Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[CH:14][N:13]=1.O>N1C=CC=CC=1>[NH2:18][C:16]1[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[CH:14][N:13]=[C:12]([NH:11][CH:1]=[O:3])[N:17]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(Cc2cnc(NC=O)nc2N)cc(OC)c1OC
Yield: 75.5 %

Procedure:
2.64 g of formic acid/acetic acid anhydride are dripped, while cooling, into a suspension of 2.9 g of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine (trimethoprim) in 35 ml of pyridine and reacted at 50° to 60° C. for two hours. The reaction mixture is then poured into 400 ml of water and the precipitate is filtered off and recrystallized from a mixture of dimethylformamide and water. 2.4 g (75% of theory) of 4-amino-2-formamido-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 240° to 242° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O>C(Cl)Cl>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N+:19]([O-:32])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Nc2nccc(-c3ccncc3)n2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: [O-][n+]1ccc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)cc1
Reaction time: 2 h

Procedure:
10.57 g (33.4 mmol) of N-(3-trifluoromethyl-phenyl)-4-pyridyl-2-pyrimidineamine are suspended in 200 ml of methylene chloride, and 10.49 g (33.42 mmol, 55% strength) of m-chloroperbenzoic acid are added. After 2 hours, 200 ml of water are added. The reaction product is isolated by filtration, washed with sodium carbonate solution and water and, after drying, N-(3-trifluoromethyl-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine is obtained. More product is obtained by chromatography (methylene chloride:methanol=9: 1) of the concentrated mother liquor; Rf =0.16 (methylene chloride:methanol=9:1).
Reaction SMILES: COC(C1C=C(COC[C@@H:14]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]#[N:16])C=CC=1)=O.O.[OH:46]N1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC.Cl.[C:75]([S:94][CH2:95][C@@H](C(N)=O)N)([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>C(Cl)Cl>[CH3:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][C@@H:19]([C:18]([NH:17][C:14](=[O:46])[C@H:15]([CH2:95][S:94][C:75]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:88]1[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=1)[C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)[NH2:16])=[O:44])[NH:20][C:21](=[O:35])[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Reactant: On1nnc2ccccc21
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-N-(2,2-diphenylacetyl-L-phenylalanine (see example 302, 1.0 g, 2.68 mmol), 1-hydroxybenzotriazole hydrate (0.41 g, 2.68 mmol) and N-methylmorpholine (0.74 mL, 6.69 mmol) in CH2Cl2 (80 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (0.77 g, 4.02 mmol) in one portion. After stirring 30 minutes at room temperature, S-trityl-L-cysteinamide (0.97 g, 2.68 mmol) is added to the solution in one portion, and the solution is stirred for 16 hours. The solution is evaporated, and the residue partitioned between water (80 mL) and ethyl acetate (80 mL). The aqueous layer is washed with EtOAc (2×80 mL), and the combined organic layers are then washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residue is triturated with Et2O/hexane (1:1) to yield N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-S-trityl-L-cysteinamide as a white solid.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:19][OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([N+:19]([O-:20])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCNO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: CCCCCC[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 76 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-n-hexylhydroxylamine, the title compound was prepared in 76% yield as the sodium salt, m.p. 225.5° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: OCC=Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccccc1
Yield: 81.7 %

Procedure:
The above alcohol (2.05 g) in pyridine (1.6 ml) with acetic anhydride (1.8 g) was stirred at 25° for 3 hours before being partitioned between ether and dilute hydrochloric acid. Work-up in the conventional manner gave 3-phenylprop-2-enyl acetate (2.2 g). NMR 1H: 7.15 (5H,m), 6.52 (1H,d), 6.22(1H,t), 4.57 (2H,d), 2.00(3H,s).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[CH:11]=1)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][N:12]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[CH:11]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(-c2nccc3ccccc23)cc1C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1cn(-c2nccc3ccccc23)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
0.62 mL (7.18 mmol) of oxalyl chloride is added to 1.1 g (3.59 mmol) of 3-carboxy-4-trifluoromethyl-1-(isoquinolin-1-yl)-1H-pyrrole dissolved in 30 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), giving 1.22 g of 3-chlorocarbonyl-4-trifluoromethyl-1-(isoquinolin-1-yl)-1H-pyrrole hydrochloride in the form of a cream-colored solid, which is used directly in the following step.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[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].C(N(CC)CC)C.ClC(OCC)=O.[NH2:52][C@H:53]([C:57]([NH:59][C@H:60]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[CH2:61][CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:58])[C@@H:54]([CH3:56])[OH:55]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:52][C@H:53]([C:57]([NH:59][C@H:60]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[CH2:61][CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:23])(=[O:17])[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: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: -20 °C
Yield: 81.5 %

Procedure:
To a solution of 3-hexadecanoyloxyoctadecanoic acid (55 g) and triethylamine (16 ml) in tetrahydrofuran (500 ml) was added ethyl chloroformate (11 ml) dropwise with stirring at -20° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added triethylamine (32 ml) and then, a solution of dibenzyl N-(L-threonyl)-L-glutamate (77 g) in tetrahydrofuran (100 ml) dropwise and the mixture was stirred for 3 hours at room temperature. Tetrahydrofuran was removed under reduced pressure to give the residue which was taken up in ethyl acetate. The ethyl acetate solution was washed with diluted hydrochloric acid and diluted sodium bicarbonate and dried. Evaporation of the solvent gave the residue which was recrystallized from ethanol to leave dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamate (79 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]([C:19]([OH:21])=O)[C:12]2=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].[Cl-].[Na+]>CN(C)C=O>[CH2:36]([NH:40][C:19]([C:13]1[C:12](=[O:22])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=2)[NH:15][CH:14]=1)=[O:21])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: O=C(O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (59 mg, 0.2 mmol) and triethylamine (59 ml, 0.42 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added ethyl chloroformate (39 mL, 0.41 mmol). After stirring at 0° C. for 1 h, n-butylamine 99 mL, 1.0 mmol) was added. The reaction mixture was stirred an additional 2 h at 0° C., then poured into saturated aqueous sodium chloride. The mixture was cooled in an ice bath, the precipitate collected, rinsed with water and ether, then dried to afford 49 mg of N-n-butyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide as a brown solid. Compound 1. An alternate name for this compound is: N-butyl(4-oxo-6-(benzylamino)(3-hydro-5-azaquinolyl))formamide.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12]([CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5]1)=[O:14])[CH3:22]
Reactant: CCNCC
Reactant: O=C1CC(C(=O)O)Sc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Temperature: 0 °C
Yield: 65.1 %

Procedure:
(+−)-4-Oxo-thiochroman-2-carboxylic acid (10.4 g, 50 mmol), prepared as described in T. Okubo et al (Bioorg. Med. Chem. 2004; 12: 3569-3580), in dry DCM (100 ml) was stirred under an atmosphere of nitrogen at room temperature with oxalyl chloride (12.6 g, 100 mmole) and one drop of DMF for 18 h. The reaction was then evaporated in vacuo to a gum and then redissolved in DCM (100 ml), cooled to 0° C. on an ice bath, stirred and treated dropwise with diethylamine (8.03 g, 110 mmol) in DCM (20 ml) over a period of 1 h. The reaction was allowed to warm to room temperature over 1 h and 10% aqueous potassium carbonate solution (100 ml) was added and the reaction mixture vigorously stirred. The DCM solution was separated. The aqueous solution was extracted with two further batches of DCM (100 ml) and the combined extracts were dried over magnesium sulphate. The DCM solution was concentrated in vacuo to give a dark green oil that crystallized on standing. The crystalline solid was triturated with diethyl ether (50 ml) and filtered to give the title compound (50) (8.57 g, 65%) as a pale green solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.06 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 3.0-3.5 (m, 6H), 4.25 (m, 1H), 7.15-7.21 (m, 2H), 7.32-7.39 (m, 1H), 8.10-8.14 (m, 1H).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])([O:3][CH3:4])=[O:2]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(Cc1ccc(OC)cc1CN)C(=O)OC
Yield: 139.8 %

Procedure:
A solution of methyl (±)-3-carbomethoxy-4-[2-bis(tert-butoxycarbonyl)aminomethyl-4-methoxyphenyl]butanoate (12 g) in chloroform (100 mL) and trifluoroacetic acid (50 mL) was stirred under argon at room temperature for 4 hr. The solution was then concentrated under vacuum to give the title compound (10 g, 100%) as a viscous oil: MS (ES) m/e 296.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.II.CSC.C(=O)(O)[O-:16].[Na+]>CS(C)=O>[CH:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[O:16]
Reactant: Cc1ccc(C#N)cn1
Reactant: O=C([O-])O
Agent: II
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CSC
Product: N#Cc1ccc(C=O)nc1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 6-methylnicotinonitrile (10.0 g, 84.6 mmol) and iodine (20.0 g, 78.8 mmol) in dimethylsulfoxide (150 mL) was heated at 150° C. under nitrogen for 20 minutes (reaction exhaust was scrubbed with bleach to remove dimethyl sulfide). After cooling to room temperature saturated aqueous sodium bicarbonate (200 mL) was added carefully and the resulting mixture was extracted with toluene (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to give the desired product as an orange oil (5.65 g, 50%) which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.06 (1H, d), 8.17 (1H, dd), 9.05 (1H, d), 10.12 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:20]#[N:21])=[O:16])=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH:5]=[C:4]([F:31])[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[C:20]([C:19]1[CH:18]=[C:17]([CH:24]=[C:23]([CH3:25])[CH:22]=1)[C:15]([C:14]1[N:9]([CH2:8][C:6]2[CH:5]=[C:4]([F:31])[N:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=2)[C:10](=[O:30])[N:11]([S:33]([CH3:32])(=[O:35])=[O:34])[C:12](=[O:29])[C:13]=1[CH:26]([CH3:28])[CH3:27])=[O:16])#[N:21]
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(N)nc(F)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)n(S(C)(=O)=O)c(=O)n2Cc2cc(F)nc(NS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
3-[3-(2-Amino-6-fluoro-pyridin-4-ylmethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (86 mg, 0.204 mmol) was dissolved in 5 mL THF. TEA (0.31 μl, 12 eq.) was added and the reaction was stirred at 0° C. for 10 minutes. MsCl (158 μl, 10 eq.) was added. The reaction was stirred at 0° C. for 40 minutes. The reaction crude was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white powder (89 mg, 75%). LC-MS shows 578.0 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.6 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 4.82 (dd, 2H), 3.63 (s, 3H), 3.56 (s, 3H), 2.43 (s, 3H), 2.22 (m, 1H), 1.22 (dd, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH2:17])([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18](N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30](Cl)=[O:31])C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:18])=[O:14])([NH:17][C:30](=[O:31])[CH2:29][C:28]([O:27][CH3:25])=[O:33])[CH2:11]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CC1(N)CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CC1(NC(=O)CC(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
3-Amino-3-methoxycarbonylmethyl-azetidine-1-carboxylic acid tert-butyl ester (2 g; 8.2 mmol) dissolved in CH2Cl2 (100 ml) and triethylamine (3.4 ml; 24.5 mmol) is cooled to −5° C. Chlorocarbonyl-acetic acid ethyl ester (1.23 ml; 9.8 mmol) is slowly added under stirring. The reaction mixture is warmed to room temperature, stirred for 20 minutes, poured on 2N HCl (15 ml) and extracted with TBME three times. The organic phases are combined, washed with a saturated solution of NaHCO3, dried over Na2SO4 and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 7:3) yields the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6): 8.62 (s, 1H); 4.08 (q, 2H); 3.88 (m, 4H); 3.60 (s, 3H); 3.21 (s, 2H); 3.02 (s, 2H); 1.38 (s, 9H); 1.18 (t, 3H). MS (m/z) ES+: 359 (80; MH+); 303 (100);
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=[O:5].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:17]=[C:16]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:13][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:5])(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(OC(=O)C(C)(C)C)cc2OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
A solution of 2.4 g (0.01 mole) of 2,2',4,4'-tetrahydroxybenzophenone and 5 g (0.04 mole) of pivaloylchloride was warmed to 50° C. in 75 mls of dry pyridine for 2 hrs with a drying tube attached. The solvent was removed via rotary evaporator and the residue was partitioned between H2O and CH2Cl2 ; the organic layer was washed with dilute K2CO3 and dried over MgSO4. After removal of solvent via rotary evaporation, the title compound was crystallized from ethanol. 4 g. (69%) yield. M.P.~154°-156° C.
Reaction SMILES: [Br-].C([N+:9]12[CH2:17][C:13]([C:18]([O:20]CC)=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2)C1C=CC=CC=1.[H][H].[ClH:25]>C(O)C.[Pd]>[ClH:25].[N:9]12[CH2:17][C:13]([C:18]([OH:20])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2
Reactant: [H][H]
Reactant: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CCC1)C2
Agent: [Pd]
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: O=C(O)C12CCCN(CCC1)C2

Procedure:
A solution of ethyl 1-benzyl-1-azoniabicyclo[3.3.1]-non-5-ylcarboxylate bromide (D2, 7.90 g, 0.021 mole) in ethanol (150 ml) was hydrogenated over 10% Pd/C (700mg) at atmospheric pressure and 40° C. until the uptake of hydrogen ceased. The reaction mixture was filtered through a pad of kieselguhr and the filtrate concentrated in vacuo to leave a yellow solid, which was treated with 8M hydrochloric acid (130 ml) and heated under reflux until TLC indicated that hydrolysis was complete. The solution was concentrated to dryness in vacuo to give the title compound (D14) as a yellow solid (4.8 g), which was used in the next stage without purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])(=[O:5])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 44.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (66 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 50 mg (45%) of the title compound.
Reaction SMILES: CO.C(N)CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3[C:20](=[CH:21]C=CC=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH3:21])[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: CCCCN
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.6 %

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of pyridine were then added to the residue. 0.31 ml of propionic anhydride was added dropwise to the resulting mixture, and then the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was thereafter subjected to silica gel column chromatography, using 2:1, 3:1 and 1:0 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 1:4, 3:7, 2:3 and 1:1 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 125 mg of the title compound as a yellow oil having an Rf value of 0.45 (silica gel thin layer chromatography; using ethyl acetate as the developing solvent).