Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccccc1O[C@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.2 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.70 mg, 24.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s, 3H), 2.60 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H) 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.8 (M+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:50])[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:37][C:26]1[CH:25]=[C:24]([N:23]([CH2:22][C:18]2[CH:17]=[C:16]([C:12]3[C:13]([CH3:15])=[CH:14][C:9]([OH:8])=[CH:10][C:11]=3[CH3:50])[CH:21]=[CH:20][CH:19]=2)[S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:39])=[O:40])[CH:29]=[CH:28][C:27]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(O[Si](C)(C)C(C)(C)C)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-(4-{[(4′-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (6.32 g, 8.76 mmol) in tetrahydrofuran (60 mL) was added tetrabutylammonium fluoride (1 M solution, 9.64 mL, 9.64 mmol) under stirring at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (4.0 g, yield 75%) as colorless crystals.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[C:17]([N+:25]([O-])=O)[C:18]([F:24])=[C:19]([F:23])[C:20]=3[Cl:22])[C:15](=[O:28])[C:14]([C:29]([O:31]CC)=[O:30])=[CH:13]2)[C:9]([F:34])=[CH:8][C:7]=1[F:35])(C)(C)C>[Fe].C(O)=O>[NH2:25][C:17]1[C:18]([F:24])=[C:19]([F:23])[C:20]([Cl:22])=[C:21]2[C:16]=1[C:15](=[O:28])[C:14]([C:29]([OH:31])=[O:30])=[CH:13][N:12]2[C:10]1[C:9]([F:34])=[CH:8][C:7]([F:35])=[C:6]([NH2:5])[N:11]=1
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: O=CO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
To 10 ml of formic acid was added 960 mg of ethyl 1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate together with 1.0 g of iron powder, and the mixture was stirred at 80 to 90° C. for 5 hours and 40 minutes. The insoluble content was separated by filtration through celite, and the content separated by the celite and the celite were washed with formic acid and chloroform. The filtrate and the washings were concentrated under reduced pressure. To the residue was added the 6 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1), and the mixture was heated under reflux for 2 hours with stirring and allowed to cool. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 625 mg of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:20]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 43 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)- 3,4-diazabicyclo[4.1.0]hept-2-en-5-one and 3.9 g (35.9 millimoles) of methoxyacetyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 4 hours, while stirring. The product was filtered off under suction at 10° C., washed first with tetrahydrofuran and then with water and recrystallized from propanol. 3.5 g (43%) of 2-[p-(methoxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one were obtained as colorless crystals. Mp.: 206° 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]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:2]=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[CH3:18][CH:14]1[CH2:13][C:12]2[C:19](=[CH:20][CH:21]=[CH:22][C:11]=2[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:15]1=[O:17]
Reactant: CC(Cc1ccccc1-c1cnc2ccccc2c1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1Cc2c(cccc2-c2cnc3ccccc3c2)C1=O
Temperature: 80 °C

Procedure:
A solution of 145 g (0.5 mol) of 2-(2-(3-quinolyl)benzyl)propionic acid in 119 g (1.0 mol) of thionyl chloride was stirred at room temperature for 18 hours. Excess thionyl chloride was removed at 10 mbar and the acid chloride was taken up in 400 cm3 of toluene. The solution was added dropwise at 10° C. to a suspension of 73 g (0.55 mol) of AlCl3 in 1000 cm3 of toluene and heated at 80° C. for 1 hour. The reaction mixture was poured onto 1000 g of ice and acidified with concentrated aqueous HCl to a pH of 1. The organic phase was separated off and the aqueous phase was further extracted 3 times with 200 cm3 each time of Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution and subsequently dried (MgSO4). This gave 64 g (47%) of 2-methyl-4-(3-quinolyl)-1-indanone which was further reacted without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]1([NH:15][C:12]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][NH:10][N:9]=2)=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1n[nH]cc1-c1ccccc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]cc1-c1ccccc1
Yield: 28.5 %

Procedure:
A solution of 4-phenyl-1H-pyrazole-3-carboxylic acid (75 mg; 0.4 mmol) (prepared according to Example 228C), aniline (45 μl; 0.48 mmol), EDAC (92 mg; 0.48 mmol) and HOBt (65 mg; 0.48 mmol) in 5 ml of DMF was stirred at room temperature overnight. The reaction was evaporated then purified by flash column chromatography eluting with 1:3 then 1:2 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 30 mg of 4-phenyl-1H-pyrazole-3-carboxylic acid phenylamide as a white solid. (LC/MS: Rt 3.12 [M+H]+ 264).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH2:29][CH:30]1[CH2:36][CH:35]2[N:37]([C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]([C:48]#[N:49])=[CH:40][CH:39]=3)[CH:32]([CH2:33][CH2:34]2)[CH2:31]1>CN(C=O)C>[C:48]([C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([N:37]2[CH:35]3[CH2:34][CH2:33][CH:32]2[CH2:31][CH:30]([NH:29][C:8](=[O:10])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:36]3)=[CH:39][CH:40]=1)#[N:49]
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Reactant: CCOCCOCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCOCC(=O)NC1CC2CCC(C1)N2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
165RL54 (19 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluorophosphate (HBTU, 49 mg, 0.13 mmol), 1-hydroxybenzotriazole (18 mg, 0.13 mmol) and triethylamine (37 PL, 0.26 mmol) were dissolved in DMF (4 mL). 165RL21 (36 mg, 0.13 mmol)) was added and the mixture was shaken at rt for 30 min. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel using ethyl acetate/methanol (9:1) as eluent, giving the desired compound (38.1 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18]C)=[O:17])[NH:7][C:6]=2[CH2:5][O:4][CH2:3]1.[OH-].[Li+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([OH:18])=[O:17])[NH:7][C:6]=2[CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)COCC3(C)C)c(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2nc3c([nH]2)COCC3(C)C)cc1C(=O)O
Temperature: 50 °C

Procedure:
To methyl 5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 449.3, 27 mg, 0.086 mmol) in THF (3 mL) was added 2 M lithium hydroxide (430 μl, 0.86 mmol) and the mixture was heated at 50° C. for 16 hrs. The volatile solvents were removed in vacuo and the resulting residue was neutralized with 2M HCl to pH=3 and concentrated in vacuo to give a white solid and used in the next reaction without doing further purification. m/z (ES−) 299 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH:18]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][S:25]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Product: Cc1ccc(NS(=O)(=O)CC2CCCCC2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 0.71 g of tert-butyl [3-amino-6-methyl-2-oxo-1,2-dihydropyridinyl]-acetate (WO 97/01338) at 0° C. under a nitrogen atmosphere was added 0.60 mL cyclohexylmethanesulfonyl chloride (J. F. King et al J. Am. Chem. Soc. 114, 1743 (1992)). After stirring at room temperature for 3 hours the reaction mixture-was concentrated. The residue was dissolved in ethyl acetate, washed successively with 0.1 N hydrochloric acid, water and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a mixture of 0.2 mL water and 1.8 mL trifluoroacetic acid. After stirring at room temperature for 4 h, water and ethyl acetate were added. The organic layer was separated, washed twice with 0.1 N hydrochloric acid, dried over sodium sulphate and concentrated. The solid residue was washed with a cold dichloromethane/diethyl ether mixture to give 0.72 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH:33]1([NH2:36])[CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>CC(O)=O.C1COCC1>[CH:33]1([NH:36][CH:11]([C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[C:6](=[O:32])[O:5][CH2:4]3)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(CC(NC4CC4)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and cyclopropanamine (6.5 mg, 0.114 mmol) in anhydrous 5% HOAc/THF (1 mL) was added NaCNBH3 (18 mg, 0.28 mmol). The reaction was sealed and shaken at ambient temperature for 16 h. LCMS showed that the product was formed. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 480 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([OH:18])([C:14](F)(F)F)=[O:13]>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:14][C:12]([OH:18])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1cccc2cccnc12
Product: O=C(O)Cc1cccc2cccnc12

Procedure:
The title compound (278 mg) was prepared from 8-bromoquinoline (3.0 g, 14.5 mmol) according to protocol P above. LCMS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (CD3OD, 400 MHz): δ 9.01 (d, 1H, J=3.6 Hz), 8.72 (d, 1H, J=6.4 Hz), 8.06 (d, 1H, J=6.8 Hz), 7.87 (d, 1H, J=5.6 Hz), 7.77 (m, 2H), 4.31 (s, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[O:12][CH:13]([CH3:17])[C:14](O)=[O:15]>C1(C)C=CC=CC=1>[Cl:29][C:21]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:6]([Cl:5])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[O:12][CH:13]([CH3:17])[C:14]([Cl:3])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)Cl
Temperature: 100 °C

Procedure:
15 g (0.126 mol) of thionyl chloride were added dropwise to a stirred solution of 19.7 g (0.05 mol) of the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethylphenoxy)-phenoxy]-propionic acid in 100 ml of toluene at 20° C. The mixture was heated to 100° C. for 2 hours. Thereafter, the reaction mixture was evaporated down by stripping off the volatile constituents under reduced pressure. In this manner, the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)-phenoxy]-propionic acid-chloride was obtained in the form of an oily product, which was used for the further reaction. ##STR37##
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13]C(=O)CCCCC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(=O)O[C@H]1CCN(Cc2ccccc2)C1
Solvent: CO
Product: O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
After removal of hexane from the eluate containing (S)-N-benzyl-3-hydroxypyrrolidine under reduced pressure, vacuum distillation of the residue (bp. 160° C./3 mm Hg) yielded 2.21 g of (S)-N-benzyl-3-hexanoyloxypyrrolidine in colorless oily form. The specific rotation of this product was [a]D20 -15.3° (c=5, MeOH). This (S)-N-benzyl-3-hexanoyloxypyrrolidine was further hydrolyzed under alkaline conditions to produce the corresponding (S)-N-benzyl-3-hydroxypyrrolidine. After tosylation, the optical purity of this product was found by HPLC to be 100% e.e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][O:46][CH:47]1[CH2:50][NH:49][CH2:48]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:49]2[CH2:50][CH:47]([O:46][CH3:45])[CH2:48]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC1CNC1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)C1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), 3-methoxy-azetidine (57 mg, 0.57 mmol) and DIPEA (0.27 mL, 1.5 mmol) in DMF (2 mL). MS (LC-MS): 373.0 [M]+
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2].[CH:18]([Mg]Br)=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:12][CH:19]=[CH:18]2)[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CCN(CC)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cc1cccc2cc[nH]c12
Temperature: -70 °C
Reaction time: 5 h
Yield: 5 %

Procedure:
N,N-Diethyl-2-(2-nitrophenyl)acetamide (87.2 g, 0.369 mol) is dissolved in tetrahydrofuran (1.5L), and the mixture is cooled to −70° C. To the mixture is added dropwise a 1M solution of vinylmagnesium bromide in tetrahydrofuran (1.11 L, 1.11 mol). After the addition, the mixture is stirred at −50° C. for additional 5 hours. The reaction solution is poured into an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography (chloroform, hexane/ethyl acetate=4/1) to give the title compound (4.02 g, yield: 5%).
Reaction SMILES: C(OC([N:8]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:9]1[N:10]=[CH:11][C:12]([C:36]2[CH2:41][CH2:40][CH:39](CS([O-])(=O)=O)[CH2:38][CH:37]=2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.[N-:54]=[N+:55]=[N-:56].[Na+]>CN(C=O)C>[N:54]([CH:39]1[CH2:40][CH2:41][C:36]([C:12]2[N:13]=[C:14]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:22][CH:21]=4)=[N:18][N:19]=3)[C:9]([NH:8][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])=[N:10][CH:11]=2)=[CH:37][CH2:38]1)=[N+:55]=[N-:56]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(CS(=O)(=O)[O-])CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N=[N+]=[N-])CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 94.8 %

Procedure:
To a solution of [4-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclohex-3-en-1-yl]methanesulfonate (138 mg, 0.18 mmol) in anhydrous DMF (1 mL) was added sodium azide (59 mg, 0.91 mmol) and the reaction mixture was heated at 70° C. under an atmosphere of nitrogen for 15 h. The reaction mixture was cooled to room temperature, quenched with water and diluted with EtOAc. An aqueous saturated brine solution was added, the layers were separated and the organic layer was washed twice more with an aqueous saturated brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to a brown oil to provide tert-butyl N-[[4-[5-[6-(4-azidocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (103 mg, 94%), which was used without any further purification in the next step. LC/MS m/z 604.7 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C1(C)C=CC=CC=1>[C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][N:9]([C:13]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:23])[CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccc(C23CNCC2C3)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)N1CC2CC2(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A mixture of 7.95 g. of 1-phenyl-3-azabicyclo-[3.1.0]hexane and 7.4 g. of phthalic anhydride in 300 ml. of toluene is refluxed for 1/2 hour and then allowed to stand overnight. The solution is extracted three times with 1N sodium hydroxide and made extremely acid with 1N hydrochloric acid. The solid which separates is extracted with chloroform, dried over magnesium sulfate, filtered and filtrate evaporated to a glass residue. This glass is triturated in hexane and filtered giving the product as a light pink solid, IR 5.85, 6.10μ.
Reaction SMILES: [NH2:1][C:2]12[CH2:6][C:4](C(=O)C)([CH2:5]1)[CH2:3]2.ClC1C=CC=[C:13]([C:17]([O:19]O)=[O:18])C=1>C(Cl)(Cl)Cl>[C:17]([O:19][C:4]12[CH2:3][C:2]([NH2:1])([CH2:5]1)[CH2:6]2)(=[O:18])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C12CC(N)(C1)C2
Solvent: ClC(Cl)Cl
Product: CC(=O)OC12CC(N)(C1)C2
Reaction time: 24 h

Procedure:
A solution of 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone (1 mmol) in 0.5 mL of chloroform is added to a stirred mixture of m-chloroperbenzoic acid (1.5 mmol) in 2 mL of chloroform at r.t. The solution is stirred in the dark for 24 h. The mixture is filtered, and the filtrate is washed with 10% sodium bicarbonate and then water. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by a flash chromatography on silica gel (EtOAc/hexanes) to give 3-aminobicyclo[1.1.1]pentan-1-yl acetate.