Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2]>ClCCl.CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([CH3:18])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 210 °C
Yield: 40.4 %

Procedure:
A mixture of 2-(2-ethoxybenzamido)-3-methylbenzamide (1.6 g, 0.0053 mol) and anhydrous zinc chloride (2.29 g, 0.016 mol) was heated at 210° C. for 5 minutes, then allowed to cool. The residue was dissolved in dichloromethane-methanol (90:10, 200 ml) and this solution washed with an aqueous solution of ethylenediamine tetraacetic acid disodium salt (12 g in 400 ml of water). The aqueous phase was then extracted with a mixture of dichloromethane-methanol (90:10, 2×50 ml) and the organic solutions combined, dried (Na2SO4) and evaporated under vacuum. The residue crystallized from ethanol to give the title compound as colourless needles (0.6 g, 40%), m.p. 177-180° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[O:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)sc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ccccc2CC(=O)O)on1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a mixture of methyl 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetate (0.44 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration and dried with air to give crystals (0.40 g, 93%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 147-148° C.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S@@:14](=O)[C:13]2([CH3:33])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(Cl)(Cl)C([N:40]=[C:41]=[O:42])=O.[O:45]1CCOCC1>>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S:14][C@:13]2([CH2:33][O:45][C:41](=[O:42])[NH2:40])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCO1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2.5 h

Procedure:
A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (7.52 g, 15.0 mmol) and trichloroacetyl isocyanate (5.0 ml, 7.9 g, 42 mmol) in dioxane (75 ml) was refluxed under nitrogen for 3.5 hours and concentrated in vacuo. The concentrate was stirred with methanol (100 ml) and the solution was decanted from a black tar with methanol rinses (2×10 ml). The solution was diluted with water (5 ml), adjusted to pH 7.4 with 5% sodium bicarbonate, and held at pH 7.4-7.5 with 3% H2SO4 for 2.5 hours. The mixture was distributed between methylene chloride (100 ml) and water (50 ml). The organic phase was washed with water (50 ml), combined with a CH2Cl2 back extract (50 ml), dried (4A molecular sieve), polish filtered with CH2Cl2 washes (2×20 ml), and concentrated in vacuo to a light brown oil.
Reaction SMILES: [N:1]1(C2(C#N)COC2)CCC[CH2:2]1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>>[N:17]1([C:12]2([C:2]#[N:1])[CH2:15][CH2:14][CH2:13]2)[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1
Reactant: C1CSCCN1
Reactant: O=C1CCC1
Reactant: N#CC1(N2CCCC2)COC1
Product: N#CC1(N2CCSCC2)CCC1

Procedure:
The title compound, white solid, MS: m/e=182.9 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and thiomorpholine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([NH:28][C:24]3[CH:23]=[C:22]([CH2:21][CH2:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76)(53 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. During this reaction, hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo. The solid was recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:29]([NH:36][CH2:37][CH2:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11]([N:41]3[CH2:42][CH2:43][CH:39]([CH2:38][CH2:37][NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:40]3)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(Cl)ccn2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCC(CCNC(=O)OC(C)(C)C)C3)ccn2c1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor A) (0.151 g) and triethylamine (0.5 ml) are dissolved in acetonitrile (6 ml). To this solution 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) (0.215 g) is added and the solution stirred at 40° C. for 18 hours. The solvent is evaporated and the residue dissolved in dichloromethane, washed with 1N hydrochloric acid and dried over sodium sulfate. The desired product is obtained by evaporation of the solvent.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[CH3:11][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1>>[CH2:1]([C:3]1[N:8]=[C:7]([N:13]2[CH2:14][CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]2[CH3:11])[N:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2]
Reactant: CC1NCCc2ccccc21
Reactant: CCc1cc(O)nc(Cl)n1
Product: CCc1cc(O)nc(N2CCc3ccccc3C2C)n1
Yield: 80.2 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 6-ethyl-2-chloro-4-hydroxypyrimidine (7.0 g, 37.5 mmol) prepared in the above Step 1 and 1-methyl-1,2,3,4-tetrahydroisoquinoline(11.04 g, 75 mmol) were used as starting materials, 8.1 g of the titled compound was prepared. (Yield: 80%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:39])[CH3:38])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)=O)(C)(C)C>C(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:38])[CH3:39])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)#[N:11]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
0.345 ml of oxalyl chloride was added dropwise, whilst ice-cooling, to a solution of 1.00 g of ethyl 1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl}methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of methylene chloride, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.69 g of the title compound as crystals.
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[C:26]=2[CH:37]=O)=[CH:21][CH:20]=1.O>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:35])[CH3:36])[C:26]=2/[CH:37]=[CH:8]/[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:21][CH:20]=1
Reactant: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 8 h

Procedure:
0.465 g (10.65 mmol) of sodium hydride (55%) are introduced into a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 10 ml of THF, rendered absolute using sodium, are added, and 1.84 g (7.46 mmol) of diethyl (N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml of THF are slowly added dropwise so that the temperature does not exceed 30° C. 1 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 10 ml of THF is then added dropwise and the clear, slightly yellow solution is stirred overnight. The reaction mixture is poured into 100 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate=2:1) and crystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of benzamidine hydrochloride (5.00 g, 31.9 mmol) and perchloromethyl mercaptan (3.43 ml, 39.2 mmol) in dichloromethane (32 ml) was added dropwise a solution of sodium hydroxide (6.38 g, 160 mmol) in water (13 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.90 g (46.2%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), Cul (0.02eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:17]([Mg]Br)([CH3:19])=[CH2:18]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:18]=[C:17]([CH3:19])[NH:1][C:4]=23)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1-c1ccc(Cl)cc1
Reactant: C=C(C)[Mg]Br
Product: Cc1cc2ccnc(-c3ccc(Cl)cc3)c2[nH]1
Yield: 32 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-chlorophenyl)pyridine prepared in Preparation 12 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 32%)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NC3CCN(C)CC3)s2)s1
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in a mixture of DCM/DMF(1/1, 10 ml). 4-Amino-1-methylpiperidine (188 mg; 1.65 mmol; 5 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After 3 hours, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml) and title compound precipitated with Et2O affording after filtration, compound (4) as a white powder (120 mg; 90%). 1H NMR (DMSO-d6) δ 1.25 (m, 2H), 1.55 (m, 2H), 1.80 (m, 2H), 2.05 (m, 2H), 2.25 (s, 6H), 2.40 (s, 3H), 3.05 (m, 1H), 6.95 (d, J=3 Hz, 1H), 7.52 (d, J=3 Hz, 1H), 12.23 (m, 1H). M− (ESI): 413.30; M+ (ESI): 415.30. HPLC, Rt: 2.08 min (purity: 99.33%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C-:15]#[N:16].[K+].C(O)(=O)C>C1COCC1.O>[C:15]([C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1-Boc-3-piperidinone (5.0 g, 0.0251 mol) in THF (15 mL) was added dropwise to a solution of potassium cyanide (1.8 g, 0.0276 mol) in water (15 mL) at 0-5° C. Acetic acid (1.6 mL, 0.0276 mol) was added and the solution was allowed to warm to room temperature and stir for 1 hr. The mixture was partitioned between water (50 mL) and ethyl acetate (1×150 mL). The organics were washed with 2×50 mL water, 1×50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to obtain 5.5 g of yellow solid. The material was used without purification. MS (ESI) m/z 265 [M+K]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH3:19])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(CBr)NC(=O)OC(C)(C)C
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(CC(C)NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 22.5 %

Procedure:
The title compound 21b was prepared from compound 2 (260 mg, 1.04 mmol) and tert-butyl (1-bromopropan-2-yl)carbamate (247 mg, 1.04 mmol) in a manner similar to that described for 21a. Yield=22.5%, 95.0 mg.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][C:5]([C:6]([CH2:8][C:9]([O-:11])=[O:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH2:18]([O:20][CH:21]([O-])[O-])[CH3:19].[C:24](O)(=O)[CH3:25]>>[F:1][C:2]1[C:13]([F:14])=[CH:12][C:5]([C:6]([C:8](=[CH:21][O:20][CH2:18][CH3:19])[C:9]([O:11][CH2:24][CH3:25])=[O:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: O=C([O-])CC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CCOC([O-])[O-]
Reactant: CC(=O)O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1[N+](=O)[O-]

Procedure:
To 3 ml of acetic acid anhydrous were added 3 g (0.01 mol) of ethyl (4,5-difluoro-2-nitrobenzoylacetate and 2.44 g (0.016 mol) of ethylorthoformate.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[C:14]=[O:15]>>[C:10]([O-:12])(=[O:11])[CH3:9].[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([NH:13][C:14](=[O:15])[NH:1][C@H:2]([CH2:9][C:10]([OH:11])=[O:12])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Product: CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)O)NC(=O)Nc1ccc(-c2ccccc2)cc1

Procedure:
According to the method described in example S11, aminocarnitine (40 mg) was reacted with 4-isocyanatobiphenyl to yield the title compound as a white solid (25.7 mg). 1H NMR (400 MHz, CD3OD): δ=7.58-7.45 (m, 6H), 7.39 (t, J=7.60 Hz, 2H), 7.28 (t, J=7.20, 1H), 4.66 (br s, 1H), 3.74 (dd, J=9.20 Hz, 13.20 Hz, 1H), 3.54 (d, 13.6 Hz, 1H), 3.23 (s, 9H), 2.65-2.55 (m, 2H), 1.98 (s, 3H). MS ESI [M+H]+, calcd for [C20H25N3O3+H]+: 356.4 found m/z 356.2 (100).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][N:4]1[C:13]2[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]3[C:13]4[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=4[N:6]=[CH:5]3)[CH2:30][CH2:29]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(SCCCN2CCNCC2)cc1
Reactant: Cn1c(=O)c2c(ncn2CC2CO2)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O

Procedure:
A solution of ethanol (2 liters) containing 7-(2,3-epoxypropyl)-theophylline (1 mole) and 1-(3-phenylthiopropyl)-piperazine (1 mole) is refluxed for 5 hours. The ethanol is partly removed. The reaction medium crystallizes. The resulting crystals are suction filtered and may be recrystallized from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:21][C:22](=O)[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:25]1=[O:37].CCN(C(C)C)C(C)C>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][C:25]3=[O:37])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)CCl)C(=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)C(=O)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
In a 20 mL scintillation vial equipped with magnetic stirrer 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.25 g, 0.73 mmol) was suspended in ethanol (5 ml) and tert-butyl 4-(3-chloro-2-oxopropyl)-3-oxopiperazine-1-carboxylate (0.32 g, 1.10 mmol) was added followed by DIEA (0.22 mL, 1.28 mmol). Resulting mixture was heated to 60° C. and agitated for 3 hours. Mixture was then diluted with ethyl acetate and washed with sodium bicarbonate solution, brine, dried and evaporated. Purified by column chromatography on silica gel, eluting with 50-100% ethyl acetate/hexane to give the title compound (0.106 g, 25.1% yield). 1H NMR (CDCl3) δ 1.41 (s, 9H), 2.79-3.42 (m, 6H), 6.55 (s, 2H), 7.03-7.12 (m, 4H), 8.12 (s, 1H), 8.95 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][C:16]1([CH3:24])[O:20][C@H:19]([CH2:21][O:22][NH2:23])[CH2:18][O:17]1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][C@@H:19]2[CH2:18][O:17][C:16]([CH3:24])([CH3:15])[O:20]2)[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC1(C)OC[C@@H](CON)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CC1(C)OC[C@@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (7.3 g, 31.1 mmol), (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamine (4.6 g, 31.1 mmol) and diisopropylethylamine (8.03 g, 62.1 mmol) in diglyme (125 ml) was stirred at 100° C. for 4 h. The reaction was filtered, evaporated and the residue chromatographed twice in chloroform-methanol 15:1 affording (S)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamino)pyrimidine(2.6 g, 24%). υmax (CHCl3) 3400, 1700, 1580, 1560 and 1470 cm-1 ; δH (CDCl3) 1.39(3H,S,CH3), 1.48(3H,S,CH3) , 3.60-4.65(5H,m,CH2ONH+CH2OCMe2 +CHOCMe2), 7.96(1H,br.m, D2O exchangeable, NH), 8.34(1H,S,CHO), 9.25(2H,br.m,D2O exchangeable, 2XNH) and 9.50(1H,S,CHO); m/z 344(M+ -H,<1%), 330(M+ -CH3, <1%).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[O:5]=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])O>>[O:4]([CH:1]([CH3:3])[CH3:2])[CH:15]1[O:16][C@H:7]([CH2:6][OH:5])[C@@H:9]([OH:10])[C@H:11]([OH:12])[C@H:13]1[OH:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)O
Product: CC(C)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The title compound was prepared in quantitative yield by the procedure described in example 10 using isopropanol (2000 ml, 26 mol) and glucose (500 g, 2.78 mol).