Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,6 dimethoxybenzaldehyde. MS (ESI) m/z 529.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[S:59]1[CH:63]=[CH:62][CH:61]=[C:60]1[CH2:64][CH2:65][NH2:66]>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26](=[O:27])[NH:66][CH2:65][CH2:64][C:60]2[S:59][CH:63]=[CH:62][CH:61]=2)=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1cccs1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0,401 g, 1.01 mmol) in dry ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.199 g, 1.04 mmol). this mixture was stirred 2 hours, then triethylamine (0.18 mL, 1.3 mmol) and 2-thiopheneethaneamine hydrochloride (0.214 g, 1.30 mmol) were added. After stirring the resulting mixture an additional 18 hours, the mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, saturated aqueous sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 67% ethyl acetate/hexane eluant), and dried for 48 hours under vacuum at 60° C. to provide 0.310 g (61%) of product; 1H NMR (CDCl3) δ1.49-1.60 (2H, m), 1.55 (3H, s), 1.65-2.00 (12H, m), 2.88 (2H, t, J 6 Hz), 3.26 (1H, d, J 14 Hz), 3.40-3.60 (3H, m), 4.82 (1H, br s), 5.17 (1H, br s), 6.36 (1H, br s), 6.69 (1H, d, J 2 Hz), 6.85-6.90 (1H, m), 6.95 (1H, d, J 2 Hz), 7.00-7.22 (3H, m), 7.36 (1H, d, J 8 Hz), 7.58 (1H, d, J 8 Hz), 8.29 (1H, br s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:52])[CH2:22][C@H:23]([NH:44]C(=O)OC(C)(C)C)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33](=[O:43])[CH2:32]3)=[CH:27][CH:26]=2)[CH2:16]1>C(Cl)Cl>[NH2:44][C@@H:23]([CH2:22][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:16]1)=[O:52])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33](=[O:43])[CH2:32]2)=[CH:29][CH:30]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(N4CCN(c5ccccc5)C(=O)C4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(N4CCN(c5ccccc5)C(=O)C4)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
tert-Butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxo-1-(4-(3-oxo-4-phenylpiperazin-1-yl)phenyl)butan-2-ylcarbamate (123A) (0.29 mmole, 206 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (45-55% CH3CN in H2O) to afford 4-(4-((R)-2-Amino-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)phenyl)-1-phenylpiperazin-2-one (233) (0.11 mmole, 14 mg, two-step yield: 7.9%). ESI-MS: m/z 609.5 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.54-1.83 (m, 1H) 1.87-2.15 (m, 3H) 2.18-2.38 (m, 3H) 2.61-2.80 (m, 1H) 2.80-2.91 (m, 1H) 2.93-3.05 (m, 2H) 3.10-3.24 (m, 2H) 3.26 (s, 3H) 3.33-3.59 (m, 4H) 3.68 (t, J=5.43 Hz, 1H) 3.74-4.09 (m, 4H) 4.49-4.78 (m, 3H) 4.84 (br. s., 1H) 6.94-7.08 (m, 1H) 7.15-7.30 (m, 2H) 7.30-7.39 (m, 2H) 7.40-7.55 (m, 3H) 7.55-7.70 (m, 3H) 7.76-7.86 (m, 1H) 7.88-7.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:23])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
6-Methyl-5-nitroisoquinoline (100.0 g, 531 mmol) in Dichlormethane (1 L) was added to a 2 L 3-necked round bottomed flask and cooled to 5° C. Purified m-chloroperoxobenzoic acid (129 g, 749 mmol) was added to this stirred solution [m-CPBA was extracted with saturated Phosphate buffer pH 7.5 and DCM]. Initially with the addition of mCPBA the reaction exothermed, but then endothermed to 2° C. After 20 min, the contents in the flask solidified to a yellow/white solid and more DCM (300 mL) was added. The reaction was allowed to stir overnight at room temperature. DCM (2 L) was added and the mixture washed with 1 N NaOH (1 L), saturated sodium bicarbonate (1 L) and brine (1 L). The solution was dried over sodium sulfate and concentrated to give 6-methyl-5-nitroisoquinoline-N-oxide (81.7 g, 75%). MS (M+H)+ 205.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:54])[CH2:21][N:22]([C@@H:43]([CH3:53])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)C([C@@H]2CCCN2S(C2C=CC3C(=CC=CC=3)C=2)(=O)=O)=O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO.O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:54])[CH2:21][NH:22][C@@H:43]([CH3:53])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@H](C)N(C[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)C(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Yield: 68.6 %

Procedure:
2.61 g of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)-N-((2S)-1-(2-naphthylsulfonyl)-pyrrolidine-2-carbonyl)amino]ethyl}carbostyril are dissolved in 100 ml of methanol, and 35 ml of 1N potassium hydroxide-methanol and 10 ml of water are added thereto. The mixture is refluxed for 3 hours with stirring. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized twice from ethyl acetate. 1.1 g of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril are obtained as colorless needles. Yield: 68.8%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].O[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:13])([F:14])[F:15])[CH2:18][CH2:19]1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.8 %

Procedure:
In a round bottom flask wrapped with foil, methyl 4-hydroxy-3-(trifluoromethyl)benzoate (500 mg, 2.13 mmol) was dissolved in methylene chloride (10 mL). 4-Hydroxy-1-methyl-piperidine (0.25 mL, 2.13 mmol), PPh3 (670 mg, 2.56 mmol), and DIAD (0.50 mL, 2.56 mmol) were added thereto, and the mixture was stirred at room temperature for 23 hours. DTAD (4.26 mmol) and PPh3 (1.12 g, 4.26 mmol) were added at 0° C. to the reaction mixture, which was stirred at room temperature for 24 hours. The resulting mixture was concentrated and then purified by silica gel chromatography (Hex/EA=1/1→DCM/MeOH=10/1) to obtain the title compound (512 mg, 76%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N+:9]([O-])=O)=[C:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:9][C:7]1[S:8][C:4]([C:1](=[O:3])[NH2:2])=[CH:5][C:6]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)Cc1cc(C(N)=O)sc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(C(N)=O)sc1N
Yield: 95.9 %

Procedure:
Ethyl 5-carbamoyl-2-nitrothiophene-3-acetate (600 mg, 2.33 mmol) was dissolved in aqueous dioxan (7 ml, 4:1 dioxan/water) and treated with reduced iron powder (1.55 g, 27.77 mmol) and iron sulfate heptahydrate (200 mg, 0.68 mmol). The reaction mixture was refluxed for 1 hour then filtered through celite filter-aid and washed through with ethyl acetate. The organic phase was washed with saturated sodium aqueous hydrogen carbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and evaporated to a red/black viscous oil and then chromatographed on silica gel using hexane/ethyl acetate (1:2) as eluent to give 510 mg of ethyl 2-amino-5-carbamoylthiophene-3-acetate. MS(ES): m/e 229 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn2cccc(O)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccn2cc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (10 g), acetic anhydride (10.3 g) and pyridine (10.7 g) in anhydrous dichloromethane (100 ml) was stirred for 1 hour at ambient temperature and allowed to stand overnight. The mixture was washed with water, and the organic layer was separated. The aqueous layer was neutralized with sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 8-acetoxy-2-methylimidazo[1,2-a]pyridine (13.1 g) as oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.COC(=O)C(OC)CC1C=CC=C(OCC2C=CC=CC=2)C=1.COC(=O)CCC1C=CC(OCC2C=CC=CC=2)=CC=1>>[CH3:1][O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Agent: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Yield: 47.1 %

Procedure:
The title compound was prepared from 3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester (Preparation 2, step 2) (3.3 gr, 10.12 mmol) via the same procedure used for the preparation of 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 3) to produce an oil that was purified by chromatography (silica gel, hexanes/ethyl acetate 6:1) to produce two compounds: 3-(4-Benzyloxy-phenyl)-propionic acid methyl ester (1.5 gr, Rf aprox. 0.65) and the desired compound (1.5 gr, Rf aprox. 0.2). MS (ES) for C19H22O4 [M+NH4]+: 332.3.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>Br.C(O)(=O)C>[Br:21][CH:9]([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.25 g. of 1-(3-benzoylpropionyl)-L-proline (Example 16) in 80 ml. of acetic acid is added 5 drops of 30% hydrogen bromide in acetic acid followed by 4.80 g. of bromine in 20 ml. of acetic acid. The mixture is stirred at room temperature for 18 hours, evaporated to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed with water and saline, dried over magnesium sulfate and evaporated to dryness giving the desired product as 10.3 g. of a white glass.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([S:19][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (5.64 g) and 1,4-dibromobutane (5.88 g) were added to a solution of thiophenol (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 6.67 g of 4-phenylthiobutyl bromide.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14]([CH3:16])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:13][C:14]1([CH3:16])[O:12][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C=O)ccc2O1
Temperature: 90 °C
Yield: 35 %

Procedure:
A suspension of 5-formylsalicylic acid (Aldrich, 4.12 g, 24.8 mmol) in TFA (30 ml), TFAA (10 ml) and acetone (10 ml) was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure. The residual oil was taken up in EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried- over MgSO4 and the solvent was removed under reduces pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (80/20)) to give 1.8 g (35%) of the title compound as a white powder. 1H NMR (CDCl3) δ: 1.80 (s, 6H), 7.09 (d, J=8.7 Hz, 1H), 8.09 (dd, J=8.7, 2.3 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.O.[H][H].CCOCC>CN(C)C=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12]/[CH:13]=[CH:14]\[C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#CCN2CCc3nc(N)sc3CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(/C=C\CN2CCc3nc(N)sc3CC2)cc1
Yield: 29.5 %

Procedure:
Prepared analogously to Example 12 by catalytic hydrogenation of 1.30 g (4.21 mmol) of 2-amino-6-(3-(4-cyano-phenyl)-2-propyn-1-yl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine. 0.3 H2O in anhydrous dimethylformamide under 1 bar of hydrogen pressure using Lindlar catalyst (5% palladium on calcium carbonate, contaminated with lead) at ambient temperature. Yield: 29.5% of theory, Melting point: 186°-188° C. (ether).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:20]([OH:21])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][N:14]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(O)c1cnccn1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2cnccn2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.38 g 1-acetyl-2-indolinone, 3.41 g pyrazine-2-carboxylic acid, 8.83 g TBTU, 4.21 g HOBT-hydrate and 21.8 ml ethyldiisopropylamine are stirred in 70 ml DMF for 15 hours at ambient temperature. The mixture is poured onto 400 ml ice water and 10 ml of conc. hydrochloric acid and stirred for 1 hour. The precipitate is suction filtered, washed with water, stirred with methanol, suction filtered again, washed with methanol and dried at 100° C.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14]OS(C)(=O)=O)=[CH:11][N:10]=[CH:9]2)=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1)#[N:2].[I-].[Na+].CCN(CC)CC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]1[N:10]=[CH:9][N:8]2[CH:7]([C:6]3[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N+:22]([O-:24])=[O:23])[CH2:14][CH2:13][C:12]=12
Reactant: CS(=O)(=O)OCCc1cncn1Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2CCc3cncn32)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The crude residue, 4-[5-(2-hydroxyethyl)imidazol-1-ylmethyl]-3-nitrobenzonitrile, is then taken up in CH2Cl2 (10 mL), cooled to 0° C., and treated with Et3N (0.58 mL, 4.19 mmol). To this solution is added methanesulfonyl chloride (0.13 mL, 1.68 mmol). After 0.5 h the solution is diluted with CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4) and concentrated to give crude methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]ethyl ester. A suspension of the methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]-ethyl ester residue, DMF (17 mL), sodium iodide (0.630 g, 4.19 mmol), Et3N (0.58 mL, 4.19 mmol), and potassium carbonate (0.580 g, 4.19 mmol) is heated to 60° C. for 1 hour and then 75° C. for an additional 2 h. At that point the suspension is concentrated and diluted with CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4). The residue is then purified via HPLC (reversed phase, CH3CN/H2O) to give 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile as a solid. MS (ESI) m/z 254.9 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.48-2.57 (m, 1 H), 2.81-2.92 (m, 1 H), 2.92-3.01 (m, 1 H), 3.35-3.47 (m, 1 H), 6.03 (dd, J=8.6, 3.5 Hz, 1 H), 6.80 (d, J=8.3 Hz, 1 H), 6.89 (s, 1 H), 7.36 (s, 1 H), 7.81 (dd, J=7.8, 1.8 Hz, 1 H), 8.41 (d, J=1.8 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH:9]=1)[CH3:2].[CH2:11]([O:13][C:14](=[O:20])[C:15](OCC)=[O:16])[CH3:12].C(Cl)(Cl)Cl.Cl>C(OCC)C.O1CCCC1.O>[CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH:6]([C:15](=[O:16])[C:14]([O:13][CH2:11][CH3:12])=[O:20])[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: CCOC1=CCCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reaction time: 8 h
Yield: 76 %

Procedure:
41.40 g (0.29 mol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 310 mL of diethyl ether and 325 mL of 1M LiN(1MS)2 in tetrahydrofuran were added dropwise at −50° C. After 30 minutes at the same temperature, 44.2 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight (TLC chloroform). 300 mL of water were then added, the pH adjusted to 4-5 by adding 1 N HCl and the resulting solution extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH2:21][CH3:22])[CH2:35][CH2:34]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccccc1N1CCN(CCCC2CC(c3ccc(OC)c(OC)c3)=NO2)CC1
Yield: 61.6 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (22.96 mg, 0.090 mmol), 1-(2-ethoxyphenyl)piperazine hydrochloride (20.0 mg, 0.082 mmol), molecular sieve (5 beads), NaBH(OAc)3 (52.4 mg, 0.247 mmol) and diisopropylethylamine (26.95 L, 0.082 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.9 mg (68.2%) of the target compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl-4(R)-t-butyldimethylsilyloxy-2(S)-hydroxymethylpyrrolidine (50.0 g, 150.8 mmol) and triethylamine (42.0 ml, 300 mmol) in CH2Cl2 (11) was added methane sulfonyl chloride (12.4 ml, 160 mmol) over a period of 5 minutes and stirring was continued for 1 hour. The solvent was evaporated in vacuo diluted with EtOAc (800 mL) and washed sequentially with aqueous citric acid and NaHCO3. The organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by chromatography (SiO2, 15% EtOAc in hexanes). The title compound was obtained as a pale yellow solid FAB Mass spectrum, m/z=410(M+1).