H, 4.8; N, 14.4%; NMR: 2.53(3H,s,2-CH3), 3.79(3H,s, COOCH3), 3.80(2H,s,CH2), 7.05-7.65(5H, complex, aromatic), 7.9-8.0 (1H, broad,N--H).
Reaction SMILES: ClCCl.[C:4]1([OH:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>O>[C:22]([O:14][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: Oc1cccc2ccccc12
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1cccc2ccccc12
Temperature: -5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
An oven dried 250 mL 2 neck round bottom flask fitted with a dropping funnel and guard tube under inert atmosphere was charged with 100 mL of dry dichloromethane, 1-naphthol (1) (5.0 g, 34.6 mmol) and triethyl amine (7.0 g, 70.0 mmol). The flask was cooled to −5° C. (ice & water bath), methacryloyl chloride (2) (5.4 g, 52.0 mmol) was added slowly over a period of 15 min at −5° C. The reaction was stirred for 2 h at −5° C. and allow to warm to room temperature and stirred for another 2 h at room temperature. Reaction was monitored by TLC (until naphthol was absent). Reaction mixture was poured into a 500 mL separating funnel and the organic layer was washed with water and aq. Na2CO3 The organic layer were again washed with water and dried over anhydrous Na2SO4. DCM was removed under reduced pressure and the product was a viscous oil (compound 3) (6.61 g, yield 90%).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:5]([Cl:13])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O.O>CCOCC>[Cl:13][C:5]1[C:4]([Cl:3])=[CH:12][C:8]([C:9](=[O:11])[CH3:1])=[CH:7][N:6]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
62 ml of a 1.6 M solution (100 mmol) of methyllithium in ether are added to a solution of 9.6 g (50 mmol) of 5,6-dichloronicotinic acid in 250 ml of absolute ether at 0° C. When the addition has ended, the mixture is subsequently stirred at 0° C. for a further 30 minutes and 200 ml of water are then added, while cooling with ice. The phases are separated and the aqueous phase is extracted once more with 50 ml of ether. The combined organic phases are dried over sodium sulphate and evaporated. 9 g (95% of theory) of 2,3-dichloro-5-acetylpyridine, melting point 80° C., are obtained.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:49]2[CH2:48][CH2:47][N:46]([CH2:45][C:41]3[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=3)[C:38]([NH:37][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:52])[CH2:51][CH2:50]2)=[O:26])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (5.90 g, 9.2 mmol, 5.52 mL) was added dropwise to a solution of 4-ammo-5-chloro-2-ethoxy benzoic acid (1 g, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.40 g, 5.1 mmol) and triethylamine (1.401 g, 13.8 mmol, 1.93 mL) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (2.08 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([O-:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([NH2:64])[C:54]1[CH:63]=[CH:62][C:59]([O:60][CH3:61])=[C:56]([O:57][CH3:58])[CH:55]=1>>[CH3:58][O:57][C:56]1[CH:55]=[C:54]([CH:63]=[CH:62][C:59]=1[O:60][CH3:61])[CH2:53][NH:64][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A mixture of 5.8 g of the compound obtained in Step 6.1, 7.02 g of DIEA and 12.38 g of HBTU is stirred for 30 minutes at room temperature. 4.37 g of veratrylamine are then added and the resulting mixture is stirred overnight at room temperature. The resulting mixture is evaporated under reduced pressure and the residue is taken up in EtOAc. This solution is washed with water and then sequentially with 1N HCl solution, with water, with saturated NaHCO3 solution, with water and with saturated NaCl solution. The resulting solution is dried over Na2SO4 and filtered, and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with an EtOAc/heptane mixture from (50/50, v/v) to (70/30, v/v) to give 7.7 g of the expected product.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S([O:62][CH2:63][CH2:64][O:65][S:66]([C:69]2[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=2)(=[O:68])=[O:67])(=O)=O)=CC=1>CN(C)C=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C@H:15]([NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:37][CH2:38]2)[CH2:25]1)=[O:23])[C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:62][CH2:63][CH2:64][O:65][S:66]([C:69]2[CH:70]=[CH:71][C:72]([CH3:75])=[CH:73][CH:74]=2)(=[O:67])=[O:68])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 200 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (25.3 mL). Cesium carbonate (298 mg, 0.92 mmol) and ethylene glycol bis-p-toluenesulfonate (203 mg, 0.55 mmol) were added. The mixture was stirred at room temperature for 2 hours and stored at 5° C. for 17 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 109 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-methoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[NH2:10][C:11](N)=[S:12]>Cl.C(O)(C)C>[NH2:10][C:11]1[S:12][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: Nc1ccccc1CO
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(C)O
Product: NC1=Nc2ccccc2CS1
Yield: 64 %

Procedure:
2-aminobenzylalcohol (2.0 g, 16 mmol) in conc. HCl (10 ml) is heated at 100° C. for 15 minutes in a sealed vial, the resulting precipitate is filtered, washed with diethyl ether to give a white solid which is dissolved in isopropanol (20 ml) and treated with thiourea. The resulting reaction mixture is refluxed for 20 hours then concentrated, and the residue taken up with H2O and basified with 2 N NaOH. The basic solution thus obtained is extracted with CH2Cl2. The organic extracts are combined, washed with H2O, dried over Na2SO4 and then concentrated. The residue is purified by chromatography through silica, eluting with petroleum ether/AcOEt (1:1), and then recrystallised from EtOH to give the desired product as a pale yellow solid, m.p. 132-135° C., with a yield of 64%. 1H-NMR (CDCl3): 3.90 (s, 2H), 5.09 (br s, 2H), 7.00-7.12 (m, 3H) 7.20-7.28 (m, 1H). 165 (M+H+). The compound is more stable as the oxalate salt, m.p. 178-182° C., prepared by precipitation with oxalic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][NH:15]3)=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:10]=2)[CH2:3]1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:24][C:14]1[NH:15][C:16]2[C:12]([N:13]=1)=[C:11]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[N:10]=[C:9]([N:4]1[CH2:5][C@@H:6]([CH3:8])[O:7][C@@H:2]([CH3:1])[CH2:3]1)[N:17]=2
Reactant: BrBr
Reactant: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc[nH]c3n2)C[C@H](C)O1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a solution of 2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (860 mg, 2.70 mmol) in CH2Cl2 (5 mL) was added bromine (0.04 mL, 3.24 mmol). The mixture was stirred at ambient temperature for 3 hours. Saturated sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane two times. Organic layers were combined and dried over Na2SO4 and solvent was removed under reduced pressure. The crude was purified by flash column chromatography (0-70% EtOAc/Heptane gradient) to furnish product as an off-white solid (362.1 mg, 34%). LC/MS analysis using method 7, mass (ES+) m/z 399.1 1HNMR (CDCl3): 4.31 (2H, d), 4.09 (4H, brs), 3.74 (4H, m), 3.59 (2H, m), 2.51 (2H, m), 1.18 (6H, d).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1C(O)=O.CN(C=O)C.C(Cl)(=O)[C:19]([Cl:21])=[O:20]>CC1OCCC1>[S:1]1[CH:2]=[C:3]([C:19]([Cl:21])=[O:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: O=C(Cl)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To benzothiophene carboxylic acid (7 g) in MeTHF (6.5 Vols, 45.5 mL) is added a catalytic amount of DMF (0.01 eq.). Then, oxalyl chloride (1.1 eq.) is charged slowly to control the gaz release. After 16 h of stirring at 20° C., the end of the reaction is controlled by HPLC. MeTHF (6.5 Vols) is next added and the reaction mixture is concentrated to 5 volumes to remove the excess of oxalyl chloride. The resulting benzo[b]thiophene-3-carbonyl chloride is stored in a MeTHF solution.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:15]2[CH2:16][CH2:17][NH:12][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CCOC(=O)C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
2-Bromo-6-(trifluoromethyl)pyridine (13.56 g, 60 mmol) and ethyl piperazine-2-carboxylate (U.S. Patent App. Publ. US2004/0147559, 9.49 g, 60.0 mmol) were mixed in dry dimethyl sulfoxide (40 mL) and then treated with N,N-diisopropylethylamine (31.1 mL, 180 mmol). The mixture was heated to 80° C. and stirred for 4 days. The solution was concentrated, and the residue was purified on a silica gel column (hexane:ethyl acetate=1:3) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.27 (t, 3H, J=7 Hz), 2.83 (ddd, 1H, J=12, 9, 3 Hz), 3.11 (ddd, 1H, J=12, 5, 3 Hz), 3.33-3.38 (m, 1 H), 3.41-3.50 (m, 1 H), 3.56-3.62 (m, 1 H), 3.81 (ddd, 1H, J=13, 4, 3 Hz), 4.15-4.25 (m, 3 H), 7.00 (t, 2H, J=8 Hz), 7.65-7.75 (m, 1 H); MS (DCI) m/z 304 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:16][N:17]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc(Br)cc1
Reactant: CN1CCCC1=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCCCCOc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 73 %

Procedure:
Prepared using General Procedure 1: A stirred a solution of 1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73 g, 14.74 mmol) and tetrakis (triphenylphosphine) palladium (76.12 mg, 0.07 mol) in dry NMP (20 mL) was degassed with N2. The reaction was heated to 100° C. for 18 h while stirring under nitrogen. The reaction mixture was cooled and poured into water (100 mL) and DCM (20 mL). The solid material was removed by filtration and the filtrate was extracted with water (3×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C14H19NO: 217.1. found 218.1 [M+H]+, tR=11.14 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H), 3.99 (t, J=6.5 Hz, 2H), 1.89-1.69 (m, 2H), 1.58-1.12 (m, 8H), 0.90 (dd, J=9.1, 4.5 Hz, 3H). 13C NMR (101 MHz CDCl3) δ 162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18, 103.58, 68.41, 31.73, 28.98, 25.89, 22.58, 14.07.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCOCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.5 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (91 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. To obtain 4 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).