Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[SH:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>>[SH:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH:32][C:2]1([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: Nc1ccccc1S
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccccc4S)CC3)c(F)c2)C(=O)O1
Yield: 56 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 2-mercaptoaniline the compound was obtained in 56% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:25][O:24][C:23](=[O:26])[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:27]N1C(=O)CCC1=O.OS(O)(=O)=O>C1COCC1.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:25][O:24][C:23](=[O:26])[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[C:15]4[Cl:27])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1OCc2c1cc1c(Cl)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Yield: 48.8 %

Procedure:
A stirred solution of 2 (104 mg, 0.3 mmol), N-chlorosuccinimide (80 mg, 0.6 mmol) and concentrated H2SO4 (10 μL) in THF (5 mL) was heated to reflux for 24 h, and then diluted with CHCl3 (50 mL). The reaction mixture was washed with 10% aqueous Na2S2O3 solution (50 mL) and water (2×50 mL), dried over MgSO4, and concentrated in vacuo. The product was purified by column chromatography on silica gel eluting with CHCl3 to afford 37 (56 mg, 49%) as a brown solid. mp 267° C. (decomp.); 1H NMR (CDCl3) δ 8.91 (s, 1H, H4), 7.47 (s, 1H, H6), 6.76-6.91 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.22 (q, 2H, lactone-CH2—, J=8.7 Hz); MS (EI) m/z 384 [M+2]+, 382 [M]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14]C)=[O:13])=[O:7].CCO>O.C1COCC1>[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([OH:14])=[O:13])=[O:7]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)c(C)c1NC(=O)c1cc(N2CCCC(CO)C2)ccc1F
Reaction time: 4 h
Yield: 23.2 %

Procedure:
A solution of NaOH (0.146 mg, 0.00366 mol) in 1.5 ml of H2O is added to a stirred solution of methyl 3-[[2-fluoro-5-[3-(hydroxymethyl)-1-piperidyl]benzoyl]amino]-2,4-dimethyl-benzoate (0.38 g, 0.000916 mol) in THF:EtOH (3 ml:2 ml). After 4 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with ethyl acetate. The organic layer are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a light yellow solid (85 mg g, 36.8%). Mass spectrum (m/z): 401.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:16]=2[CH:15]=[CH:14]1>>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[C:16]=3[CH:15]=[CH:14]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cc1c(Cl)cccc1S(=O)(=O)n1ccc2c(N3CCNCC3)nccc21
Product: Cl

Procedure:
3-Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (6.3 mg). LC/MS RT: 1.563 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 96%. MS: 392 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:1][CH:3]3[O:5][CH2:4]3)=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C([O-])c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCC1CO1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 89.0 g. of epichlorohydrin, 92.0 g. of sodium 4-(8-cyclohexyloctylamino)benzoate, and 350 ml. of hexamethylphosphoramide is stirred at 105° C. for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield the product.
Reaction SMILES: O=[C:2]1[C:19]2[C:20]3[C:5](=[C:6]4[C:21]5[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:10]=5[C:9](=O)[CH:8]=[CH:7]4)[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2>[Zn].N1C=CC=CC=1.C(O)(=O)C>[CH:11]1[C:10]2[C:21]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[C:19]5[C:20]=4[C:5]([C:6]=3[CH:7]=[CH:8][CH:9]=2)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]2=[CH:2]5)=[CH:13][CH:12]=1
Reactant: O=c1ccc2c3c1cccc3c1cccc3c(=O)c4ccccc4c2c31
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: c1ccc2c(c1)cc1cccc3c4cccc5cccc(c54)c2c13

Procedure:
In accordance with a conventional manner, 7,14-dioxo-7,14-dihydrobenzo[a]perylene was treated in zinc powder contained in pyridine, and then, treated in 80% acetic acid. The resultant was refined in a conventional manner to thereby obtain a target material, benzo[a]perylene.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[N:14][C:13]([CH3:18])=[CH:12][N:11]=1.N1C=CC=CC=1>ClCCl>[CH3:17][O:16][C:15]1[C:10]([NH:9][C:6](=[O:7])[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:11][CH:12]=[C:13]([CH3:18])[N:14]=1
Reactant: COc1nc(C)cnc1N
Reactant: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(C)cnc1NC(=O)OCC(C)C

Procedure:
Isobutylchloroformate (4.79 ml) was added to a stirred solution of 2-amino-3-methoxy-5-methylpyrazine (5 g) and pyridine (2.91 ml) in dichloromethane (10 ml) at ambient temperature. After 90 minutes the reaction mixture was diluted with dichloromethane (10 ml) and washed with 2M hydrochloric acid (3×20 ml), water (20 ml) and saturated sodium chloride solution (20 ml) and then dried (MgSO4). Volatile material was removed by evaporation to give a solid which was recrystallised from hexane to give isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)carbamate (6.5 g); 1H NMR (CDCl3): 1.0 (d, 6H), 2.0 (m, 1H), 2.4 (s, 3H), 4.0 (d, 2H), 4.02 (s, 3H), 7.3 (s, 1H), 7.8 (s, 1H); mass spectrum (postive chemical ionisation (+ve CI)): 240 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>COCCOC.CCOC(C)=O.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3ncccn3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 4-(4-Bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (355 mg; 1.002 mmol); 2-tributylstannanyl-pyrimidine (1.1 g; 2.98 mmol); triphenylphosphine palladium dichloride (35 mg, 0.049 mmol) was stirred in DME (4 ml) at 100° C. overnight. Reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml) and water (50 ml). Separated organic layer, washed with brine, dried over Na2SO4, then chromatographed on silica gel eluting with 70% v/v EtOAc/Hexanes yielding product at solid (110 mg; 31%)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([OH:25])=O.S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:23]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN(C)C
Reaction time: 2 h

Procedure:
To a mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylic acid (9 g), dichloromethane (72 ml) and N,N-dimethylformamide (20 ml), thionyl chloride (2.1 ml) was added at 7° C. under ice cooling. After stirring for 1.5 hours at the same condition, 2-dimethylaminoethylamine (5.9 g) was added and stirred for 2 hours. The reaction mixture was adjusted to pH=8.5 by saturated potassium carbonate and extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on alumina eluting with a mixture of n-hexane and ethyl acetate (5:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford N-(2-dimethylaminoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:6][CH:14]([OH:15])[C:13]([OH:17])=[O:16])=[O:5]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1c(F)cccc1F
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(O)C(=O)O)c1c(F)cccc1F
Yield: 52.5 %

Procedure:
A mixture of 50 g (0.318 mol) of 2,6-difluorobenzamide, 32 g (0.349 mol) of glyoxylic acid monohydrate and 200 mL of acetone was refluxed for 5 h. The reaction was cooled and solvents evaporated to give a white solid. It was triturated with cold acetone to afford 38.56 g of a white solid: mp 125°-127° C. 1H-NMR (DMSO-d6)δ9.55 (d, 1H), 7.50 (m, 1H), 7.15 (t,2H), 5.45 (d,1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:28][C:29]([C:31]2[CH:40]=[C:39]([O:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[O:30])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:28][C:29]([C:31]2[CH:40]=[C:39]([O:41][CH2:42][C:43]([OH:45])=[O:44])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[O:30])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccccc3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OCC(=O)O)NC(=O)c2cc(OCC(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.4 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxy)carbonyl)methoxy)carbonylpropyl]aminocarbonyl-4-((1,1-dimethylethoxy)carbonyl)methoxyquinoline (38 mg, 0.05 mmol) in 1 mL CH2Cl2, was added 2 mL trifluoroacetic acid, then the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil. The oil was diluted in water (5 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×10 mL). The organic layer was evaporated in vacuo to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-((carboxy)methoxycarbonyl)propyl]aminocarbonyl-4-(carboxy)methoxyquinoline as a white solid (30 mg); NMR (DMSO-d6), 1.16 (t, 3), 1.90 (m, 1), 2.10 (m, 1), 2.45 (m, 2), 3.3–3.9 (m, 8), 4.02 (q, 2), 4.52 (q, 2), 5.04 (m, 1), 5.13 (s, 2), 7.46 (s, 1), 7.68 (t, 1), 7.84 (t, 1), 8.08 (d, 1), 8.23 (d, 1), 9.95 (m, 1) ppm.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[C:1]([CH:3]1[CH2:5][N:4]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: N#CC1CN1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CC1C#N

Procedure:
In an analogous manner, by reacting 2-cyano-aziridine with ethyl chloroformate, there is obtained ethyl 2-cyano-1-aziridine-carboxylate; b.p. 70°-75°C./0.01 mm.Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 800 mg, 4.1 mmol) in DMF (40 mL) was added glycine ethyl ester hydrochloride (625 mg, 4.5 mmol), HOBt (0.55 g, 4.1 mmol) and DIPEA (2.13 mL, 12.2 mmol). After 5 min, EDCI (1.01 g, 5.3 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (100 mL) and ethyl acetate (3×80 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (4:96) to give the title compound as a yellow solid. δH (CD3OD): 1.28 (3H, t), 4.14 (2H, s), 4.23 (2H, q), 7.10 (1H, s), 7.68 (1H, s), 8.59 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:15][C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:8]=[O:9])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Yield: 75.7 %

Procedure:
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH2Cl2 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2Cl2, washed with 1N HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CCN(CC)CC>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Temperature: 55 °C
Yield: 69.8 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 55° C. for about 22 h before concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2×100 mL), then concentrated and further washed with acetone (2×10 mL) to give 9.87 g (70%) of pure 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:10][C:11]1[CH:31]=[CH:30][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[C:20]([Cl:29])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[C:48]([O:52][C:53](=[O:70])[CH2:54][C:55]1[CH:56]=[C:57]([NH:61][CH2:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH:58]=[CH:59][CH:60]=1)([CH3:51])([CH3:50])[CH3:49].N1C=CC=CC=1>ClCCl.O>[C:36]([O:35][C:33]([NH:32][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([N:61]([CH2:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:57]3[CH:58]=[CH:59][CH:60]=[C:55]([CH2:54][C:53]([O:52][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:70])[CH:56]=3)=[O:27])=[C:20]([Cl:29])[CH:19]=2)=[O:16])=[CH:30][CH:31]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCC(=O)O)c(Cl)c2)cc1
Reactant: CC(C)(C)OC(=O)CNc1cccc(CC(=O)OC(C)(C)C)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CCc2ccc(OC(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 3-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]propanoic acid (200 mg) in dichloromethane (3.00 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.0700 mL) under ice-cooling, followed by stirring at room temperature for 1 hour. Under ice-cooling, a solution of tert-butyl N-[3-(2-tert-butoxy-2-oxoethyl)phenyl]glycinate (170 mg) and pyridine (0.0500 mL) in dichloromethane (3.00 mL) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(3-{(2-tert-butoxy-2-oxoethyl)[3-(2-tert-butoxy-2-oxoethyl)phenyl]amino}-3-oxopropyl)-3-chlorophenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (210 mg).
Reaction SMILES: Cl[CH:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16](=O)[CH:17]=[CH:18][CH2:19][CH3:20].S(=O)(=O)([O-])[NH2:23].[NH4+]>C(O)C>[CH2:17]([C:18]1[CH:19]=[CH:20][N:23]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH3:15]
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)OCC
Reactant: CCC=CC(C)=O
Reactant: NS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1ccnc(C(=O)OCC)c1C(=O)OCC
Yield: 18.6 %

Procedure:
A solution of diethyl 3-chloro-2-oxosuccinate (137.4 g, 0.69 mol), hexen-2-a1 (72.5 g, 0.74 mol) and ammonium sulphamate (190.2 g, 1.66 mol) in ethanol (450 ml) was stirred under reflux for 36 hours and then filtered. The filtrate was evaporated under vacuum, the resulting residue dissolved in water (500 ml) and this solution extracted with ethyl acetate (6×500 ml). The combined organic extracts were dried (MgSO4) and evaporated under vacuum, then the resulting residue was chromatographed on silica gel (50 g), using an ethyl acetate in hexane elution gradient (0-20% ethyl acetate), to give the title compound as an orange oil (34.1 g, 21%). Rf 0.20 (ethyl acetate:hexane, 20:80).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:73]([OH:75])=[O:74])[CH2:69][C:70]([OH:72])=[O:71]>O>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:73]([O-:75])=[O:74])[CH2:69][C:70]([O-:72])=[O:71]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
Amphotericin B methyl ester (9.36 g, 0.01 Mol) is added in portions to a solution of L-aspartic acid (1.33 g, 0.01 Mol) in 500 ml of water and stirred until complete dissolution. The clear solution is then lyopholized. The product has a solubility of more than 10% water at RT.
Reaction SMILES: [H][H].[OH:3][CH:4]([CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[C:5]([F:8])([F:7])[F:6].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO.[Pt]>[CH2:16]([NH:23][C@H:12]1[CH2:13][CH2:14][C@@H:9]([CH:4]([OH:3])[C:5]([F:8])([F:7])[F:6])[CH2:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(C(O)C(F)(F)F)CC1
Reactant: NCc1ccccc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: OC([C@H]1CC[C@@H](NCc2ccccc2)CC1)C(F)(F)F

Procedure:
At 50° C. and a hydrogen pressure of 5 bar, 43.0 g of 4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexanone and 24.0 g of benzylamine in 400 ml of methanol were hydrogenated in the presence of 1.5 g of platinum (5% on carbon). The catalyst was filtered off and the mixture was concentrated. The cis/trans isomers were separated by silica gel chromatography (ethyl acetate/ethanol 9:1). The cis isomer eluted first of the two isomers, to give the title product as a colourless oil.