Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][NH:17][CH2:4][C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-5-fluoro benzyl bromide (0.5 g, 1.86 mmol) and 3,5-bis(trifluoromethyl)benzylamine (0.45 g, 1.86 mmol) in methylene chloride (10 ml) at 0° C., triethyl amine (0.39 ml, 2.80 mmol) was added. The solution was slowly warmed to room temperature and stirred for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (2:8) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 2H), 7.80 (s, 1H), 7.53 (dd, J=8.8, 5.3 Hz, 1H), 7.18 (dd, J=9, 3.3 Hz, 1H), 6.91 (dt, J=8.5, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[O:5]=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[C:20]1[CH:27]=[N:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.CO.C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH:1]1([NH:4][CH2:22][C:21]2[CH:24]=[CH:25][N:26]=[CH:27][C:20]=2[N:7]2[CH2:8][CH2:9][C:10]3[C:15](=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]2=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
Cyclopropanamine (25.8 μL, 0.3737 mmol) was added to a stirred solution of 3-(1-oxo-7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)isonicotinaldehyde (I-53c: 100 mg, 0.3114 mmol) in acetic acid (5 mL) and resulting reaction mixture was stirred for 4 hours at room temperature. The reaction mass was cooled to 0° C. and added NaBH(OCH3)3 (99 mg, 0.4674 mmol). The resulting reaction mass was stirred for 12 hours at room temperature. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure, the crude residue obtained was diluted with ice, basified using saturated NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 25 mg of the product (22% yield).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][CH:34]([NH2:37])[CH2:35][OH:36]>>[OH:36][CH2:35][CH:34]([NH:37][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:33]
Reactant: CC(N)CO
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Product: CC(CO)Nc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and DL-2-amino-1-propanol. White solid. MS (ESI): 529.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:20]Cl.[C:22]([O-])(=O)[CH3:23].[Na+].Cl[O-].[Na+]>C=CC>[Cl:1][C:2]1[C:11]([C:12]2[CH2:20][CH:22]([CH3:23])[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: ClCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C=CC
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Propene was passed for 30 minutes at room temperature into a solution of 15.0 g (52 mmol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 200 ml of dichloromethane. After 1.6 g of sodium acetate had been added, 42.8 ml of sodium hypochlorite solution were added dropwise at room temperature while simultaneously passing in propene. Propene was subsequently passed in for a further 15 minutes at room temperature. After the mixture had been refluxed for 3 hours, it was stirred for 12 hours at room temperature, propene was again passed in for 5 hours under reflux, and the mixture was stirred for a further 12 hours at room temperature. After the phases had been separated, the organic phase was washed with water, dried and concentrated. This gave 15.5 g (89% of theory) of methyl 2-chloro-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5]2.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31].C(Cl)Cl>CCO>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Ic1ccc2c(c1)CNC2
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A product of Example 2, Step C (1.32 g; 2.71 mmol) in 60% CF3CO2H/CH2Cl2 (10 ml) was stirred for 10 min at room temperature under N2, then diluted to 30 ml with EtOH and stirred for additional 15 min. This was evaporated to dryness under reduced pressure and the residue was dissolved in EtOAc (10 ml) and hexane (20 ml) was added. After standing overnight at room temperature, the precipitate formed was filtered off, washed with hexane and dried to give the title compound (0.77 g; 79%), as off white solid, which was used in the next step without further purification. 1H-NMR (CDCl3) 4.47 (5, 2H); 4.51 (s, 2H); 6.7-6.8 (m, 1H); 7.0-7.21 (m, 1H); 7.4-7.7 (m, 1H); 10.6 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[C:6]([OH:8])[CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27]Br>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[N:13]([CH:12]=[CH:11][N:10]=3)[CH2:26][CH2:27][O:8][C:6]=2[CH:7]=1
Reactant: Oc1cc(F)ccc1-c1ncc[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)OCCn1ccnc1-2
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
5-fluoro-2-(1H-imidazole-2-yl)phenol (0.90 g, 5.0 mmol) was dissolved in N,N-Dimethylformamide (40 mL, 500 mmol). Cesium carbonate (6.6 g, 20 mmol) was added, followed by 1,2-Dibromoethane (1.7 mL, 20 mmol) and heated at 90° C. with a vigreux condensation column attached for 3 hours. Complete by LCMS. Diluted with water and extracted with ethyl acetate. Acidified the aqueous layer to pH ˜5 with HCl and extracted with ethyl acetate. The combined organics were concentrated in vacuo and purified by flash chromatography on the ISCO 0-50% ethyl acetate in hexanes and concentrated in vacuo to give 9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.69 g, 67% yield)
Reaction SMILES: [P:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(Cl)Cl.[NH:10]([CH2:13][CH3:14])[CH2:11][CH3:12].[Li][CH2:16]CCC.Cl.[Mg]>CCOCC.CCCCCC.C1COCC1>[N:10]1[CH:13]=[CH:14][CH:16]=[CH:12][C:11]=1[PH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: [Li]CCCC
Reactant: CCNCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc(Pc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of Cl2PPh (30 mL, 220 mmol) in Et2O (800 mL) in a 1 L Schlenk flask was cooled to −78° C. and a solution of HNEt2 (46 mL, 440 mmol) added through a dropping funnel over 30 min with stirring. The solution was allowed to rise to room temperature and stood overnight. The resulting yellow solution was cannula transferred into a clean Schlenk flask and the solvent removed under vacuum. To the solid residue was added ether (500 ml) and the mixture rapidly stirred for 1 hour and then stood overnight. The ether extracts were then combined and the dried under vacuum. This gave pale oil. The yellow oil was then dissolved in ether (500 ml) and a solution of LiPy {prepared by adding BrPy (21 mL, 220 mmol) to a solution of BuLi (88 mL of a 2.5 M solution in hexane) in Et2O (100 mL) dropwise over 30 min at −78° C., the solution was then stirred for 1 h} was added via a cannula over 30 min. The solution was allowed to reach room temperature and was then stirred overnight. This gave a pale brown suspension. HCl (110 mL of a 2 M solution in Et2O) was added over 20 mins with vigorous stirring, generating a large quantity of pale brown precipitate. Further HCl (110 mL of a 2 M solution in Et2O) was added. The suspension was then allowed to stand and the yellow solution cannula transferred into a clean Schlenk flask. The brown precipitate was washed again with THF (500 mL) and the washings combined before removing the THF under vacuum leaving a red/orange solid. The solid was then dissolved in THF (300 mL) then added to an ice cooled solution of magnesium powder (9 g) in THF (100 mL) over 30 mins with stirring. The solution was kept under ice cooling for a further 30 min, then allowed to rise to room temperature and stirring overnight. The solution was filtered to remove excess magnesium and quenched with water (100 mL, degassed with nitrogen gas for 20 minutes). The organic layer was then cannula transferred into a clean Schlenk flask and then dried under vacuum to give viscous orange oil, yield=15.1 g, 36%. 31P NMR (121 MHz, CDCl3) ä: −37.79 (d, JPH=222 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[O:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27]([CH3:30])([OH:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Temperature: -78 °C

Procedure:
3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone (100 mg, 248 mols) was dissolved in dry THF (1.0 mL) under inert atmosphere and cooled to −78° C. A solution of MeMgBr (40 μL, 322 mols) in toluene: THF (75:25) was added slowly to the cooled solution. After 24 h of reaction at rt the reaction was cooled to 0° C. and quenched with NH4Cl sat. aq. solution and the aqueous layer was washed with EtOAc (2×). The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 2-5% ((7N NH3) in MeOH):CH2Cl2], yielding 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH2:50])([CH3:46])[CH3:45]>C(Cl)(Cl)Cl.O>[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH:50][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[O:23][CH3:24])=[O:42])([CH3:46])[CH3:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (68 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:29][CH2:30][C:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1.N12CCCN=C1CCCCC2>CN(C=O)C>[F:29][CH2:30][C:31]1([S:34]([NH:37][C:14]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:16])(=[O:36])=[O:35])[CH2:33][CH2:32]1
Reactant: NS(=O)(=O)C1(CF)CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(CF)CC1
Temperature: 55 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1′-carbonyldiimidazole (“CDI”, 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”, 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH˜2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl(1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96%). MS: MS m/z 361.4 (M+−1).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:23])[N:14]=1>>[F:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:23])[N:14]=[C:13]2[NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccncc1Br
Reactant: Cn1nc(N)c2cc(F)ccc21
Product: Cn1nc(Nc2cnccc2C(=O)O)c2cc(F)ccc21
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 3-bromoisonicotinate and 3-amino-5-fluoro-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.01 (3H, s), 7.31-7.41 (2H, m), 7.67 (1H, dd, J=9.1, 4.1 Hz), 7.78 (1H, d, J=5.0 Hz), 8.16 (1H, d, J=5.0 Hz), 9.49 (1H, s), 10.33 (1H, br s). [M+H] calc'd for C14H11FN4O2, 287; found 287.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)cc1
Yield: 78.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 4-methoxyphenyl isocyanate (0.016 g, 14.2 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 4 (0.037 g, 0.086 mmol, 78%) as a white solid. LCMS m/z (%)=431 (M+H79Br, 89), 433 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.02 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of nitrobenzene 51 (2.07 g) and NH4Cl (1.84 g) in EtOH (40 mL)-H2O (10 mL), was added iron powder (1.92 g). The mixture was heated to reflux for 1 h. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat.NaHCO3 (30 mL) and extracted with AcOEt (30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Concentration of the solvent afforded the aniline 52 (1.77 g, 95%) as a yellow solid. 1H NMR (300 MHz/CDCl3) δ 3.77 (2H, brs), 6.63 (1H, dd, J=2.7 Hz, J=8.6 Hz), 6.83 (1H, d, J=2.7 Hz), 6.99 (1H, d, J=8.6 Hz), 7.24 (1H, d, J=2.8 Hz), 7.49 (1H, m), 7.56-7.64 (2H, m), 8.08 (1H, m), 8.86 (1H, J=2.8 Hz)
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH:30]2[CH2:32][CH2:31]2)[C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:30]1([N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)[CH2:11][CH2:12]2)[C:17](=[O:29])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (5.20 mL) is added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (266 mg) and N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (600 mg) in ethyl acetate (25 mL). The reaction mixture is stirred at 50° C. for 3 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 2 h in a mixture of ethanol (10 mL) and glacial acetic acid (5 mL). The solvents are evaporated and the residue is chromatographed on silica gel [ethyl acetate/cyclohexane/methanol 9:9:2] to give the title compound. LC (method 6): tR=1.66 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.Cl.[NH2:15][CH2:16][C:17]#[C:18][CH3:19].O1CCCC1>C(N(CC)CC)C>[CH3:19][C:18]1[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:10]=2[N:15]=[CH:16][CH:17]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a mixture of 5-(2-thienyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.82 g), molecular sieves 4A (3 g) and tetrahydrofuran (30 ml) was added triethylamine (0.78 g). The mixture was stirred at room temperature for 1 hour, refluxed for refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and to the residue was added diphenylether (80 ml), and the mixture was stirred at 250° C. for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (0.67 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(OCC)C.C>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-isopropoxy-4-(tri-n-butyl-stannyl)-3-cyclobutene-1,2-dione (J. Org. Chem. 1990, 55, 5359-5364) (8.00 g, 18.65 mmol) in N,N-dimethyl-formamide (40 mL) was added 4-iodoanisole (4.85 g, 20.72 mmol). The flask was purged with nitrogen and cooled to 0° C. Benzylchloro-bis-(triphenylphosphine)palladium (II) (0.942 g, 1.24 mmol) and cuprous iodide (0.355 g, 1.87 mmol) were added and the mixture was stirred at room temperature overnight. Diethylether (200 mL) was added and the mixture was washed successively with saturated aqueous ammonium chloride, 10% aqueous potassium fluoride and saturated brine. The organic phase was filtered through a plug of silica. The filtrate was dried (MgSO4) and concentrated to give crude product which was dissolved in hot ethyl acetate, decolorized (charcoal) and filtered. The filtrate was treated with hexane and allowed to cool. 3-Isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione preci-pitated as a light yellow solid (2.46 g, 54%): 1H NMR (DMSO-d6) δ7.89(d,2H), 7.15(d,2H), 5.45(hept,1H), 3.82(s,3H), 1.48(d,6H).
Reaction SMILES: P([Cl:9])(OCC)(OCC)=O.[CH3:10][O:11][CH2:12][C@H:13]([NH:38][C:39]([C:41]1[S:45][C:44]([CH3:46])=[N:43][CH:42]=1)=[O:40])[C:14]([NH:16][C@@H:17]([CH2:35][O:36][CH3:37])[C:18]([NH:20][C@@H:21]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([C@@:24]1([CH3:27])[CH2:26][O:25]1)=[O:23])=[O:19])=[O:15]>ClCCl.O.Cl[Ti](Cl)(Cl)Cl>[Cl:9][CH2:26][C@:24]([OH:25])([CH3:27])[C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:38][C:39]([C:41]1[S:45][C:44]([CH3:46])=[N:43][CH:42]=1)=[O:40])[CH2:12][O:11][CH3:10])[CH2:35][O:36][CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CCl
Temperature: 25 °C
Reaction time: 9 h
Yield: 60.6 %

Procedure:
Diethyl chlorophosphate (120 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL). A solution of TiCl4 (1 mg, catalytic) in dichloromethane (2 mL) was added, followed by N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (300 mg, 0.58 mmol) in dichloromethane (10 mL). The reaction mixture was stirred 9 h at room temperature, then diluted with dichloromethane (10 mL) and water (10 mL). The organic layer was separated and washed with brine (5 mL) and dried over MgSO4. It was concentrated to dryness, and the residue purified on silica gel column (dichloromethane:methanol=100:1 to 80:1) to give product as a white solid (200 mg, yield 63%); MS for C25H33ClN4O7S m/z: 570 (M+H)+.