Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a solution of (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (100 mg, 0.211 mmol, example 7) in methylene chloride (3 mL) cooled to 0° C. were added triethylamine (30 uL, 0.211 mmol) and 2-piperazinone (23 mg, 0.232 mmol), respectively. After 15 min, thin layer chromatography (silica gel, 20% ethyl acetate in hexanes) showed no starting material left. The reaction mixture was loaded into a flash silica gel column (12 g). Purification by flash column chromatography (eluting with 5% methanol and 0.1% triethylamine in ethyl acetate using Intelliflash 280 system) gave 4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one as a white foam (69 mg). HR-MS (ES, m/z) calculated for C30H31N4O4Cl2 [(M+H)+] 581.1717, observed 581.1717
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)#[N:16].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]1=[O:14])#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 4-Boc-2-piperazinone (2.0 g, 10 mmol), 3-cyanobenzyl bromide (1.8 g, 10 mmol) in DMF (35 mL) at 0° C. was added sodium hydride (480 mg of a 60% suspension in mineral oil, 12 mmol) in several portions over a period of 15 min. The mixture was stirred a 0° C. for 1 h and then at ambient temperature for 1 h. Acetic acid (1 mL) was added and the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was triturated in ether and the white solid was collected by filtration to give 1-(3-cyanobenzyl)4-Boc-2-piperazinone (2.6 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)C.[Li+].[BH4-].O>C1COCC1>[OH:18][C:6]1([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO)C1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxylate (6.35 g) in THF (100 mL) was added LiBH4 (1.01 g), followed by heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (4.72 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2[CH2:24][CH2:25][CH2:26][CH2:27][C:19]1=2.C(Cl)Cl>C(O)(=O)C>[Cl:17][C:4]1[CH:3]=[C:2]([N:1]2[C:21](=[O:22])[C:20]3[CH2:24][CH2:25][CH2:26][CH2:27][C:19]=3[C:18]2=[O:23])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)CON(Cc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2Cl)C1=O
Yield: 83.6 %

Procedure:
A solution of 2.0 grams (0.008 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.008 mole) of 3,4,5,6-tetrahydrophthalic anhydride in 20 mL of acetic acid was stirred at ambient temperature for four hours and then was heated under reflux for six hours. The cooled reaction mixture was poured into 300 mL of methylene chloride and was washed in turn with two 100 mL portions of water, two 50 mL portions of a saturated aqueous sodium bicarbonate solution, and one 50 mL portion of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.6 grams of 2-[[2-chloro-4-(3,4,5,6-tetrahydrophthalimido)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 102°-104° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: BrC(Br)(Br)Br
Reactant: C#CCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
To an ice-cold solution of 11-hydroxyundecyne (10 g, 59.4 mmoles) in 400 ml of methylene chloride under argon was added in one portion carbon tetrabromide (40.5 g, 0.1224 mole). The reaction mixture was stirred at 0° C. for 5 minutes and triphenylphosphine (29.43 g, 0.1122 mole) was added. The reaction was kept at 0° C. for an additional 15 minutes and stirred at room temperature for 3 hours. The methylene chloride was removed in vacuo. The residue was treated with hexane and the combined organic extract was concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluting with straight hexane, to give 7.2 g (52%) of 11-bromoundecyne as a colorless oil. Following the procedures of Examples 20 and 39(a), a mixture of salicylaldehyde, 11-bromoundecyne and potassium carbonate in dimethylformamide is reacted to furnish 2-(10-undecynyloxy)benzaldehyde.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:32].[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])(=[O:32])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCS(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (37.3 mg, 0.84 mmol) in methanol (4 mL) at 0° C. was added a solution of potassium permanganate (13.3 mg, 0.084 mmol) in water (2 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silica gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to give the residue. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfonyl-1H-pyrrolo[2,3-b]pyridine (8 mg, 21%): LC/MS m/e calcd for C23H28N2O4S2 [M+H]+ 461.62, observed 461.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.59 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.88-7.92 (m, J=8.3 Hz, 2H), 7.59-7.63 (m, J=8.3 Hz, 2H), 6.62 (s, 1H), 4.36 (t, J=8.0 Hz, 1H), 3.25 (q, J=7.4 Hz, 4H), 3.07-3.13 (m, 4H), 2.26-2.34 (m, 1H), 2.11-2.19 (m, 1H), 1.61-1.71 (m, 2H), 1.46-1.53 (m, 2H), 1.23 (t, J=7.3 Hz, 5H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=1>C(O)C.C(OCC)(=O)C>[CH3:1][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=1
Reactant: CC(=O)NCCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(C)=O)cc1
Yield: 61 %

Procedure:
Potassium carbonate (3.5 g, 25.5 mol) and iodomethane(2.0 ml, 31.9 mmol) was added to a solution of N-(4-hydroxyphenylethyl)acetamide (4.4 g, 24.6 mmol) in ethanol(2.4 ml), which was then refluxed for 12 hours. The resulting solid was filtered and washed with ethanol. The filtrate was concentrated to give oily residue, which was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the resulting solid was suspended in ethylether, filtered, and dried to give 2.9 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: Cc1cc(B(O)O)ccc1OC(F)(F)F
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(C)c2)c1

Procedure:
2.7 g (12.5 mmol) of methyl 5-bromonicotinate and 3.3 g (15.0 mmol) of [3-methyl-4-(trifluoromethoxy)phenyl]boronic acid were reacted according to the General Method 1A. Yield: 3.1 g (80% of theory)
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH3:28][C:29]1([CH3:36])[O:34][CH2:33][CH:32](O)[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:36])[O:34][CH2:33][CH:32]([O:22][C:18]2[C:19]([CH3:21])=[CH:20][C:15]([C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[C:6]([CH3:25])[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:26][CH3:27])[CH:9]=4)[O:14][N:13]=3)=[CH:16][C:17]=2[CH2:23][CH3:24])[CH2:31][O:30]1
Reactant: CC1(C)OCC(O)CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC1COC(C)(C)OC1
Yield: 49.5 %

Procedure:
4-[5-(2-Diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.273 mmol, Example 12) is reacted with 2,2-dimethyl-[1,3]dioxan-5-ol (54 mg, 0.409 mmol) under Mitsunobu conditions as described in Example 18, step a) to give (4-{3-[4-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyridin-2-yl)-diethyl-amine (65 mg) as yellow oil; LC-MS: tR=0.97 min; [M+1]+=481.27. This material (65 mg, 0.135 mmol) is dissolved in 25% aq. HCl (3 mL) and the resulting mixture is stirred at rt for 2 h. The solvent is evaporated and the crude product is purified by prep. HPLC to give the title compound (23 mg) as yellow solid; LC-MS: tR=0.80 min; [M+1]+=441.24; 1H NMR (CD3OD): δ 1.22 (t, J=7.0 Hz, 6H), 1.28 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 2.82 (q, J=7.5 Hz, 2H), 3.61 (q, J=7.0 Hz, 4H), 3.78 (dd, J=11.3, 4.8 Hz, 2H), 3.84 (dd, J=11.5, 5.0 Hz, 2H), 4.11-4.18 (m, 1H), 7.02 (s, 2H), 7.77 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:23])([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:11]=[N:10][N:9]=1)(=O)C>C(O)C.O>[F:24][S:19]([F:20])([F:21])([F:22])([F:23])[C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([CH2:7][OH:6])=[N:9][N:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Lithium hydroxide (553 mg, 22.2 mmol) was added to a solution of {1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 43, 5.30 g, 15.3 mmol) in ethanol:water (2:1), at 0° C. The reaction mixture was stirred for 3 hr at room temperature. The solvent was removed by under reduced pressure and the residue was diluted with DCM, washed with ice-water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30%-40% EtOAc/pet-ether gave the title compound (3.98 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:4][CH:3]=1.Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:26]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(/C=C/c1ccc(Br)cc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To 160 mL of an ethanol solution of 13.0 g (45.1 mmol) of (E)-3-(4-bromophenyl)-1-(2-pyridyl)-2-propen-1-one, 7.3 g (46.6 mmol) of benzamidine hydrochloride and 3.6 g (90 mmol) of sodium hydroxide were added under argon atmosphere, and the mixture was stirred for 16 h under heat refluxing. After cooling the reaction mixture to room temperature, a formed solid was collected by filtration and washed with water and methanol to obtain 4.31 g (yield: 25%) of 4-(4-bromophenyl)-2-phenyl-6-(2-pyridyl)pyrimidine as a pale brown solid.
Reaction SMILES: [C:1]([C:4]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C(OC(C)(C)C)=O)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([CH:4]([C:1](=[O:3])[CH3:2])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:30])#[N:29]
Reactant: CCOC(=O)CCCCC(C(C)=O)(C(=O)OC(C)(C)C)C(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCC(C(C)=O)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate (4.2 g) was added trifluoroacetic acid (20 mL) in an ice-water bath. After 30 minutes, the bath was removed and the reaction mixture was stirred at ambient temperature. After 1 hour, the mixture was concentrated. The residue was dissolved in toluene and was evaporated in vacuo to give ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.20 g, 100.4%) as colorless oil.
Reaction SMILES: [C@H]1(NC([C@@H]2CC3C(=CC(OS(C(F)(F)F)(=O)=O)=CC=3)CN2C(OC(C)(C)C)=O)=O)C2C(=CC=CC=2)CCC1.[N+:39]([C:42]1[CH:51]=[C:50]2[C:45]([CH2:46][C@@H:47]([C:52]([NH:54][C@H:55]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH2:58][CH2:57][CH2:56]3)=[O:53])[NH:48][CH2:49]2)=[CH:44][CH:43]=1)([O-:41])=[O:40].[C:65]([O:69][C:70]([NH:72][C@@H:73]([C:77]([CH3:80])([CH3:79])[CH3:78])[C:74](O)=[O:75])=[O:71])([CH3:68])([CH3:67])[CH3:66]>>[CH3:78][C:77]([CH3:80])([CH3:79])[C@H:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:68])([CH3:67])[CH3:66])[C:74]([N:48]1[C@H:47]([C:52](=[O:53])[NH:54][C@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][CH2:56]2)[CH2:46][C:45]2[C:50](=[CH:51][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=2)[CH2:49]1)=[O:75]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Yield: 97.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D, (S)-7-nitro-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1.69 g, 4.81 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.22 g, 5.29 mmol) were converted to the title compound (2.65 g, 98%). MS (ESI+) m/z 565.3 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[N:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>O1CCCC1.O.CO>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[CH:28][C:19]=1[N:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of (R)-1-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 1, Step A, 14.1 g, 37.2 mmol) in a 3:1:1 mixture of tetrahydrofuran/water/methanol (375 mL) was added lithium hydroxide hydrate (4.7 g, 112 mmol). This mixture was stirred at room temperature for 1 h 45 min, concentrated, and extracted with chloroform (6×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 2% methanol/chloroform) to give 11.3 g (90%) of the title compound as a pale yellow solid after tritration with hexanes. mp: 106.5-108° C.; 1H NMR (CDCl3, 250 MHz) δ 8.62 (s, 1H), 8.26 (d, 1H), 7.92 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.45 (d, 1H), 4.75 (m, 1H), 3.95-3.85 (c, 8), 1.54 (d, 3H); MS (CI/NH3) 337 (MH+); [α]D+15.3 (c 2.3, MeOH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]3[C:23]([CH2:26][OH:27])=[CH:24][CH:25]=[C:14]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.C1COCC1>[C:35]([O:27][CH2:26][C:23]1[N:15]2[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]3([CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[C:14]2=[CH:25][CH:24]=1)(=[O:37])[CH3:36]
Reactant: OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol (1.66 g, 4.60 mmol) and 4-(dimethylamino)pyridine (561 mg, 4.60 mmol) in dry THF (40 mL) was cooled to 0° C. Triethylamine (2.56 mL, 18.4 mmol) was then added to the reaction mixture followed by dropwise addition of acetic anhydride (1.27 mL, 13.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. It was then concentrated and purified by column chromatography (silica gel: 10-40% EtOAc in hexanes) to give (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (1.32 g, 61% yield over two steps). ESI-MS m/z calc. 402.5, found 403.7 (M+1)+; Retention time: 1.31 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Br:18])[C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Yield: 87.6 %

Procedure:
A mixture of 2-(4-chlorophenyl)-4-methylbenzoxazole (P0001; 5.44 g), N-bromosuccinimide (4.77 g) and 2,2′-azobisisobutyronitrile (92 mg) in CCl4 (54 ml) was refluxed overnight. The insoluble was removed by filtration, and the filtrate was concentrated and cooled. The precipitates were collected and washed with CCl4 to give pale brown crystals of 2-(4-chlorophenyl)-4-(bromomethyl)benzoxazole (P0002; 6.31 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:18])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9]1.Cl[CH2:20][C:21]([CH2:23]Cl)=[CH2:22]>O1CCOCC1>[CH3:7][CH:8]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:22][C:21](=[CH2:20])[CH2:23][O:18][C:13]3=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: CC1CCc2cc(O)c(O)cc21
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1COc2cc3c(cc2OC1)C(C)CC3
Yield: 36.4 %

Procedure:
A suspension of 25.7 g (186 mmol) of potassium carbonate were heated to reflux with stirring. At this temperature, over the course of 5 h, a mixture of 15.3 g (93.2 mmol) of 1-methylindane-5,6-diol and 11.6 g (92.8 mmol) of 3-chloro-2-chloromethylprop-1-ene dissolved in 50 ml of dioxane was added dropwise. When addition was complete, the mixture was stirred for a further 1 h under reflux and the inorganic solids precipitated out were filtered off with suction after cooling the reaction mixture. The solids were washed with acetone and the combined organic phases freed from solvent on a rotary evaporator. After flash chromatography (pentane/ether, 19:1, Rf=0.66) on silica gel, 7.3 g (36%) of 1-methyl-7-methylene-2,3,7,8-tetrahydro-1H,6H-5,9-dioxacyclohepta[f]indene were obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]1=[O:24])C.[OH-].[K+].Cl.[Cl-].[K+]>CO>[Cl:12][C:11]1[N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:7](=[O:24])[C:8]([NH:13][CH2:14][C:15]([F:22])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:9][CH:10]=1
Reactant: CCOC(=O)Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: O=C(O)Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O
Reaction time: 3 h

Procedure:
To a stirred solution of 7.27 g (19.5 mmol) of [6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester in 200 mL of methanol was added 39 mL (39.0 mmol) of 1M aq. potassium hydroxide. After 3 h the solution was acidified to pH=7 using conc. HCl, and concentrated at reduced pressure (azeotrope with PhCH3) to give a white solid containing potassium chloride and the product. 1H NMR (CD3OD) δ 8.64 (d, 1H, 4.8 Hz), 7.93 (ddd,1H, 7.7, 7.7, 1.5 Hz), 7.70 (d, 1H, 8.0 Hz), 7.49 (dd, 1H, 5.2, 7.4 Hz), 6.80 (s, 1H), 4.67 (s, 2H), 4.27 (t, 2H, 13.9 Hz).