Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:17].CS(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:17][CH:23]1[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(CN2CCOCC2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN2CCOCC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.55 g, 12.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 2-methyl-4-(morpholin-4-ylmethyl)phenol—see WO 2006133567—(2.0 g, 9.6 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.2 g, 12.5 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.6 g (75%) of 12A as an oil. 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.34-2.49 (m, 4H), 3.40 (s, 2H), 3.62-3.76 (m, 4H), 3.94-4.07 (m, 2H), 4.23-4.35 (m, 2H), 4.79-4.92 (m, 1H), 6.38 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27](#[N:29])[CH3:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:2]1[N:3]=[CH:4][C:28]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:8][C:6]=3[N:7]=2)=[CH:27][N:29]=1
Reactant: CC#N
Reactant: CC(C)(O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(O)c1nc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1

Procedure:
2-(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)propan-2-ol, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. The solution was evaporated to dryness and purified by reverse phase silica gel chromatography to give the product 137.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: CCc1ncnc(O)c1I
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1I
Temperature: 90 °C

Procedure:
A suspension of 90 g (0.36 mol) 4-hydroxy-5-iodo-6-ethyl pyrimidine in 600 mL POCl3 is heated for 1 h at 90° C. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated solid is collected by filtration and washed with water. After drying, the desired product is obtained as a solid (65 g; 67%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH3:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]([CH3:12])[S:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC1CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCC2(CC1)OCCO2)S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methyl-amine (1.5 g, 9 mmol), CH2Cl2 (50 mL), and Et3N (1.7 mL, 12 mmol) was stirred with 4-fluorobenzene sulfonyl chloride (1.7 g, 9 mmol) at room temperature. After 1 hour, the reaction mixture was concentrated and the residue purified by flash chromatography on silica gel to afford 2.1 g of N-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-fluoro-N-methyl-benzenesulfonamide. Mass spectrometric data [M+H]+=330.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][NH:26][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nn[nH]n2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nnn(C)n2)cc1
Yield: 58.9 %

Procedure:
To a stirred solution of (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole (0.72 g, 1.86 mmol) in acetone (30 ml) was added at room temperature potassium carbonate (0.51 g, 3.72 mmol) and methyl iodide (0.23 ml, 3.72 mmol) and the reaction mixture was heated under reflux conditions for 3 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 2:3) and crystallization from ethyl acetate/hexane yielded the title compound (0.44 g, 59%) as a white solid, m.p. 150° C. and MS: m/e=402.4 (M+H+). As second product of this reaction (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-tetrazole (0.26 g, yield 35%) was obtained as a white solid, m.p. 186° C. and MS: m/e=402.4 (M+H+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(Cl)c4Cl)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.039 g, 49%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(N)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (2.00 g) and tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (2.25 g) in DMF (50 mL) was added sodium hydride (60% in oil, 0.564 g), and the mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.75 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: Cc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-methylbenzyl)-1H-indole (Step 1 of Example 25) and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 382. 1HNMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.76 (d, 2H, J=8.8 Hz), 7.52 (s, 1H), 7.53 (d, 2H, J=8.1 Hz), 7.41-7.38 (m, 3H), 7.11 (m, 4H), 6.54 (d, 1H, J=3 Hz), 5.39 (s, 2H), and 2.23 ppm (s, 3H). Elemental Analysis for C23H18F3NO: Calculated: C, 72.43; H, 4.76; N, 3.67. Found: C, 72.38; H, 4.70; N, 3.59.
Reaction SMILES: Br[C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:11]([C:8]1[C:7](=[O:13])[NH:6][C:5]2[S:14][C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[C:9]=1[OH:10])#[N:12]
Reactant: N#Cc1c(O)c2c(-c3ccccc3)c(Br)sc2[nH]c1=O
Reactant: C#CCCCCC(=O)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2c(-c3ccccc3)c(C#CCCCCC(=O)O)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Bromo-4-hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.45 mmol) in 4.5 mL DMF was added diethylamine (0.48 mL, 4.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (10 mg, 0.015 mmol), and triphenylphosphine (36 mg, 0.12 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (0.19 mL, 1.5 mmol) was added. The reaction was then heated to 120° C. using microwave for 25 min, filtered, concentrated and purified by reverse phase HPLC. MS (ESI) m/e 393 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 1.28–1.56 (m, 4H), 2.12–2.30 (m, 4H), 7.20–7.35 (m, 5H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:23])=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)C2CCCCC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)C1CCCCC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Heat a mixture of cyclohexyl-p-tolyl-methanone (1 g, 4.943 mmol), NBS (1.232 g, 6.92 mmol), and AIBN (41 mg, 0.247 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Add additional NBS (264 mg) and AIBN (19 mg) and reflux the mixture for 4 h. Cool the reaction mixture to ambient temperature and filter. Concentrate the filtrate in vacuo to provide the desired intermediate as oil (1.132 g, 81%) that was used without any further purification.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([CH2:17][C:18]#[N:19])=O)=[CH:13][CH:12]=1>C(O)C>[NH2:19][C:18]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:15]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:21][CH:20]=2)[CH:17]=1
Reactant: NNC(N)=O
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccc(F)cc2)cc1N
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
To a stirred solution of 12.0 g of semicarbazide hydrochloride in 200 ml of ethyl alcohol is added 5.35 g of sodium methoxide. The reaction mixture is stirred for 15 minutes and 16.3 g of p-fluorobenzoylacetonitrile added. The reaction mixture is heated at reflux for 2 hours, cooled and concentrated in vacuo to a separated solid which is filtered and washed with water and air dried. The solid is dissolved in 200 ml of ethyl alcohol and 5 ml of triethylamine followed by reflux for 1 hour. The volatiles are evaporated in vacuo to a solid which is filtered, washed with water and air dried to give 8.0 g of the desired product as a solid, m.p. 140° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[NH:12])[CH:2]=1.[C:14]([CH2:19][C:20](OCC)=[O:21])(=O)[CH2:15][CH2:16][CH3:17].[O-]CC.[Na+]>C(O)C>[CH2:15]([C:14]1[N:13]=[C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:12][C:20](=[O:21])[CH:19]=1)[CH2:16][CH3:17]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N=C(N)c1cnc2ccccc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(=O)[nH]c(-c2cnc3ccccc3c2)n1
Yield: 57.6 %

Procedure:
Quinoline-3-carboxamidine (314 mg), ethyl butyrylacetate (290 mg), and sodium ethoxide (21 wt % in ethanol, 1.1 mL) were refluxed for 48 h in 20 mL of ethanol. The solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The ethyl acetate phase was dried with sodium sulfate and the solvent was evaporated. Silica gel chromatography (50:45:5 ethyl acetate/hexanes/methanol) provide 280 mg of 6-propyl-2-quinolin-3-yl-3H-pyrimidin-4-one.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccs2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 44.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (600 mg, 1.59 mmol) and 4-(dimethylamino)pyridine (19.8 mg, 162 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethyl acetate) to give Compound 11f (446 mg, 706 μmol, 44.4%) as a colorless solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.97 (s, 9H), 3.65 (s, 2H), 0.678-6.86 (AA′BB′, 2H), 6.97-7.06 (m, 3H, includes AA′BB′), 7.19-7.27 (AA′BB′, 2H), 7.51 (dd, 1H, J=0.9, 3.7 Hz), 7.69 (dd, 1H, J=0.9, 5.0 Hz), 8.06-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.60 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.4 (2C), 127.8, 127.9, 128.0, 128.2 (2C), 128.4, 129.5, 130.5 (2C), 137.3, 140.5, 140.6, 142.5, 148.0, 153.9, 157.0, 170.3; IR (KBr, cm−1) 419, 519, 673, 704, 741, 781, 802, 839, 916, 1169, 1265, 1335, 1362, 1373, 1414, 1439, 1472, 1510, 1605, 1667, 2857, 2887, 2930, 2955, 3221; HRMS (ESI+) m/z 654.2617 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:3]([OH:5])=[O:4].Cl[C:14]([O:16][CH3:17])=[O:15]>O1CCOCC1.[OH-].[Na+]>[CH3:17][O:16][C:14]([NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: NC(Cc1ccccn1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.1 %

Procedure:
A solution of 2-amino-3-pyridin-2-yl-propionic acid (0.168 g, 1.0 mmol) in 1,4-dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methyl chloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, and extracted with dichloromethane. The aqueous phase was acidified to pH 7 with 1 N HCl and evaporated to dryness. The resulting solid was trituated with 3:1 dichloromethane/isopropanol, filtered, and the filtrate was concentrated to yield a yellow solid (0.146 g, 65%) which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24](N)=[CH:23][CH:22]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: CN(C)c1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 25 %

Procedure:
Prepared from VII and N,N-dimethyl-p-phenylene-diamine. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 25%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2228, 1609, 1572, 1523, 1460, 1368, 1274, 1229, 1204, 1188, 1163, 1141, 1058, 1009, 948, 842, 811; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=9.0 Hz), 8.16 (s, 1H), 7.86 (d, 1H, J=9.0 Hz), 7.37 (d, 2H, J=8.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 3.00 (s, 6H); HRMS calcd for C18H15N6S (M+H+): 347.1079, found 347.1066.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CC(=O)NNc1ccc(N=Cc2ccccc2)cc1
Temperature: 75 °C

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (8.25 g, 0.05 mole) and benzaldehyde (5.3 g, 0.05 mole) were mixed in ethanol (50 ml). The mixture was stirred thoroughly and was warmed to approximately 75° C for one-half hour. The addition product precipitated out of the reaction mixture. The mixture was chilled in ice and then filtered. The solid was washed with ether and dried. The product was a white crystalline powder. Yield 12.0 g (94%), m.p. 172°-174° C.
Reaction SMILES: Cl.N[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+].O>C(OCC)C>[OH:15][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H](O)Cc1ccccc1
Yield: 41.8 %

Procedure:
L-Phenylalanine hydrochloride (12.2 g, 60.5 mmol) was added to 183 ml of 5% sulfuric acid (sulfuric acid: 96.0 mmol) and the solution was treated with a mixture of 8.35 g (121 mmol) of sodium nitrite and 44.5 g of water at 0° C. for 3 hours. Thereafter, 100 ml of diethyl ether was added to the reaction mixture and, after stirring, the organic phase was separated (extract 1). Further, 50 ml of diethyl ether was added to the aqueous phase and, after stirring, the organic phase was separated (extract 2). The extracts 1 and 2 were combined. The combined extract (95.0 g) contained 4.2 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 42%, optical purity 92.6% ee). The proton concentration (normality) in the reaction of this comparative example was 1.4 mol/kg, the amount of the protonic acid was 4.0 equivalents (relative to L-phenylalanine), and the reaction temperature was 0° C.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(O)C>CCCCCC>[C:5]([C:4](=[C:3]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[S:9][CH3:10])[C:7]#[N:8])#[N:6]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(CNC(SC)=C(C#N)C#N)cc1
Temperature: 25 °C

Procedure:
A mixture of 17.03 g (0.1 mol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 12.98 ml (0.1 mol) of 4-methoxy-benzylamine and 60 ml of ethanol is heated under reflux for 2 hours. Approx. 90 ml of hexane are then added dropwise to the hot solution which is then allowed to cool to RT. The title compound which has precipitated in the form of colorless crystals is filtered off, washed with diethyl ether and dried under a HV; m.p. 100-101° C.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C:25]1[C:26]([I:40])=[C:27]([CH2:33][CH:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36])[C:28]([I:32])=[CH:29][C:30]=1[I:31])=[O:23])=[O:15]>O>[C:35]([CH:34]([CH2:38][CH3:39])[CH2:33][C:27]1[C:26]([I:40])=[C:25]([NH:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][N:12]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][N:9]([CH2:2][C:3]([OH:5])=[O:4])[CH2:8][CH2:7][N:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:2][C:3]([OH:5])=[O:4])[C:30]([I:31])=[CH:29][C:28]=1[I:32])([OH:37])=[O:36]
Reactant: O=C(O)CBr
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CNCCNCCN)c1I)C(=O)O
Solvent: O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O)c1I)C(=O)O
Yield: 41.3 %

Procedure:
According to the procedure described in Example 1, 52.1 g of bromoacetic acid (0.375 mol) are reacted with 62 g of compound (B) 3-[6- [[[2-[(aminoethyl)amino]ethyl]amino]acetylamino]-1-oxohexyl]amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.075 mol) in 400 ml of H2O. 32.9 g of 18-[[3-(2-carboxybutyl)-2,4,6-triiodophenyl]amino]-3,6,9-tris(carboxymethyl)-11,18-dioxo-3,6,9,12-tetraazaoctadecanoic acid (0.031 mol) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH2:11][CH2:10]1.[O:20]1[C:24]2[CH:25]=[C:26]([C:29](Cl)=[O:30])[CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]3[NH:22][C:21](=[O:32])[O:20][C:24]=3[CH:25]=2)=[O:30])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Reactant: O=C(Cl)c1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc3[nH]c(=O)oc3c2)CC1
Yield: 87.5 %

Procedure:
According to the method of Example 7, trans-4-[4-(2-methyloxyphenyl)piperazinyl]-2-buten-1-yl-amine and benzoxazolin-2-one-6-carbonyl chloride were subjected to acylation in the presence of sodium carbonate to obtain the product. Yield: 87.5%. mp: 200-202° C. 1HNMR (ppm, DMSO-d6) δ: 2.50 (m, 4H), 2.96 (s, br., 4H), 3.31 (m, 2H), 3.75 (s, 3H), 3.89 (t, 2H), 5.62-5.67 (m, 2H), 6.86 (m, 2H), 6.91 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.73-7.77 (m, 2H), 8.63 (t, J=5.6 Hz, 1H).