Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][C:7](=[N:20]O)[CH2:8]2)[CH2:3]1.CCCCCC.[H][H]>C(O)(C)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][CH:7]([NH2:20])[CH2:8]2)[CH2:3]1
Reactant: [H][H]
Reactant: COc1cccc(C23CCN(C)CC2(C)CCC(=NO)C3)c1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cccc(C23CCN(C)CC2(C)CCC(N)C3)c1
Temperature: 50 °C
Yield: 9.5 %

Procedure:
A slurry of oxime 19 (2.35 g, 0.077 mol) in anhydrous isopropanol (100 mL) and anhydrous toluene (200 mL) was heated to reflux until the solution became clear. The heat was turned off, and Na (20 g, 0.87 mol) was added carefully in a such rate that a steady reflux was maintained (make 30-40 pieces and store under hexane) over 1.5 h. The first addition was kept small. (Note hydrogen evolution!). At the end the reaction was slower, so the heating mantle was turned back on to speed things up. The reaction mixture was heated to reflux until all Na was consumed followed by cooling to 50° C. and quenching with careful addition of water (250 mL). The toluene layer was separated and the aqueous layer extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (50% CMA80 in CHCl3) to afford 2.11 g (94%) of 20 as a colorless oil: LCMS (APCI): m/z 289.4 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.14-7.44 [m, 3H], 6.71-6.74 [m, 1H], 3.80 [s, 3H], 3.05 [m, 1H], 2.77 [m, 1H], 2.64 [d, J=12 Hz, 1H], 2.27-2.30 [m, 2H], 2.26 [s, 3H], 2.02-2.12 [m, 3H], 1.68-1.71 [m, 2H], 1.46-1.49 [m, 2H], 1.24 [m, 3H], 1.20 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 159.2, 150.2, 128.5, 121.8, 116.5, 110.0, 65.4, 55.5, 53.0, 47.1, 46.7, 43.8, 43.3, 36.6, 36.2, 32.2, 25.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:20])[CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[O:20][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
In DMF (10 ml), 3-benzyloxy-5-methoxy-4-nitrophenol (1.43 g, 5.20 mmol), potassium carbonate (1.08 g, 7.79 mmol) and methyl bromoacetate (591 μl, 6.24 mmol) were stirred at room temperature for 2 days. The reaction mixture was poured in water (200 ml), followed by extraction with ether (200 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (20:1) eluate fractions, the title compound (1.53 g, 85%) was obtained as a yellow crystalline solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[N:17]2[C@@:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)([CH3:30])[C:19](=[O:29])[N:20]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[C:16]2=[N:15][CH:14]=1)=[O:12])[C:7](O)=[O:8])(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:69]1[CH2:74][CH2:73][CH2:72][CH:71]([C:75]([NH2:77])=[O:76])[CH2:70]1>CN(C=O)C.O>[NH2:2][C:1](=[O:3])[CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[N:17]2[C@@:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=3)([CH3:30])[C:19](=[O:29])[N:20]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:16]2=[N:15][CH:14]=1)=[O:12])[C:7]([N:69]1[CH2:74][CH2:73][CH2:72][CH:71]([C:75](=[O:76])[NH2:77])[CH2:70]1)=[O:8]
Reactant: NC(=O)C1CCCNC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CCC(N)=O)C(=O)O)n21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CCC(N)=O)C(=O)N3CCCC(C(N)=O)C3)n21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
To a solution of (S)-4-carbamoyl-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-butyric acid (50 mg, 0.088 mmol) in DMF (1 mL) was added (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25 mg, 0.132 mmol), benzotriazol-1-ol (18 mg, 0.132 mmol) and triethylamine (47 μL, 0.395 mmol). The reaction mixture was stirred at room temperature for 20 min then piperidine-3-carboxylic acid amide (17 mg, 0.132 mmol) was added. The reaction mixture was stirred at room temperature for 64 h. The reaction mixture was then diluted with water and filtered through a glass frit. The solution was then extracted with CH2Cl2 (×3). The combined organic layers were then washed with water (×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified via reverse phase HPLC to afford 60 mg of the title compound as a white solid, m/z 679.6 [M+1]+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:8])C.[OH-].[Na+]>Cl>[C:10]1([NH:9][C:7]2[NH:8][CH:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(CNC(=N)Nc1ccccc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Nc2ncc[nH]2)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
The guanidine (b) was dissolved in HCl (5 mL, 6 M) at 0° C. and then stirred for 2 h. After the starting material was consumed, NaOH (25%) was added until a precipitate formed. This mixture was stirred for 30 min. The reaction was then poured into NaOH (0.5 M), extracted with CH2Cl2, dried and concentrated. Flash chromatography afforded (c) (0.95 g, 50%). NMR (500 MHz, DMSO-d6) δ 8.58 (s, br, 1H), 7.34-6.74 (m, 5H), 6.68 (s, 2H), 6.62 (br, 2H), 3.82 (s, 6H), 3.73 (s, 3H). MS: 157.6 (M−H)−; 160.0 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=1[CH2:66][NH2:67]>CN(C)C=O>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][C:57]=1[CH2:66][NH:67][C:8](=[O:10])[C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C(=O)NCc1cc(C(F)(F)F)ccc1F)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of (S)-2-phenylbutanoic acid (1-d, 50 mg, 0.30 mmol, Sigma-Aldrich, Milwaukee, Wis.) and diisopropylethylamine (98 uL, 0.60 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 158 mg, 0.30 mmol). After 15 min, (2-fluoro-5-(trifluoromethyl)phenyl)methanamine (1-g, 60 mg, 0.30 mmol, Synthesis, Inc., Wyndham, N.H.) was added. The reaction mixture was stirred for 3 h, partitioned between dichloromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was concentrated in vacuo to give the desired product (1-1); HRMS (M+1)=340.129; 1H NMR (500 MHz, CDCl3) δ7.49 (bs, 1 H), 7.41 (d, 1 H, J=6.5 Hz), 7.34-7.26 (m, 5 H), 7.10 (t, 1 H, J=9.0 Hz), 5.77 (bs, 1 H), 4.47 (d, 1 H, J=3.0 Hz), 3.30 (t, 2 H, J=7.5 Hz), 2.22 (m, 1 H), 1.82 (m, 1 H), 0.89 (t, 3 H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (75 mg, 0.19 mmol) in tetrahydrofuran/methanol (2.5 mL/2.5 mL) was added 1M sodium hydroxide aqueous solution (2.89 mL, 2.89 mmol). The mixture was heated to reflux and stirred for 1.5 h. LC-MS indicated that 2005467-012-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid solution. The precipitated solid was filtered, and dried to give 56.7 mg of 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 78.5%.MS (ESI+APCI) M+1=375.2.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[Cl:23][CH2:24][C:25]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:26]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (2.76 g, 12.2 mmol) and triethylamine (2.13 mL, 15.3 mmol) in dry tetrahydrofuran (50 mL) at 0° C. was gradually added a solution of chloroacetyl chloride (0.97 mL, 12.2 mmol) in dry tetrahydrofuran (10 mL). After stirring at room temperature for 2 hours, the mixture was filtered. The solid cake was washed with THF, and the filtrate and washings were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue taken up in toluene and concentrated to dryness under reduced pressure to provide the titled compound. MS (CI) m/z 302 (M+1)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:17]1[C:12]2([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NNc1ccc(Br)cc1
Reactant: CC1CCCCC1=O
Agent: Cl
Product: CC12CCCCC1Nc1ccc(Br)cc12
Yield: 63 %

Procedure:
This compound was prepared by the procedure of Example 1 using 4-bromo-phenyl hydrazine hydrochloride (2.0 g, 8.95 nmmol) and 2-methylcyclohexanone (1.0 g, 8.95 mmol). The subtitled compound (1.5 g, 65%) was obtained as ayellow oil: 1H NMR (CDCl3) δ 1.26 (s, 3H), 1.38-1.46 (rn, 4H), 1.56-1.68 (m, 4H), 3.4 (t, J=4.4 Hz, 1H), 3.6 (br s, 1H), 6.53 (d, J=8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ 21.45, 21.87 (t), 23.96 (q), 27.92, 35.32 (t), 43.56 (s), 66.65 (d), 110.73 (s), 111.88, 125.25, 129.99 (d), 142.17, 149.03 (s), MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH:11](=[N+:18]([CH3:20])[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:11]([N:18]([CH3:20])[CH3:19])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:2]2)=[CH:25][CH:24]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Product: COc1ccc(Cn2cc(C(c3ccccc3)N(C)C)c3ccccc32)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 and 5 from 1H-indole, benzylidene-dimethyl-ammonium chloride and 4-methoxybenzyl chloride
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]([Br:17])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2cnc3cncnc32)cc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)Cl
Product: Brc1nc2cncnc2n1Cc1ccccc1

Procedure:
To a stirred solution of 12 (10.68 g, 50.7 mmol) in chloroform (500 mL) was added N-bromosuccinamide (45.20 g, 253.9 mmol) and the reaction mixture stirred under an atmosphere of nitrogen and at reflux temperature for 5 h. The reaction mixture was transferred to a separatory funnel and washed with saturated sodium sulfite solution (2×250 mL) followed by brine solution (2×250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated and the reddish oil was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 6.05 g. (41.2%). Mp 119-121° C.; 1H NMR (CDCl3): δ 5.53 (s, 2H, CH2), 7.35-7.39 (m, 5H, Ar—H), 9.03 (s, 1H, purine C8—H), 9.09 (s, 1H, purine C2—H).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([F:26])[CH:25]=1)[NH2:22].CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:7](=[O:8])[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[N:13][C:5]=2[O:4][CH2:3][CH:2]([F:17])[F:1])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F
Reactant: Nc1cc(F)cc(Cl)c1
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(Cl)c1)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
Prepared analogously to example 6c with 2-(2,2-difluoro-ethoxy)-5-nitro-nicotinic acid chloride (prepared analogously to 6b) (179 mg; 0.67 mmol); 3-chloro-5-fluoroaniline (98 mg; 0.67 mmol) and TEA (112 μL; 0.81 mmol) in 5 mL DCM. Yield: 230 mg (91%); MS: [m+H]+=376 (Cl isotope pattern); HPLC: Rt=2.35 min (Method MC-6)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[C:35](Cl)(=[O:37])[CH3:36].C(N(C(C)C)C(C)C)C>>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]3[C:27]([NH:29][C:30]3([C:33]#[N:34])[CH2:31][CH2:32]3)=[O:28])=[O:17])[CH2:19][CH2:20]2)[CH2:26][CH2:25]1)(=[O:37])[CH3:36]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (38 mg, 75.1 μmol) in methylenehloride (0.75 mL) was added under stirring ethyldiisopropyl amine (19.7 μL, 113 μmol) and acetyl chloride (5.99 μL, 82.6 μmol). The reaction was stirred at room temperature for 5 hours and additional ethyldiisopropyl amine (19.7 μL, 113 μmol) and acetyl chloride (5.99 μL, 82.6 μmol) was added. The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (28.8 mg, 70%). MS ISP (m/e): 548.3/550.4 (100/41) [(M+H)]+.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[N:7]=[C:6]1[C:25]([NH:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:26])[CH2:2][CH2:3][CH3:4].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].[I-].[Na+]>COCCOC>[ClH:31].[CH2:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[N:7]=[C:6]1[C:25]([NH:27][CH2:28][CH2:29][CH2:30][NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCCCl
Reactant: NCC(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCCNCC(F)(F)F
Product: Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
90 mg (0.19 mmol) of 1-butyl-N-(3-chloropropyl)-4-[({[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-1H-imidazole-2-carboxamide (Example 151) in 3 ml of 1,2-dimethoxyethane are mixed with 97 mg (0.97 mmol) of 2,2,2-trifluoroethylamine and 29 mg (0.19 mmol) of sodium iodide under argon and stirred at 90° C. overnight. The reaction mixture is concentrated in vacuo and purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([F:14])[C:11]([CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([F:14])[C:11]([CH:15]=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(NCc2ccc(Cl)cc2)nc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To [6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-yl]-methanol (63, 1.0 g, 3.7 mmol) in tetrahydrofuran (50.0 mL) was added Dess-Martin periodinane (1.75 g, 4.12 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (64, 0.67 g, 68.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>CN(C)C=O>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[CH2:29][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: ClCc1nccs1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3nccs3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50.0 mg, 0.19 mmol) described in Manufacturing Example 5-1-1 were added tetrahydrofuran (3 mL) and a 5N aqueous sodium hydroxide solution (37.3 μL, 0.19 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (29.8 mg, 0.22 mmol) described in Manufacturing Example 88-1-2 was added to a suspension of this solid and N,N-dimethylformamide (2 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (53.0 mg, 78%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:15]([O:14][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1c(O)ccc2occc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In 200 ml of N,N-dimethylformamide were dissolved 40.0 g of 4-t-butyl-5-hydroxybenzofuran [J. Org. Chem. 53, 4135 (1988)], 43.0 g of benzyl bromide and 28.8 g of potassium carbonate, and the mixture was stirred at room temperature for a whole day and night. After N,N-dimethylformamide was distilled off under reduced pressure, the solution was combined with water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 49.1 g of 5-benzyloxy-4-t-butylbenzofuran as a colorless oil (yield 83%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25][I:26])[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[I:26][CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([O:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21][CH2:20]1)=[O:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (20 g) in methylene chloride (400 ml) containing triethylamine (8.4 ml) was cooled to -5° and added dropwise with good stirring to a cooled (-5°) solution of methanesulphonyl chloride (3.77 ml) in methylene chloride (50 ml) at such a rate that the temperature did not exceed +1°. After 30 minutes a further portion of methanesulphonyl chloride (3 ml) and triethylamine (6 ml) was added in a small volume of methylene chloride. After 10 minutes the solution was washed with water, dried and evaporated to give a yellow solid (22.43 g). Crystallization of a small portion afforded an analytical sample of title compound, m.p. 142°-143°, [α]D +83.2°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH3:30])([CH3:29])[O:21][C:20]1=[O:31]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:29])([CH3:30])[O:21][C:20]2=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1(C)OC(=O)C(N)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)OC(C)(C)c2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,1-dimethyl-3-isochromanone, the title compound could be prepared.