Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[NH2:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[CH:31]=[N:32][C:27]([NH2:26])=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Nc1ccc(B(O)O)cn1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Yield: 58 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45 mmol), Pd(Ph3P)2Cl2 (15 mg), and aqueous Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 60%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(O)CO.CS(C)=O>[CH:13]12[O:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][N:11]([C:4]1[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:3]=1)[CH2:12]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2sccc2n1
Reactant: Nc1ccc(O)cc1
Solvent: OCCO
Solvent: CS(C)=O
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3sccc3n2)cc1
Yield: 63.6 %

Procedure:
30 mg (0.11 mmol) of 2-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-thieno[3,2-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.5 mmol (54 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (2×30 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 25 mg (0.07 mmol, 66%) of the title compound.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCN(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (514 mg, 2 mmol) in THF (10 mL) at −78° C. was added dropwise LDA (1.5 M in cyclohexane, 2 mL, 3 mmol). After stirring for 30 minutes, 2-bromo-N,N-dimethylethanamine (370 mg, 2.4 mmol) in THF (3 mL) was added. The reaction was stirred for 30 min at −78° C., then allowed to warm to room temperature, stirred for 2 hours, then quenched with sat. aq. NaHCO3, diluted with EtOAc, washed with sat. aq. NaHCO3 and brine (with back extraction), dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (40 g SiO2, 0-15% MeOH:CH2Cl2) to give the title compound (328 mg, 1.0 mmol, 50%) as a yellow oil. MS (ES+) [M+H]+=329.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[S:8][CH3:9].[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:12][N:10]([CH3:11])[C:3]1[C:2]([NH:1][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:7]([S:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CSc1ncnc(N(C)C)c1N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(SC)ncnc1N(C)C

Procedure:
5-Amino-4-dimethylamino-6-methylthiopyrimidine (prepared by reacting 5-amino-4-dimethylamino-6-chloropyrimidine with sodium thiomethoxide) was coupled with oleoyl chloride using the procedure described in Example 4 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[S:46]1[CH2:51][CH2:50][CH:49](O)[CH2:48][CH2:47]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][CH:49]2[CH2:50][CH2:51][S:46][CH2:47][CH2:48]2)[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: OC1CCSCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCSCC2)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (3.0 g, 4.73 mmol), tetrahydro-2H-thiopyran-4-ol (0.62 g, 5.20 mmol) and triphenylphosphine (1.36 g, 5.20 mmol) in tetrahydrofuran (60 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.79 mL, 6.15 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture were added reagents (tetrahydro-2H-thiopyran-4-ol, triphenylphosphine and diethyl azodicarboxylate) in a half amount as mentioned above, and the mixture was further stirred for 8 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (3.5 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:24]=C([Mg]Br)[CH:26]=[CH:27][CH:28]=1.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1cccc(F)c1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (23.45 g, 104 mmol) in abs. THF (100 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of 3-fluorophenylmagnesium bromide in THF (208 ml, 208 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:23])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)c1cccc(C(=O)N2CCc3occc3C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 3-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O([CH2:24][C:25]([F:28])([F:27])[F:26])S(C(F)(F)F)(=O)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:3]=1[CH3:9]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(Br)ccc(=O)n1CC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred mixture of 3-bromo-6-hydroxy-2-methylpyridine (25.0 g, 133 mmol) and cesium carbonate (52.0 g, 160 mmol) in 1,4-dioxane (600 mL) was added 2,2,2-trifluoroethyl triflate (40.1 g, 173 mmol) and the resulting mixture was heated at 50° C. for 4 h and then allowed to cool to ambient temperature. The resulting mixture was filtered and the filtrate was concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=269.9 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17]([OH:19])=[O:18])[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.[Li].C1C(=O)N(Cl)C(=O)C1.[NH2:29][CH:30]([C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=[O:42])[CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[C:36]#[N:37].[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[C:36]([C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][CH:30]([NH:29][S:17]([C:12]2[C:11]3[CH:10]=[CH:9][NH:8][C:16]=3[CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:19])[C:41]([N:43]2[CH2:44][CH2:45][CH:46]([CH3:49])[CH2:47][CH2:48]2)=[O:42])[CH:40]=[CH:39][CH:38]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)n1ccc2c(S(=O)O)cccc21
Reactant: CC1CCN(C(=O)C(N)CCc2cccc(C#N)c2)CC1
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1CCN(C(=O)C(CCc2cccc(C#N)c2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To 0.29 g (0.77 mmol) of lithum 1-(tert-butoxycarbonyl)-1H-indole-4-sulfinic acid stirring in 1 mL of THF is added 62 mg (0.47 mmol) of NCS. After stirring for 5 minutes, 0.10 g (0.31 mmol) of 3-[3-amino-4-(4-methylpiperidin-1-yl)-4-oxobutyl]benzonitrile is added and the mixture is stirred for 4 h when 10% Na2SO3 and CH2Cl2 are added. The organic phase is dried over Na2SO4, filtered, and concentrated. Preparative TLC (33% EtOAc in hexanes) provides 70 mg (40%) of the sulfonamide. This material (30 mg, 0.053 mmol) in 1 mL of CH2Cl2 is treated with 0.2 mL of TFA for 90 minutes. The mixture is concentrated and purified by preparative TLC (5% MeOH in CH2Cl2) to provide 21 mg (85%) of Example 71. ESI MS Calc. 464.2; Found: 465.7 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[OH:1])=[O:12]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)=O)c(O)c1
Product: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-hydroxy-4-methoxyphenyl)ethane-1-one (20 g, 120 mmol) and N,N-dimethylformamide dimethylacetal (23 g, 181 mmol) was stirred at 90° C. for 2 hours. After cooling to room temperature the reaction mixture provided a yellow precipitate, which was washed with ethyl acetate (3×30 ml), water (2×50 ml), and dried under reduced pressure to yield 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (9) as the trans isomer; MS 222.1 (M+H)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][CH3:21].[CH3:25][Si:26](Cl)([CH3:30])[CH:27]([CH3:29])[CH3:28].CI>C1COCC1.CCCCC>[CH3:25][Si:26]([O:22][C:19]([O:23][CH3:24])=[CH:20][CH3:21])([CH3:30])[CH:27]([CH3:29])[CH3:28]
Reactant: CCC(=O)OC
Reactant: CC(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CC=C(OC)O[Si](C)(C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
One g of diisopropyl amine was dissolved in 7.5 ml of THF at 0° C., and 7 ml of a 1.6M BuLi hexane solution was dropwise added. The mixture was stirred for 15 minutes at 0° C. The reaction solution was cooled to -78° C., and then 0.88 g (10 mmol) of methyl propionate was added. Thirty minutes later, 1.64 g (12 mmol) of dimethyl isopropyl silyl chloride was added thereto, and the mixture was stirred for 30 minutes. To the reaction solution, 1.9 ml of methyl iodide and 5 ml of pentane were added at -78° C., and then the reaction mixture was stirred at 0° C. for 30 minutes by means of ice bath. Then, the reaction mixture was left to stand overnight in a refrigerator. The reaction mixture was subjected to filtration, and the filtrate was distilled under reduced pressure, whereby 1.24 g (66%) of crude methylketene methyl dimethylisopropylsilyl acetal was obtained. NMR(CCl4)δ(ppm): 0.12(6H, s, (CH3)2Si), 0.96(6H, s, CH(CH3)2), 0.99(1H, s, CH(CH3)2), 1.40(3H, d, J=6 Hz, =CHCH3), 3.45(3H, s, OCH3), 3.57(1H, q, J=6 Hz, CH3CH=).
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16]C)=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][C:4]([O:5]C)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[OH:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[CH:18][CH:19]=2)=[O:10])=[CH:2][CH:3]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 200 °C
Yield: 85.4 %

Procedure:
Desoxyanisoin (5.00 g, 19.5 mmol) and pyridine hydrochloride (9.02 g, 78.0 mmol) were added to a round-bottom flask equipped with a condenser. The mixture was refluxed for 5 h at 200° C., cooled to room temperature, and poured into water. The precipitate was filtered and recrystallized from acetic acid to give 3.8 g (85% yield) of a pale yellow crystalline solid. 1H NMR (DMSO-d4, 300 MHz, ppm): 10.35 (s, 1H, HO—Ar—CO), 9.28 (s, 1H, HO—Ar—CH2), 7.91 (d, 2H, J=8.7 Hz, Ar—H), 7.04 (d, 2H, J=8.5 Hz, Ar—H), 6.84 (d, 2H, J=8.7 Hz, Ar—H), 6.68 (d, 2H, J=8.5 Hz, Ar—H), 4.11 (s, 2H, Ar—CO—CH2—Ar). 13C NMR (DMSO-d6, 75 MHz, ppm): 196.5, 162.3, 156.2, 131.3, 130.7, 128.1, 125.9, 115.5, 115.4, 43.7.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[C:21]2[CH:34]=[C:33]3[C:24]([N:25]4[C:30]([CH2:31][O:32]3)=[N:29][NH:28][C:27](=[O:35])[C@H:26]4[CH3:36])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]=1[C:21]1[CH:34]=[C:33]2[C:24]([N:25]3[C:30]([CH2:31][O:32]2)=[N:29][NH:28][C:27](=[O:35])[C@H:26]3[CH3:36])=[CH:23][CH:22]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4N4CCN(C(=O)OC(C)(C)C)CC4)ccc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4N4CCNCC4)ccc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-[3-fluoro-2-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-7-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (enantiomer 1, 0.070 g, 0.141 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give (R)-7-(2-fluoro-6-piperazin-1-yl-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.06 g, 85%) as a solid. 1H NMR (CD3OD, 400 MHz): δ 7.36 (m, 1H), 7.27 (m, 2H), 7.18 (s, 1H), 6.96 (m, 2H), 4.87 (m, 1H), 4.66 (d, J=13.0 Hz, 2H), 3.08 (s, 8H), 1.51 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.684 min; MS m/z: 396 [M+H]+. SFC (Table 1, Method 33) Rt=4.921 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8](=[N:10][OH:11])[NH2:9].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8]1[NH:9][C:39](=[O:40])[O:11][N:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33.3 mg, 0.06 mmol) in acetonitrile (2 mL) were added 1,1′-carbonyldiimidazole (19.3 mg, 0.119 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL, 0.238 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford 3-{7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31Cl2N7O3 [M+H]+=584. found=584. 1H NMR (600 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.92 (d, J=1.2 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.46 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.77-3.86 (m, 2H), 3.56-3.62 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.87 (m, 1H), 2.31 (m, 1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.81 (m, 1H), 0.65-0.74 (m, 6H), 0.46 (m, 1H), 0.30-0.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24]([O:40][CH3:41])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:28]([C:26]1[CH:25]=[C:24]([O:40][CH3:41])[N:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:27]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(OC)n3)CC1)C(=O)N2

Procedure:
633 mg (2.3 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 700 mg (2.28 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 953.6 mg (6.9 mmol) potassium carbonate were stirred in 5 mL of NMP for 8 h at 130° C. The undissolved solid was filtered off and the filtrate was purified by HPLC. The product-containing fractions were combined and concentrated to dryness by rotary evaporation. For further purification the residue was combined with DMF and the undissolved solid was suction filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:8][CH:9]=1
Reactant: O=c1ccc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: Nc1ccc(-n2c(=O)ccc3ccccc32)cc1
Yield: 82.6 %

Procedure:
To 10% Pd--C (0.1 g) is added acetic acid (20 ml) and then 1-(4-nitrophenyl)carbostyril (0.9 g) and the mixture is subjected to catalytic reduction at 80° C. under normal pressure. After completion of the reaction, 10% Pd--C is removed by filtration and the resulting solution is concentrated under reduced pressure. To the concentrate is added water and the solution is made alkaline with an aqueous sodium hydroxide solution and then extracted with dichloromethane. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography and recrystallized from ethanol to give 1-(4-aminophenyl)carbostyril (0.66 g) as brown powders, m.p. 225°-230° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>C(OCC)C>[ClH:30].[ClH:30].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOCC
Product: FC(F)(F)c1ccccc1-c1nccnc1N1CCNCC1
Reaction time: 2 h

Procedure:
Suspend 3′-(2-trifluoromethylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (408 mg, 1.00 mmol) in HCl in diethyl ether (1 M, 10 mL), stir for 2 hr. then concentrate in vacuo. Add more HCl in diethyl ether (1 M, 20 mL) and stir overnight at room temperature and concentrate. Add HCl in dioxane (4 M, 10 mL) and stir for 2 hr.s, then concentrate to give the title preparation as yellow solid (471 mg, 123%). MS (ES): m/z=309 [M+H]+.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]2=[N:6][C:5]=1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([S-:23])[O:22][C:18]=2[CH:17]=1.[K+]>CO>[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]2=[N:6][C:5]=1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([S:23][CH3:1])[O:22][C:18]=2[CH:17]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc4nc([S-])oc4c3)nc2c1
Reactant: CI
Agent: [K+]
Solvent: CO
Product: CSc1nc2ccc(CCc3nc4cc(C)ccn4c3C)cc2o1
Reaction time: 3 h

Procedure:
Methyl iodide (0.38 ml) was added dropwise to a solution of potassium 6-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]-2-benzoxazolethiolate (2.00 g) in methanol (30 ml) under ice-water cooling. After being stirred for 3 hours keeping the temperature below 5° C., the solvent was evaporated in vacuo. The residue was mixed with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methylthiobenzoxazole (1.31 g).