Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH3:21])[CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:20][CH3:21])[CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H](N)COCC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-(2-(tert-butoxycarbonylamino)butoxy)acetate (1 eq, from the previous step) in DCM (0.4 M) at room temperature was added a solution of 4 M HCl in dioxane (10 eq). The reaction was stirred for 2 hours, at which time more 4 M HCl in dioxane (3 eq) was added and stirred for 1 hour. The reaction mixture was concentrated en vaccuo to give the product as an oil. The material was carried onto the next step without further purification.
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[C:44]([CH2:45]O)=[C:43]([F:47])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2.[C:48]1(=[O:58])[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50](=[O:57])[NH:49]1>C1COCC1>[F:34][C:35]1[C:44]([CH2:45][N:49]2[C:50](=[O:57])[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:48]2=[O:58])=[C:43]([F:47])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2
Reactant: OCc1c(F)cc2ncccc2c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1c(F)cc2ncccc2c1F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (4.72 g, 23.36 mmol) and triphenylphosphine (6.13 g, 23.36 mmol) in THF (100 mL) was stirred for 15 min, and a solution of (5,7-difluoroquinolin-6-yl)methanol (3.80 g, 19.47 mmol) and isoindoline-1,3-dione (3.15 g, 21.42 mmol) in THF (200 mL) was added dropwise. The reaction mixture was heated at 40° C. for 24 h. After cooling and evaporating, the residue was purified by silica gel with hexane:EtOAc to provide 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 81%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (m, 1H), 8.39 (m, 1H), 7.85 (m, 2H), 7.72 (m, 2H), 7.59 (d, 1H), 7.43 (m, 1H), 5.15 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+].Cl.O>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=C[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
p-Methoxybenzaldehyde (11.19 g, 82.2 mmol) and nitromethane (5.0 g, 82.2 mmol) were dissolved in methanol (20 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (4.27 g, 0.107 mol) in ice/water (10 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during addition and additional methanol was added to allow efficient stirring. After the addition the reaction mixture was diluted with ice/water and the resulting clear solution was added dropwise to a solution of HCl/H2O (40 mL/60 mL); a yellow precipitate formed during the addition. The precipitate was filtered on a buchner funnel and crystallized from methanol obtaining 4-methoxy-β-nitrostirene (10.66 g, 72%). Yellow needles. M.p. 57-58° C. ESI-MS: 180 (MH±); (Calc. for C9H9NO3: 179 u.m.a.).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@H:15]2[CH2:17][O:16]2)[CH:9]=[C:10]([F:12])[CH:11]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@H:15]([OH:16])[CH2:17][CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1
Solvent: C1CCOC1
Product: C=CC[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Vinylmagnesium bromide was added to copper (I) bromide-dimethyl sulfide complex in tetrahydrofuran at low temperature. Tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2R)-oxiran-2-yl]ethylcarbamate (31) in tetrahydrofuran was added. At room temperature, the reaction was quenched with saturated ammonium chloride, extracted, and dried over sodium sulfate. A white solid (32) was obtained upon concentration.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[NH:5][C:4]=1[CH2:14][CH2:15][CH3:16])[CH3:2].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.Br>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4]=1[CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCCc1[nH]c2ccc(OC)cc2c1CC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1[nH]c2ccc(O)cc2c1CC
Yield: 98.8 %

Procedure:
3-Ethyl-5-methoxy-2-propyl indole (2.92 g) in 15 ml of hydrogen bromide acetic acid solution was heated at 100° C. for 4 hours. The cooled solution was poured into an aqueous sodium bicarbonate solution (100 ml) and ethyl acetate with stirring. The separated organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was chromatographed on silica gel using 30% ethyl acetate in n-hexanes as eluent to yield 3-ethyl-5-hydroxy-2-propyl indole (2.7 g).
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([C:24]3[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>C(Cl)Cl.CCCCCCC>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([C:24]3[NH:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Agent: FB(F)F
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1c[nH]c(-c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.1 %

Procedure:
Boron trifluoride diethyl etherate (0.16 ml, 1.3 mmol) was added dropwise to a cool (0° C.), stirred solution of 4-(3,4-dichloro-phenyl)-6-[4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrimidine (0.064 g, 0.13 mmol) in DCM (2 ml) under a nitrogen atmosphere. The mixture was stirred at this temperature for 10 minutes before being allowed to warm to room temperature and stirred overnight. The solution was diluted with heptane (5 ml) and the resulting precipitate was collected by filtration and dried under vacuum before being purified by prep HPLC to give the title compound (0.05 g, 15% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80 42 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (83 mg, 81%) as a white foam: [α]31589=−25.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C22H28N3O2F3 (M+H)+ 424.2207, observed 424.2207; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.05-1.19 (m, 2H, CH2), 1.32-1.80 (m, 8 H, 4×CH2), 2.01-2.21 (m, 1H, CH), 3.86 (s, 2H, NCH2), 3.82-3.94 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.50 (d, J=2.3 Hz, 1H, Ar), 7.52-7.74 (m, 4H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:21]4[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=4)[CH:15]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:14][C:13]3=[O:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mn]([O-])(=O)(=O)=O.[K+].C(O)=O>O1CCOCC1.O>[C:1]12([CH2:11][N:12]3[C:21]4[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=4)[C:15]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:14][C:13]3=[O:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1NC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1CC12CC3CC(CC(C3)C1)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.8 g of 1-(1-adamantylmethyl)-4-phenyl-6-nitro-3,4-dihydro-2(1H)-quinazolinone in 70 ml of dioxane was added a suspension of 1.5 g of potassium permanganate in 10 ml of water and the mixture was stirred at room temperature for 3 hours. Then, 7 ml of formic acid was added and stirring was continued for 30 minutes. The brown precipitate was filtered off and the filtrate was diluted with water. The resulting mixture was extracted with chloroform. The chloroform extract was washed, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of ethanol and chloroform to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 228°- 231°C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH:17]2[CH2:18][CH2:19][CH:13]1[CH2:14][CH:15]([NH2:20])[CH2:16]2.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[N:24][N:23]=1>>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26]([C:25]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[N:24][N:23]=[C:22]2[NH:20][CH:15]2[CH2:16][CH:17]3[N:12]([CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:13]([CH2:19][CH2:18]3)[CH2:14]2)=[CH:27][CH:28]=1
Reactant: NC1CC2CCC(C1)N2Cc1ccc2ccccc2c1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Product: COc1ccc(-c2nnc(NC3CC4CCC(C3)N4Cc3ccc4ccccc4c3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting N-[8-(naphthalen-2-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]amine and 1-chloro-7-methoxy-4-(4-methoxyphenyl)phthalazine.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]#[N:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CCOCC>[CH2:23]([O:24][C:25](=[O:26])[CH2:27][C:13]1([C:15]#[N:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:22]
Reactant: N#CC1c2ccccc2Sc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)CC1(C#N)c2ccccc2Sc2ccccc21
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
9H-thioxanthene-9-carbonitrile [33] (1.20 g, 5.37 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (2.14 mL, 5.37 mmol, 2.5M soln. in hexanes) was added dropwise over 10 min. with continuous stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.83 mL, 7.52 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.97 g (59%) of the product as a colorless oil. 1H NMR (CDCl3)d: 1.08-1.12 (t, J=6 Hz, CH3), 3.08 (s, 2H, CH2), 3.95-4.03 (q, 2H, CH2), 7.31-8.00 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 38.49, 47.63, 60.76, 118.91, 127.00, 127.24, 127.80, 128.15, 130.73, 130.98, 167.66.
Reaction SMILES: [Cl-].CS(C)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl.O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1
Reactant: OCC1CCN(Cc2ccc(F)cc2)CC1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A solution of oxylyl chloride (0.59 ml, 3.95 mmol) in CH2Cl2 (20 ml) was cooled to −78° C. DMSO (0.95 ml, 13.38 mmol) was added dropwise into the oxylyl chloride solution. The reaction mixture was stirred for 5 minutes, and 1-[(4-fluorophenyl)methyl]-4-piperidinemethanol (0.99 g, 4.46 mmol) in CH2Cl2 (20 ml) was added dropwise into the reaction solution. Stirring was continued for an additional 20 minutes. Et3N, 8.0 ml was added and the reaction mixture was stirred for 10 minutes and then allowed to warm to room temperature. Water (50 ml) was added and the mixture was extracted with CH2Cl2. The combined CH2Cl2 solution was dried over NaSO4. The evaporation of solvent gave an oil, 0.77 g (79% yield).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[S:22][CH3:23]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[S:22][CH3:23]
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: CSc1ccc(B(O)O)cc1Cl
Product: COC(=O)c1ccc2occ(-c3ccc(SC)c(Cl)c3)c2c1
Yield: 84 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-chloro-4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: COc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)ccn1
Yield: 100 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 100% yield, starting from 2-methoxypyridine-4-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, 1 H), 7.23-7.34 (m, 8 H), 7.09-7.23 (m, 3 H), 6.96 (dd, 1 H), 6.80 (dd, 1 H), 6.70-6.78 (m, 2 H), 4.31-4.37 (m, 1 H), 4.03-4.10 (m, 1 H), 3.91 (s, 3 H), 3.62-3.73 (m, 4 H), 2.90-3.07 (m, 2 H), 2.43-2.49 (m, 1 H); MS (ESI) m/z 437[M+H+].
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=O)=[CH:32][CH:31]=1.[CH:40]1[C:48]2[C:47]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:46]=3[O:45][C:44]=2[CH:43]=[CH:42][C:41]=1[NH2:54]>ClCCl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:54][C:41]2[CH:42]=[CH:43][C:44]3[O:45][C:46]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:47]=4[C:48]=3[CH:40]=2)=[O:39])=[CH:34][CH:35]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(F)cc1)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Triethylamine (0.52 mL, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.37 g, 1.9 mmol), N-hydroxybenzotriazole (0.26 g, 1.9 mmol) and 4-fluorophenylacetic acid (0.27 g, 1.8 mmol) were added sequentially to a solution of 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at ambient temperature and then concentrated. The crude material was dissolved in ethyl acetate and washed with 1 N NaOH and water, dried (MgSO4) and concentrated to give 2-(4-fluorophenyl)-N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)acetamide (0.47 g). MS (ESI) m/z 338 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5](N(OC)C)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[O:6]
Reactant: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(Br)c1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A solution of 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide in 100 ml of anhydrous tetrahydrofuran was added dropwise to 43 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran at below 5° C., and stirred for 1 hour. 100 ml of saturated ammonium chloride solution was then added cautiously followed by 100 ml of a 1M solution of hydrochloric acid and the mixture was extracted twice with 400 ml of diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 6.8 g of 3-bromo-4-chlorobenzaldehyde as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C1CCNc2ccccc2N1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (0.87 g) and triethylamine (0.55 g) in dichloromethane (5 ml) was added a solution of 4-nitrobenzoyl chloride (1.00 g) in dichloromethane (5 ml) at ambient temperature. After being stirred at ambient temperature for 2 hours, the solution was washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine. The organic layer was dried over magnesium sulfate, filtered and the solvents was evaporated. Trituration with a mixture of diethyl ether and diisopropyl ether (1:1) of a crude product afforded 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.60 g) as a slightly brown powder.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23]([OH:25])=O)[N:22]=1)[CH2:16][CH3:17])[CH3:14])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=[N:32]C=2C=1>ClCCl>[C:5]([O:9][C:10](=[O:11])[NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23](=[O:25])[NH2:32])[N:22]=1)[CH2:16][CH3:17])[CH3:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: On1nnc2ccccc21
Reactant: CC[C@@H](c1nc(C(=O)O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1N aqueous sodium hydroxide (5.69 ml, 5.69 mmol) was added in one portion to a solution of methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (711 mg, 2.28 mmol) in anhydrous THF (9.11 ml). The reaction was allowed to stir at room temperature for 3.5 hours before evaporating the organic in vacuo. The remaining aqueous was cooled to 0° C. and acidified to pH 4 using 1N HCl. The aqueous phase was then extracted with ethyl acetate (3×25 mL). The aqueous pH was re-checked and judged to be ˜pH 6-7. A small amount of 1N HCl was added to re-acidify the aqueous layer which was once again extracted with an additional portion of ethyl acetate (1×25 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to give crude 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (679 mg, 2.28 mmol, 100% yield) as a white solid which was used immediately in the next reaction. EDC (545 mg, 2.84 mmol) was added in one portion to a mixture of 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (679 mg, 2.28 mmol) and HOBT (436 mg, 2.84 mmol) in anhydrous dichloromethane (23.0 ml) and the reaction allowed to stir at room temperature under a nitrogen atmosphere for 30 minutes. Ammonia was then bubbled through for approximately 5 minutes and the resulting white suspension allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo and the residue partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give tert-butyl-((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (677 mg, 2.28 mmol, 100% yield) which was used immediately in the next step. LC/MS: M+H+320.15, ret. time=1.89 min. Column: Phenomenex, 2.0×30 mm, 2.5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.05% TFA; Mobile Phase B: 90:10 methanol:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. HPLC: ret. time=2.73 min. Column: YMC CombiScreen ODS-A, 4.6×50 mm; Mobile Phase A: 10:90 methanol:water with 0.2% H3PO4; Mobile Phase B: 90:10 methanol:water with 0.2% H3PO4; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes, then a 0.75-minute hold at 100% B; Flow: 4 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:4][C:3]2[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=2[F:10])[CH2:13][CH2:12]1
Reactant: O=Cc1c(F)cccc1F
Reactant: NC1CC1
Product: Fc1cccc(F)c1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2,6-difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(Cl)c(C#N)cc1F

Procedure:
Using 2-chloro-4,5-difluorobenzonitrile (240 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (390 mg) and lithium carbonate (152 mg), the title compound was obtained as a colorless solid (yield: 200 mg) by an operation similar to that in Example 3.