Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[CH2:3][C@H:4]([NH:37]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].N1CCCCC1>C(Cl)Cl>[NH2:37][C@@H:4]([CH2:3][C:2]([F:55])([F:56])[F:1])[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate (10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 30-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12 (2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s), 6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91 (1H, d, J=13.14 Hz), 3.71 (1 H, d, J=13.39 Hz), 2.66 (2H, m). (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was prepared in the same method here and isolated as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m), 6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07 Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H, m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) and (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was assigned arbitrarily.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:22][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNC3CCCCC3)cc2)cc1
Reaction time: 48 h
Yield: 91 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.0 mmol) and cyclohexylamine (2.5 g, 25 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (1.57 g, 25.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 6.4 g (91%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.05-1.35 (m, 5H), 1.55-1.65 (m, 1H), 1.70-1.80 (m, 3H), 1.85-2.00 (m, 2H), 2.45-2.55 (m, 1 H) 3.80 (s, 2H), 6.95-7.04 (m, 4H), 7.05 (tt, J=7.5, 1.5 Hz, 1H), 7.25-7.35 (m, 4H). MS (DCl/NH3) m/e 282 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][CH2:8][N:9]([CH2:27][C:28]([OH:30])=[O:29])[C:10]([O:12][CH2:13][CH:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].[CH3:31]O>>[ClH:3].[NH2:6][CH2:7][CH2:8][N:9]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:10]([O:12][CH2:13][CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NCCN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Product: COC(=O)CN(CCN)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.15 ml of thionyl chloride are added dropwise, at 0° C., to 75 ml of anhydrous methanol. Subsequently, 7.5 g (20 mmol) of N-(2-aminoethyl)-N-(9-fluorenylmethoxycarbonyl)aminoacetic acid hydrochloride are added in portions. The mixture is stirred at 0° C. for one hour, allowed to warm to room temperature, and then stirred further overnight. The reaction solution is concentrated and the precipitate is filtered off with suction and dried.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:6]=[N:7][N:8]([CH3:13])[C:9](=[O:12])[C:10]=1[Cl:11]>CO>[Cl:11][C:10]1[C:9](=[O:12])[N:8]([CH3:13])[N:7]=[CH:6][C:5]=1[O:2][CH3:1]
Reactant: C[O-]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
295 g of 30% strength sodium methylate solution was added to 293 g (1.64 mol) of 4,5-dichloro-1-methyl-6-pyridazone in 690 ml of methanol in such a manner that a temperature of 30° C. was not exceeded. After cooling and stirring for 12 hours at 25° C., the precipitate which had formed was filtered off, washed and dried. There was obtained 241 g (84.3%) of 5-chloro-4-methoxy-1-methyl-6-pyridazone of melting point 189°-191° C.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6].[NH3:20]>CO>[NH2:20]/[C:12](/[CH2:11][S:10][CH2:9][CH2:8][NH:7][CH:5]=[O:6])=[CH:13]\[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: N
Reactant: CCOC(=O)CC(=O)CSCCNC=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\N)CSCCNC=O
Temperature: 0 °C

Procedure:
Acetic acid is added to a solution of ethyl 4-(2-formylamino-ethylthio)-3-oxo-butanoate (12.5 g) in MeOH (ml 120), previously saturated with ammonia at 0° C. and cooled at 0° C., up to pH 4-45. The mixture is refluxed for 2 hours and the excess solvent is evaporated in vacuum, to give a syrup from which a solid material is separated by treatment with AcOEt. After filtration, the organic phase is washed with water (8×10 ml), and with a saturated aqueous solution of NaHCO3 (3×10 ml), dried (Na2SO4) and concentrated in vacuum to give 11,5 g of ethyl 3-amino-4-(2-formylaminoethylthio)crotonate as a yellow oil.
Reaction SMILES: O[Li].O.C([C:6]1([C:22]([O-:24])=[O:23])[CH2:21][N:9]2[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C:8]2=[N:7]1)C>CO.O>[C:17]([O:16][C:14]([N:12]1[CH2:11][CH2:10][N:9]2[CH:21]=[C:6]([C:22]([OH:24])=[O:23])[N:7]=[C:8]2[CH2:13]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCC1(C(=O)[O-])CN2CCN(C(=O)OC(C)(C)C)CC2=N1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
LiOH.H2O (8.8 mmol, 4.0 equiv.) was added at 0° C. to a solution of 7-tert-butyl 2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (2.2 mmol, 1.0 equiv.) in methanol/water (2.5:1, 35 ml), and the mixture was then stirred for 2 h at 25° C. When the reaction was complete (TLC monitoring), the methanol was removed in vacuo, the residue was diluted with water (40 ml), and extraction with ethyl acetate (2×40 ml) was carried out. The aqueous phase was then adjusted to pH 2-3 with 1N HCl solution, and the resulting solid was filtered out. The solid was taken up in toluene, and the solvent was then removed in vacuo (2×) to yield the desired product in the form of a white solid. Yield: 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1COCC1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([NH:23][CH2:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C(CNC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 422.2 %

Procedure:
A solution of methyl 2-(4-chlorophenyl)acrylate (2.00 g, 10.2 mmol) in 1:1 THF:ethanol (20 mL) was treated with tert-butyl amine (389 uL, 2.23 mmol) at 60° C. The reaction stirred for 20 hours to completion, and the solvent/excess amine were removed in vacuo. The residue was purified by chromatography on silica gel (eluted with 1:1 hexanes:ethyl acetate) to afford the pure methyl 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (2.54 g, 93%) as a colorless oil. LCMS (APCI+) m/z 270.0 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:2]1.C(O)(=O)C.[BH4-].[Na+].CCOC(C)=O>C(Cl)Cl>[CH:1]1([C@H:4]2[C@H:8]([OH:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(=O)[C@@H]1C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O)[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (15) (4.0 g, 17.62 mmol) was dissolved in CH2Cl2 (90 mL) and acetic acid (10 mL) and cooled to 0° C. NaBH4 (1.33 g, 35.24 mmol) was added in several portions and the reaction stirred for 16 hr at rt. EtOAc (300 mL) was added and the organics were washed with sat. aq. NaHCO3 (300 mL), brine (200 mL), and dried over Na2SO4. Concentration of the solution in vacuo led to isolation of (2S,3R)-tert-butyl 2-cyclopropyl-3-hydroxy-5-oxopyrrolidine-1-carboxylate (16) (1.34 g, 33%) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1[F:41])[C:30]([OH:32])=O.[C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(=[O:45])[NH:43][NH2:44].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1[F:41])[C:30]([NH:44][NH:43][C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:32]
Reactant: O=C(O)C(CCCCl)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1c(F)cc(F)cc1F
Yield: 41.9 %

Procedure:
IPEA (1.1 mL) and BOPCl (798 mg) were added to a solution of 5-chloro-2-(2,4,6-trifluorophenyl)pentanoic acid (560 mg) synthesized according to the method described in Tetrahedron Letters, 2003, vol. 44, p. 365 and tert-butyl carbazate (276 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 333 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]([C:8](=[O:30])[CH2:9][N:10]([CH2:20][C:21](=[O:29])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:35]1[CH:36]=[CH:37][C:38]2[N:43](O)N=[N:41][C:39]=2[CH:40]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:41][C:39]1[CH:40]=[CH:35][CH:36]=[CH:37][C:38]=1[NH:43][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:10]([CH2:9][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:20][C:21](=[O:29])[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:13]=1
Reactant: O=C(CN(CC(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1)Nc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)c1ccc(N(CC(=O)Nc2ccccc2)CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[bis(2-anilino-2-oxoethyl)amino]benzoic acid (20 mg, 0.050 mmol) in DMF was added EDC (28 mg, 0.149 mmol), HOBt (20 mg, 0.149 mmol) and phenylenediamine (27 mg, 0.248 mmol) and the reaction was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (25 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (30-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired N-(2-aminophenyl)-4-[bis(2-anilino-2-oxoethyl)amino]benzamide: 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 2H), 9.31 (s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.64 (dd, J=8.6, 1.0 Hz, 4H), 7.33 (m, 4H), 7.07 (m, 3H), 6.89 (t, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.60 (d, 9.1 Hz, 1H), 6.53 (t, J=7.2 Hz, 1H), 4.79 (s, 2H), 4.42 (s, 4H); MS: cal'd 494.2 (MH+), exp 494.2 (MH+).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[S:11]([CH2:21][N+:22]#[C-:23])([C:14]1[CH:20]=[CH:19][C:17](C)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[C-:24]#N.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:1]2[O:10][CH:23]=[N:22][C@@H:21]2[S:11]([C:14]2[C:15]([CH3:24])=[CH:16][CH:17]=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: COc1ccc([C@H]2OC=N[C@@H]2S(=O)(=O)c2ccccc2C)cc1

Procedure:
In a manner analogous to Preparation 1, p-anisaldehyde (0.49 mL, 4.03 mmol), tosylmethylisocyanide (0.75 g, 3.84 mmol) and NaCN (0.02 g, 0.40 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 662.9 (2M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(-c2ccco2)c2ncn(C(=O)OCc3ccccc3)c2n1
Temperature: 5 °C
Yield: 97.5 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.201 g, 1.0 mmol), benzyl chloroformate (0.20 mL, 1.1 mmol), triethylamine (0.21 mL, 1.5 mmol) and DMAP (15 mg) in DMF (10 mL) was stirred at room temperature for 4 h, poured into cold water, cooled for 30 min at 5° C. and the resulting solid filtered and dried at 40° C. to give the title compound (0.327 g, 98%) as a cream solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][NH2:22].[CH2:25](O)[CH3:26]>>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][NH:22][C:2]1[C:3]([C:4]([O:6][CH2:25][CH3:26])=[O:5])=[CH:7][CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CCO
Reactant: CC(C)(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(C)nc1NCCC(C)(C)C
Temperature: 160 °C

Procedure:
A solution of 2-chloro-6-methylnicotinic acid (0.500 g, 2.91 mmol) in ethanol (5.0 mL) was treated with potassium carbonate (0.810 g, 5.80 mmol) followed by (3,3-dimethylbutyl)amine (0.590 mL, 4.35 mmol). The mixture was stirred at reflux for 3 h and then heated to 160° C. for 1 h in a Biotage Initiator microwave synthesizer. A solid was decanted and the mother liquor was further diluted with ethanol (5.0 mL) and treated with concentrated sulfuric acid (3.0 mL). The solution was then refluxed overnight, cooled to ambient temperature, and neutralized to pH ˜7 using 6N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The title compound was obtained as a clear oil (0.578 g, 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=7.8 Hz, 1H), 7.84 (br. s., 1H), 6.35 (d, J=7.8 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.44-3.58 (m, 2H), 2.92-3.05 (m, 2H), 2.42 (s, 3H), 1.37 (t, J=7.2 Hz, 3H), 0.99 (s, 9H). MS(ES+) m/e 265 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[CH3:26][C:27]1([CH3:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:26][C:27]1([CH3:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[CH2:28]1
Reactant: CC1(C)CNc2ccccc21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccccc21

Procedure:
70 mg (0.21 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 30.33 mg (0.21 mmol) 3,3-dimethyl-2,3-dihydro-1H-indole, 71 mg (0.22 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:35])[N:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[CH:29]=O)[N:26]=[C:7]3[C:6]=2[C:5]([F:36])=[CH:4][CH:3]=1.[CH2:37]([NH2:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C.ClCCl>[CH2:37]([NH:39][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:25]1[C:24](=[O:35])[C:8]2=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)[C:11]3[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:36])[C:6]=3[C:7]2=[N:26]1)[CH3:38]
Reactant: O=Cc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(6,9-Difluoro-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde [(Example 39) 15 mg, 0.031 mmol] was suspended in acetonitrile (1.5 mL), treated with ethylamine (0.15 mL, 0.15 mmol, 1.0 M tetrahydrofuran solution, 5 equiv), acetic acid (10 μL, 0.17 mmol, 5.6 equiv) and powdered 4 Å molecular sieves (15 mg, 1 wt equiv) and stirred for 30 minutes at ambient temperature. Sodium triacetoxyborohydride (6.6 mg, 0.031 mmol, 1 equiv) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with dichloromethane (5 mL), filtered and concentrated in vacuo. The residue was diluted with dimethylsulfoxide (1 mL) and water (0.1 mL) and treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 7.0 mg, 0.031 mmol, 1 equiv). After stirring for 30 minutes, the mixture was filtered and purified by preparative reverse phase HPLC (5:95 to 95:5; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid:acetonitrile), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.24 (1H, s), 8.80 (2H, br s), 8.47 (1H, d, J=2.5 Hz), 7.82 (2H, d, J=8.7 Hz), 7.73-7.68 (3H, m), 7.64-7.58 (2H, m), 7.55-7.50 (2H, m), 7.35 (2H, d, J=8.6 Hz), 6.54 (1H, dd, J=2.4, 1.9 Hz), 5.86 (2H, d, J=3.2 Hz), 4.16 (2H, br m), 2.97-2.92 (2H, m), 0.91 (3H, t, J=7.5 Hz) ppm; high resolution mass spectrometry (ES+) m/z 511.2035 [(M+H)+; calculated for C29H25F2N6O: 511.2053].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH:21]2[OH:27])=[C:15]([N+:28]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:57](OC2C=CC=CC=2)=[N:58][C:59]#[N:60])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@@H:21]3[OH:27])/[C:57](=[N:58]/[C:59]#[N:60])/[NH:28][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CCC(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])C(O)C1
Agent: [Pt]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CC[C@H](n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.6 %

Procedure:
Dissolve 4-[4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenylamino]-1-methyl-piperidin-3-ol (0.012 mol, 5.97 g) in tetrahydrofuran (50 mL). Add triethylamine (0.024 mol, 2.44 g) and 10% platinum on carbon (2.9 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through diatomaceous earth. Add pyridine (50 mL) and diphenyl N-cyanocarbonimidate (0.012 mol, 2.88 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure, dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.7 g, 27%) as an off-white solid. LC-MS m/z 514.4 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[S:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1>C(O)C>[Br:9][C:10]1[S:14][C:13]([CH:15]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
A solution of pyruvic acid (12.1 mL, 174.4 mmol) in ethanol (15.0 mL) was added to a 0.5 M sodium hydroxide solution (476.2 mL). The reaction mixture was stirred at room temperature for 20 minutes. A solution of 5-bromo-thiophen-2-carbaldehyde (30.3 g, 158.6 mmol) in ethanol (140.0 mL) was slowly added to the reaction mixture at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then the precipitate solid was filtered. The resulting solid was washed with diethyl ether, acidified by a 3N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 39.6 g of the titled compound as a yellow solid.