Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-tert-butyl-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:4][CH:5]1[C:9](=[O:10])[C:8]([CH2:11][CH2:12][CH:13]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH2:6]1)(=O)C.CC(C)(O)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:20]([O:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:8]1[CH:7]([C:25]#[N:26])[CH2:6][CH:5]([OH:4])[C:9]1=[O:10])(=[O:22])[CH3:21]
Reactant: CCCCCC(CCC1=CCC(OC(C)=O)C1=O)OC(C)=O
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CCC1C(=O)C(O)CC1C#N)OC(C)=O
Yield: 96.9 %

Procedure:
5-Acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone (15.5 g.) [prepared as described in (h) above], acetone cyanohydrin (6.0 g.), aqueous sodium carbonate solution (10.0% w/v; 5 ml.) and methanol (75 ml.) were stirred together and heated at reflux for 4 hours. Methanol was removed in vacuo, water (50 ml.) was added and the mixture extracted with diethyl ether. The ethereal extract was washed with water, dried with magnesium sulphate and evaporated in vacuo to give 2-(3-acetoxyoctyl)-3-cyano-5-hydroxycyclopentanone (14.3 g.) which was used as starting material in the following preparation (k) of 3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentane carbonitrile without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[F:18][C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@H:19]([F:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](F)CN1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](F)CN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
79B was prepared from 1A and 79A as described for 1C: MS: 462/464(M+H)+, HPLC (Method F) Ret time: 2.61 min.
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1.[C:30](=[O:32])=[O:31]>O1CCCC1>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH3:29])=[CH:27][C:28]=1[C:30]([OH:32])=[O:31]
Reactant: Cc1ccc(Cl)nc1
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc(Cl)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5M solution of butyllithium in hexane (9.4 mL, 23.5 mmol) was added to tetrahydrofuran (50 mL) and the mixture cooled to −78° C. The mixture was treated with 2,2,6,6-tetramethylpiperidine (4.4 mL, 26.0 mmol) and stirred at −78° C. for 30 minutes. The reaction mixture was then treated with 2-chloro-5-methylpyridine (3.00 g, 23.5 mmol) and stirred at −78° C. for a further 2.5 hours. The reaction mixture was poured into a beaker of dry ice and warmed to room temperature on a water bath, then extracted into water. The mixture was acidified with 2M hydrochloric acid, extracted into ether and washed with water (×2) and brine. The solution was dried over magnesium sulphate to yield the title product as a yellow solid, 1.65 g.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:20][OH:21]>O>[OH:21][N:20]=[C:11]([CH:2]1[CH:3]([C:8]([OH:10])=[O:9])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)[OH:12]
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2C=CC(C2)C1C(O)=NO
Temperature: 25 °C

Procedure:
30 ml of water was added to 24.6 g of 5-norbornene-2,3-dicarboxylic acid anhydride, and while cooling the reaction temperature below 20° C., 10.6 g of sodium carbonate and then 13.9 g of hydroxylamine hydrochloride were added. The mixture was reacted at room temperature for 1 hour and then reacted at a temperature of 60° to 70° C. for 1 hour. After cooling to room temperature, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide thus formed was collected by filtration.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:52])[N:30]([C@H:40]3[CH2:45][CH2:44][C@H:43]([O:46][CH:47]([CH3:51])[C:48]([NH2:50])=O)[CH2:42][CH2:41]3)[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:52]=[C:29]1[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:5][N:14]=3)=[CH:26][CH:25]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[C@H:40]1[CH2:45][CH2:44][C@H:43]([O:46][CH:47]([CH3:51])[C:48]#[N:50])[CH2:42][CH2:41]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(N)=O)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C#N)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogen carbonate (0.93 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL), pyridine (0.18 mL) and trifluoroacetic acid anhydride (0.15 mL) were added at 0° C., and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 47%).
Reaction SMILES: C(OC=[C:6]1[O:24][CH2:23][C@:9]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:12][CH2:13][C@@H:8]2[CH2:7]1)(=O)C.I([O-])(=O)(=O)=[O:34].[Na+].ClCCCl.O>C(#N)C.[Ru](Cl)(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@:9]12[CH2:23][O:24][C:6](=[O:34])[CH2:7][C@H:8]1[CH2:13][S:12][C:11]([NH:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:10]2
Reactant: CC(=O)OC=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC#N
Product: O=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [(4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4a,5,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6(4H)-ylidene]methyl acetate (C11) (430 mg, 0.938 mmol), ruthenium(III) chloride (5.8 mg, 28 μmol) and sodium periodate (98.5%, 407 mg, 1.87 mmol) in acetonitrile (0.5 mL) and a 1:1 mixture of 1,2-dichloroethane and water (5 mL) was stirred for 3 hours at room temperature, then allowed to stand for 18 hours without stirring. After dilution with saturated aqueous sodium thiosulfate solution (25 mL), the mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) provided the product as a white solid. Yield: 237 mg, 0.589 mmol, 63%. LCMS m/z 403.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.99 (br d, J=8 Hz, 2H), 7.49-7.54 (m, 1H), 7.43 (br dd, J=8, 7 Hz, 2H), 7.32 (ddd, J=9.0, 9.0, 6.3 Hz, 1H), 6.81-6.93 (m, 2H), 4.85 (d, J=11.7 Hz, 1H), 4.24 (d, J=11.5 Hz, 1H), 3.35-3.44 (m, 1H), 2.87-2.97 (m, 2H), 2.80 (dd, half of ABX pattern, J=18.7, 7.5 Hz, 1H), 2.63 (dd, J=13.1, 3.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([O:22][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl N-(3,4-difluoro-2-hydroxyphenyl)aminomethylenemalonate (80 mg) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 ml) was added benzyl bromide (30 μl). The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyloxy-3,4-difluorophenyl)-aminomethylenemalonate (90 mg), mp 87° C.; MS m/z 405 (M+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[N:8]([CH2:16][C:17]#[C:18][CH3:19])[C:9]([C:14]#[N:15])=[C:10]([C:12]#N)[N:11]=1.[CH2:20]([OH:22])[CH3:21]>>[Br:6][C:7]1[N:8]([CH2:16][C:17]#[C:18][CH3:19])[C:9]([C:14]#[N:15])=[C:10]([C:12]([O:22][CH2:20][CH3:21])=[O:2])[N:11]=1
Reactant: CCO
Reactant: CC#CCn1c(Br)nc(C#N)c1C#N
Reactant: O=S(=O)(O)O
Product: CC#CCn1c(Br)nc(C(=O)OCC)c1C#N
Temperature: 25 °C

Procedure:
25 ml of concentrated sulfuric acid was added to a 500 ml ethanol solution of 48.0 g of 2-bromo-1-(2-butynyl)-1H-imidazole-4,5-dicarbonitrile, and the mixture was heated under reflux for 110 hours. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in a mixture consisting of 500 ml of ethyl acetate and 500 ml of water, and the pH of the solution was adjusted to 8 using potassium hydroxide. The aqueous layer was extracted with 500 ml of ethyl acetate, and the organic layers were combined together. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 21.7 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:3).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[F:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])=[O:12])=[CH:9][CH:8]=1.[Na]>C(O)C>[NH2:4][C:3]1[N:5]=[C:15]([OH:16])[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][C:7]([F:6])=[CH:8][CH:9]=2)=[C:20]([OH:21])[N:2]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(NC(=O)c2ccc(F)cc2)c(O)n1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
Guanidine hydrochloride (1.35 g, 14.1 mmol) and diethyl 2-(4-fluorobenzamido)malonate (example 1, 3.0 g, 10.1 mmol) were added to a solution of sodium (0.46 g, 20.2 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours. The reaction was cooled down to room temperature. The solid product was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to give the title compound as a white solid (1.41 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([NH:23][C:24]([NH:26][C@H:27]3[CH2:32][C@H:31]4[CH2:33][C@H:29]([C:30]4([CH3:35])[CH3:34])[C@@H:28]3[CH3:36])=S)=[CH:18][CH:19]=2)[N:14]=[CH:13]1.N=C=N>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:23]=[C:24]=[N:26][C@H:27]3[CH2:32][C@H:31]4[CH2:33][C@H:29]([C:30]4([CH3:35])[CH3:34])[C@@H:28]3[CH3:36])=[CH:18][CH:19]=2)[N:14]=[CH:13]1
Reactant: COc1ccc(CCn2cnc3cc(NC(=S)N[C@H]4C[C@H]5C[C@@H]([C@@H]4C)C5(C)C)ccc3c2=O)c(F)c1
Agent: N=C=N
Solvent: C1CCOC1
Product: COc1ccc(CCn2cnc3cc(N=C=N[C@H]4C[C@H]5C[C@@H]([C@@H]4C)C5(C)C)ccc3c2=O)c(F)c1

Procedure:
N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]thiourea was gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hours in THF. The resin was filtered off and the solution of carbodiimide A was diluted to a known volume to give a solution of known molarity.
Reaction SMILES: O=C1C=CC=CC1C[C@@H]1COCN1[C:10](=[O:28])[C@@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[OH:33]O.O[Li].O>C1COCC1>[C:16]([O:15][C:13]([CH2:12][C@H:11]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:10]([OH:28])=[O:33])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1COC[C@H]1CC1C=CC=CC1=O
Reactant: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[(4R)-2-oxo-4-benzyl-(1,3-oxazolidin-3-yl)](3S)-3-[(4-chlorophenyl)methyl]-4-oxobutanoate (Step 3) (0.3 g, 0.656 mmol) in 10 mL of THF was added 0.1 mL of H2O2 (35%) and 33 mg of LiOH-H2O (0.787 mmol). The reaction was stirred at RT for 3 h and extracted with 30 mL of Et2O. The aqueous solution was acidified with 2N HCl to pH˜2 and extracted with 50 mL of EtOAc. These EtOAc extractions were combined, dried over Na2SO4 and concentrated in vacuo. (2S)-3-[(tert-Butyl)-oxycarbonyl]-2-[(4-chlorophenyl)methyl]-propanoic acid was obtained as light yellow oil (0.15 g) and was used in the next step without further purification. MS (ESI, pos. ion) m/z: 299.0 (M+1). Calc'd for C15H19ClO4: 298.10.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:28]=[C:29]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C1(CCBr)CCCCC1>>[CH:20]1([CH2:19][CH2:18][N:38]2[CH2:37][CH2:36][N:35]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([F:26])[CH:28]=3)[CH2:40][CH2:39]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(N2CCNCC2)cc1F
Reactant: BrCCc1ccccc1
Agent: BrCCC1CCCCC1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1ccc(N2CCN(CCC3CCCCC3)CC2)cc1F

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(3-fluoro-4-methoxyphenyl)piperazine (456 mg) and 2-cyclohexylethyl bromide (377 μL), respectively. Thus obtained crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=30:1) to provide 1-(2-cyclohexylethyl)-4-(3-fluoro-4-methoxyphenyl)piperazine (229 mg).
Reaction SMILES: [I:1][C:2]1[S:19][C:5]2[NH:6][N:7]=[C:8]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[C:4]=2[CH:3]=1.N1C2SC(C#N)=CC=2C=N1.[H-].[Na+].[C:32](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.O>[I:1][C:2]1[S:19][C:5]2[N:6]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:7]=[C:8]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[C:4]=2[CH:3]=1
Reactant: Ic1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#Cc1cc2cn[nH]c2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1cc2c(-c3ccc4ccccc4c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2s1
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of 75 mg of 5-iodo-3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole in 1 m L of N,N-dimethylformamide 1 was added 12 mg of sodium hydride at room temperature, stirred for 15 minutes, then added with 56 mg of trityl chloride, and stirred at this temperature for a day. The solution was added with water and diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30), to afford 93 mg of the title compound as colorless crystals.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11](O)(C)C.C(=O)=O.C([Mg]Cl)(C)C.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=1>C1COCC1.O.CO>[CH3:11][O:8][C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH:32]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[OH:33])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)c2ccc(C(=O)OC)cc2)cc1
Temperature: -25 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
(Andersen, K. E.; Mane, R. B.; Desai, U. V.; Hebbalkar, G. D. Collection Czechoslovak Chem. Commun. 1988, 53, 646-657.) 4-Iodobenzoic acid 3 (5.00 g, 19.1 mmol) is dissolved in anhydrous THF (60 ml), the solution is cooled to an internal temperature of −30° C. in a bath of iso-propanol/dry-ice, and i-PrMgCl (2 M in THF; 10.5 ml, 21.0 mmol) is slowly added dropwise, in order to keep the internal temperature at between −20° C. and −30° C. After the reaction mixture is stirred for an additional 40 min at a temperature of −25° C., a solution of 4-formylbenzoic acid methylester (16; 4.07 g, 24.8 mmol) in anhydrous THF (25 ml) is added dropwise, in order to keep the internal temperature at below −20° C. The mixture is stirred for an additional 30 min at −25° C. and is thawed over night to RT. Subsequently, methanol (30 ml) is added, the mixture is poured into water (500 ml), and extracted with Et2O. The organic phases are unified, washed with a saturated solution of NaCl, and dried over MgSO4. The solvent is removed, and the crude product as obtained is crystallized from chloroform/petroleum ether, in order to obtain 4.05 g (71%) of compound 5 as a colorless solid. Melting point 116° C. (Andersen, K. E.; Mane, R. B.; Desai, U. V.; Hebbalkar, G. D. Collection Czechoslovak Chem. Commun. 1988, 53, 646-657.) 123° C.). The spectroscopic data of the isolated compound 5 correspond to the values as published (Andersen et al. 1988, see above).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.I.[NH2:32][C:33]1[C:34]([C:41]([NH:43][C:44](=[NH:47])SC)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1>C(O)C>[NH2:32][C:33]1[C:34]([C:41]([N:43]=[C:44]([NH2:47])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=2)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCCNCC(N)=O)cc1
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)CNCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution composed of compound 4 (0.065 g, 0.194 mmol), Hunig's base (0.17 mL, 0.97 mmol) and ethanol (6 mL) was heated at 65° C. for 30 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (5, 0.072 g, 0.213 mmol) was added. The resulting solution was continuously stirred at 65° C. temperature for an additional three hours, then cooled to room temperature. The solvent was then removed by evaporation, and the resulting residue was column chromatographed on silica gel eluting with a mixture of methanol (0-22%), ammonium hydroxide (0-2.2%) and dichloromethane (100-75.8%). This afforded compound 6 (0.078 g, 84%) as a yellow solid. m.p. 92-94° C. (decomposed). 1H NMR (500 MHz, DMSO-d6) δ 1.54 (m, 4H), 2.51 (m, 2H), 2.89 (m, 2H), 3.20 (s, 2H), 3.31 (m, 2H), 4.00 (m, 2H), 6.89 (d, 2H), 7.08 (br, 2H), 7.12 (d, 2H), 7.57 (br, 2H), 9.08 (br, 1H). m/z (ESI) 478.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([NH2:16])[C:4]=2[CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([NH:16][C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC1c2ccccc2Sc2ccc(Cl)cc21
Product: O=C(CCc1ccccc1)NCC(=O)NC1c2ccccc2Sc2ccc(Cl)cc21

Procedure:
Prepared in analogy to example 1.1 from rac-2-chloro-9H-thioxanthen-9-ylamine (CA [51065-24-8]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).