Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:28])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=1.CC#N.CC(O)=O.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=4)[CH2:15][C:14](=[O:28])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Br
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Br)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Temperature: 90 °C
Yield: 55.1 %

Procedure:
A mixture of 16A (2 g, 4.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 16B (1.1 g, 55% yield).
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=3)=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[CH:25][C:24]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]CCCl>>[ClH:50].[CH3:22][C:23]1[N:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:26]=[CH:25][C:24]=1[CH2:34][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=3)=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)c1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cnn(-c4ccccc4)c3C)CC2)cc1
Product: Cl
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Dissolve 1-[4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-ethanone (0.250 g, 0.885 mmol) in 1,2 dichloroethane (4 mL). Add 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (1.5 eq., 0.250 g, 1.33 mmol). Stir for 30 min. Add sodium triacetoxyborohydride (2.0 eq., 0.375 g, 1.77 mmol). Stir at room temperature for 48 hr. Purify by SCX column followed by normal phase chromatography with a gradient of 100% EtOAc to 5% 7N ammonia in methanol/EtOAc to give the freebase of the title compound, (0.312 g, 78% yield). MS (ES): m/z=453.2[M+H]. Dissolve in a mixture of acetonitrile (2 mL) and water (3 mL). Add aq. 1N HCl (1 eq., 0.69 mmol, 0.69 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.268 g, 80% yield). MS (ES): m/z=453.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[N:35]([CH:37]=[O:38])C.CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([C:37](=[O:38])[NH2:35])=[CH:4][CH:3]=1
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(C(N)=O)c2C1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 71 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran (2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol), 1,3-bis(diphenylphosphino)propane (95 mg, catalytic amount), palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated two times). The reaction mixture was stirred at 70° C. for 7.5 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/sat. NaHCO3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a crude which was purified by flash chromatography (SiO2, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71% yield).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[C:33]([CH3:35])[N:34]=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:32]3[S:31][C:30]([CH3:29])=[N:34][C:33]=3[CH3:35])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3sc(C)nc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) were dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroian-2-yl)-1,3-thiazole (78 mg, 0.325 mmol, available from Maybridge), followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. for 18.5 hours reaction time. The reaction mixture was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter extracted twice more using EtOAc (2×40 mL). Organic fractions were combined, dried (brine (80 mL) and sodium sulfate), filtered and evaporated to dryness to give a pale white solid (0.123 g). This was purified on a 25+M Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 1:3). Product-containing fractions were evaporated to dryness to give a clear, colourless solid which was repurified on a 12+M column using the same solvent system. Analysis of the product still showed contamination and it was further purified using MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (41 mg). LCMS (Method C): Rt=0.76, MH+=402
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=O)=[C:8]([OH:18])[N:7]=[C:6]([CH3:19])[N:5]=1)[CH3:2].CN(C)C1C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[O:18][C:8]=2[N:7]=[C:6]([CH3:19])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(C)nc(O)c1NC(=O)c1ccco1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1nc(C)nc2oc(-c3ccco3)nc12
Yield: 77.3 %

Procedure:
A mixture of 4-ethoxy-5-(2-furanylcarbonyl)amino-6-hydroxy-2-methylpyrimidine (2.07 g, 7.87 mM), phosphorus oxychloride (30 ml) and dimethylaniline (1.5 ml, 11.7 mM) was heated at reflux for one hour. After cooling, the excess phosphorus oxychloride was removed by distillation under reduced pressure. Ethanol was then added, and the mixture partitioned between methylene chloride and water. The organic layer was separated, washed with sodium bicarbonate, water, dilute hydrochloric acid, water, and dried. The solvent was then removed by distillation under reduced pressure. Ethanol (10 ml) was added and the solid filtered off. This solid was further purified by flash column chromatography eluting with ethyl acetate/hexane (1:3). There was thus produced 7-ethoxy-5-methyl-2-(2-furyl)-oxazolo[5,4-d]pyrimidine (1.49 g, 77% yield); m.p. 104°-105.5° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH2:16])[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH:16][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c3c2n1CCC3
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1CCC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A mixture of (5)-1-(7-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethylamine (48.5 mg, 0.221 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (52.9 mg, 0.221 mmol), and DIPEA (0.113 mL, 0.663 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (3 mL) and the resulting solution was cooled in an ice bath. HCl in isopropanol (1.25 M, 2 mL) was added and the mixture stirred at 0° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-14% 2M NH3/MeOH in DCM) afforded 398 as a white solid (43.4 mg, 58%). LCMS (Method J): RT 4.80 min [M+H]+ 338.2. 1H NMR ((CD3)2SO, 400 MHz): 12.81 (1H, bs), 8.23 (1H, s), 8.15 (1H, s), 7.96 (1H, d, J=7.8 Hz), 7.37 (1H, dd, J=8.8, 4.2 Hz), 6.92 (1H, dd, J=10.5, 8.8 Hz), 5.80 (1H, bs), 4.29-4.16 (2H, m), 2.87 (2H, t, J=6.1 Hz), 2.16-2.05 (2H, m), 1.68 (3H, d, J=6.8 Hz)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1

Procedure:
Under an argon atmosphere, to a mixture of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (1.80 g, 6.76 mmol) in CH2C2 (15 mL) was added DMF (4 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (1.20 mL, 14.2 mmol) at 0° C. and the mixture was stirred for an hour while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=3)[C:10]2=[O:21])[CH2:5]1)=[N+]=[N-].C(O)C>ClCCl>[NH2:1][C@H:4]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=3)[C:10]2=[O:21])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Solvent: CCO
Solvent: ClCCl
Product: N[C@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1

Procedure:
Trans 2-(3-azido-cyclopentyl)-5,6-dichloro-isoindole-1,3-dione (0.727 g, 2.24 mmol) and lindlar catalyt (0.36 g) was added to a mixture of ethanol and dichloromethane and placed under a hydrogen balloon overnight. The mixture was filtered and the solid rinsed with dichloromethane. The organic layers were concentrated in vacuo, dissolved in methanol and diluted with acetonitrile. The solid was removed by filtration and the filtrate purified by preparative TLC (dichloromethane/methanol/triethylamine). The solid and material from TLC was recrystallized from MeCN/MeOH to give trans 2-(3-amino-cyclopentyl)-5,6-dichloro-isoindole-1,3-dione as an off white solid (0.145 g, contains also trans 2-(3-amino-cyclopentyl)-5-chloro-isoindole-1,3-dione)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc[nH]c1=O
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Temperature: 80 °C

Procedure:
28.5 g (228 mol) of 3-methoxypyridin-2(1H)-one are dissolved in 850 ml of dimethyl sulfoxide and admixed at RT with 31 g (273 mmol) of potassium tert-butoxide. The suspension is stirred at RT for 30 min, before 35 g (228 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added, and the reaction solution is heated to 80° C. for 20 h. The mixture is then cautiously diluted with 1 l of water and brought to pH 1-2 with 1N hydrochloric acid. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid is washed with a little tert-butyl methyl ether, filtered off and dried under reduced pressure. This affords 42.8 g (72% of theory) of the desired compound.
Reaction SMILES: C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:6].[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CS(C)=O>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:6])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.0 g (2.5 mmol) diethylenetriamine pentaacetic acid in 50 ml dimethyl sulfoxide (DMSO) was added 1.28 g (6.25 mmol) dicyclohexyl carbodiimide (DCC) and this was stirred for 24 hr at room temperature. During this time the granular solid of DTPA was consumed and the white fluffy solid of dicyclohexyl urea formed. The reaction mixture was filtered and washed with DMSO. The filtrate was split into two equal volumes. The first fraction was concentrated to a thick oil under reduced pressure and heat. A solid precipitated from the oil upon the addition of 30 ml acetonitrile. The solid was collected by filtration, washed with cold acetonitrile and dried under vacuum to give 0.32 g (68%) of a brown solid mp 110°-130° C. NMR analysis revealed an average of one anhydride/DTPA.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][CH2:32]Cl>CN(C=O)C.CCOC(C)=O>[Cl:30][CH2:31][CH2:32][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) were added potassium carbonate (0.220 g, 1.58 mmol) and 1,2-dichloroethane (0.50 m, 6.32 mmol). The reaction was heated to 130° C. via microwave irradiation and held at that temperature for 1 hour. The reaction was then diluted with EtOAc, washed with water and brine and dried over Na2SO4 before being concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 0-50% EtOAc in hexane as eluant to afford 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.11 g, 0.29 mmol, 92%) as a white solid. LCMS (1) 2.25 min; m/z (ES+) 379/381.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[C:19]([O:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH:18]=2)=[O:16])[CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[NH:3])[NH2:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:18]=2)=[O:16])[CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[NH:2])[NH2:3]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Reaction time: 5 h

Procedure:
To the solution of the compound prepared in (d) (50 mg, 0.089 mmole) in anisole was added trifluoroacetic acid under ice-cooling. The mixture was stirred for 5 hours, during which the temperature of the mixture was left rising up to room temperature. After isopropyl ether was added to the reaction mixture, solids deposited were collected to give 31 mg of the title compound as the colorless solid (yield, 62%).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12](CC([Cl:19])=O)([CH3:15])([CH3:14])[CH3:13].[CH3:20][CH2:21][O:22]CC>FC(F)(F)C(O)=O>[C:12]([CH:5]([N+:2]([CH3:3])([CH3:4])[CH3:1])[C:6]([C:21](=[O:22])[CH3:20])([CH2:7][C:8](=[O:10])[O-:9])[OH:11])([CH3:15])([CH3:14])[CH3:13].[Cl-:19]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CCOCC
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(O)(CC(=O)[O-])C(C(C)(C)C)[N+](C)(C)C
Product: [Cl-]

Procedure:
Carnitine chloride (1.97 g; 0.01 moles) was dissolved in trifluoroacetic acid (10 cc). To the solution tert-butyl acetyl chloride (1.4 cc; 0.01 moles) was slowly added under stirring. The resulting mixture was kept under stirring at room temperature for 48 hours. To te mixture Et2O was added and the thus obtained precipitate was filtered off. The raw product was crystallized from isopropanol-ethyl ether, thus obtaining a pure product. MP 164°-165° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](N(CC)C(C)C)([CH3:33])[CH3:32].[CH2:40](Br)[CH:41]=[CH2:42]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:42][CH:41]=[CH2:40])[CH2:33][CH:31]=[CH2:32])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 56.6 %

Procedure:
To a solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (156 mg, 0.39 mmol) in CH2Cl2 (4 mL) was added N,N-diisopropylethylamine (65 μL, 0.37 mmol). Allyl bromide (35 μL, 0.40 mmol) was added dropwise and the resultant mixture stirred at room temperature for 3 days. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed consecutively with H2O (2×5 mL), saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford a light yellow foam (100 mg). Purification by column chromatography on silica gel (200:1:1 followed by 100:1:1—CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (1000:1:1—EtOAc:MeOH:NH4OH) afforded AMD9725 (24.5 mg, 14%) as a light yellow foam. 1H NMR (CDCl3) δ 1.62-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.22-2.30 (m, 1H), 2.66-2.77 (m, 1H), 2.77-2.92 (m, 1H), 3.01 (d, 4H, J=6.3 Hz), 3.48 (s, 2H), 3.74 (s, 2H), 3.99 (d, 1H, J=16.8 Hz), 4.07-4.12 (m, 1H), 4.18 (d, 1H, J=16.8 Hz), 5.09-5.17 (m, 4H), 5.83 (ddt, 2H, J=16.8, 10.2, 6.3 Hz), 7.15-7.20 (m, 5H), 7.34 (d, 2H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.48-7.56 (m, 1H), 7.60-7.69 (m, 1H), 8.69 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 19.69, 21.65, 27.53, 46.90, 52.08, 54.63, 55.44, 58.47, 109.24, 115.61, 117.04, 119.79, 120.49, 126.67, 127.13, 132.99, 134.17, 135.45, 136.13, 136.56, 145.22, 154.64, 155.80. ES-MS m/z 478.4 (M+H). Anal. Calcd. for C31H35N5.0.5H2O: C, 76.51; H, 7.46; N, 14.39. Found: C, 76.67; H, 7.45; N, 14.18.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[N:20]([CH:23]([C:25]1[N:26]=[C:27]2[S:35][CH:34]=[C:33]([CH3:36])[N:28]2[C:29](=[O:32])[C:30]=1Br)[CH3:24])=[N+:21]=[N-:22]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]([CH:23]([C:25]1[N:26]=[C:27]2[S:35][CH:34]=[C:33]([CH3:36])[N:28]2[C:29](=[O:32])[C:30]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:24])=[N+:21]=[N-:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccn3)c(=O)n12
Temperature: 65 °C
Yield: 13.1 %

Procedure:
A mixture of 2-(tributylstannyl)pyridine (Aldrich, 0.176 g, 0.382 mmol), 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (from example 8, step 3; 0.10 g, 0.318 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.0184 g, 0.0159 mmol) in 1,4-dioxane (0.5 mL) was heated at 65° C. overnight. After being cooled and quenched with saturated ammonium chloride, the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to provide the desired product (13 mg, 13%). LCMS calculated for C14H13N6OS (M+H)+: m/z=313.1. Found: 313.0.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].Cl.[CH3:17][O:18][C:19]([CH:21]1[C:26](=O)[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:20]>C1C=CC=CC=1>[CH3:17][O:18][C:19]([CH:21]1[CH2:22][NH:23][CH2:24][CH2:25][C:26]21[O:15][CH2:12][CH2:13][O:14]2)=[O:20]
Reactant: COC(=O)C1CNCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: COC(=O)C1CNCCC12OCCO2
Yield: 63.8 %

Procedure:
PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1 g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. H2O was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5% aqueous NAHCO, and CH2Cl2 were added, and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (5×), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography with 20:1 CH2Cl2:2N NH, in EtOH to provide 91 (16.7 g, 64%). 1H NMR (CDCl3) 3.82-3.70 (4H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43 (1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm. 13C NMR (CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm.