Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@@H:41]([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[CH3:45])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 83.3 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (279 mg) were used, whereby tert-butyl (2S)-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate (688 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (455 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: Cc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: Cc1cccc(CBr)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C

Procedure:
A mixture of 43.0 g (185 mmol) of 2-(2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 42.9 g (241 mmol) of N-bromosuccinimide, and 0.40 g (3.27 mmol) of AIBN in 1000 ml of acetonitrile was refluxed for 2 h. Then, this mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in 500 ml of hexane. The precipitate was filtered on glass frit (G3), and the filtrate was evaporated to dryness to give yellowish crystalline solid. Yield 37.9 g (66%). Anal. calc. for C14H20BBrO2: C, 54.06; H, 6.48. Found: C, 54.35; H, 6.72. 1H NMR (CDCl3): δ 7.21 (m, 1H, 4-H), 7.15 (m, 1H, 3-H), 7.07 (m, 1H, 5-H), 4.72 (s, 2H, CH2Br), 2.44 (s, 3H, 6-Me), 1.42 (s, 12H, Bpin).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@@H:29](F)[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@@H](F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
87 μl (490 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.8 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 3 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 60 mg (120 μmol) of 5-(4-fluorophenyl)-6-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 22A) in 3 ml of tetrahydrofuran are then slowly added dropwise, and the mixture is stirred at room temperature for 3 days. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 20:1) gives the target compound.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[C:25](=[O:26])[N:24]3[CH2:27][CH:28]([OH:30])[CH2:29][N:23]3[C:22]2=[O:31])[CH:17]=[C:18]([Cl:20])[CH:19]=1.[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:20][C:18]1[CH:17]=[C:16]([N:21]2[C:22](=[O:31])[N:23]3[CH2:29][CH:28]([O:30][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([Br:32])=[CH:34][CH:35]=4)[CH2:27][N:24]3[C:25]2=[O:26])[CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=c1n(-c2cc(Cl)cc(Cl)c2)c(=O)n2n1CC(O)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OC1Cn2c(=O)n(-c3cc(Cl)cc(Cl)c3)c(=O)n2C1)c1ccc(Br)cc1
Reaction time: 72 h
Yield: 12.5 %

Procedure:
EDCI, HCl (70 mg, 0.37 mmol) and DMAP (4 mg, 0.03 mmol) were added to a solution of 2-(3,5-dichlorophenyl)-6-hydroxy-dihydro-pyrazolo[1,2-α][1,2,4]triazole-1,3-dione (100 mg, 0.33 mmol) (Preparation 6), TEA (92 μl, 0.66 mmol) and 4-bromobenzoic acid (73 mg, 0.36 mmol) in DCM (2 ml). After 72 h at RT, the reaction mixture was washed with a citric acid solution (0.5 M) and a sodium bicarbonate solution, then concentrated. The residue was purified with preparative HPLC to yield the above compound (20 mg). 1H NMR (CDCl3):7.71 (2H, d, J=7 Hz), 7.55 (2H, d, J=7 Hz), 7.40 (3H, m), 5.67 (1H, m), 4.34 (2H, d, J=12.7 Hz), 3.80 (2H, dd, J1=12.7 Hz, J2=2.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[C:25]([C:27](=[O:35])[NH:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)[CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:26]=[C:25]([C:27](=[O:35])[NH:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)[CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1ccc(C(=O)NCC2CCCO2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1ccc(C(=O)NCC2CCCO2)cc1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-nitro-4-((tetrahydrofuran-2-yl)methylcarbamoyl)benzyl(2-(pyridin-2-yl)ethyl)carbamate, from above, (238 mg, 0.492 mmol) and SnCl2.2H2O (279 mg, 1.23 mmol) were suspended in ethanol (1.6 mL) and stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness, re-suspended in ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, concentrated onto silica gel and purified by flash chromatography (20 methanol:1 triethylamine:79 dichloromethane isocratic) to afford the desired intermediate, tert-butyl 2-amino-4-((tetrahydrofuran-2-yl)methylcarbamoyl)benzyl(2-(pyridin-2-yl)ethyl)carbamate (103 mg). LC/MS: Calc. C25H34N4O4 454.25 amu; Obs. [M+H]+=455.5 amu.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CS(=O)c1ccc(Br)cc1
Product: CS(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of αethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of 4-bromophenylsulfinylmethane, 177 mg (9%) of the expected sulfoxide compound, with a melting point of 121°-122° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:34])[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:34]=[C:30]([CH2:31][CH2:32][CH3:33])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 3.5 g, 16.80 mmol) was dissolved in dry DMF (35 mL). 1,1′-Carbonyldiimidazole (CDI) (3.0 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-butyramidine (1.88 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (2.99 g, 18.48 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 7 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.[Cl:18][C:19]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:18][C:19]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:23][CH2:24][N:25]([C:15](=[O:17])[CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])[CH2:26][CH2:27]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol), 1-(2,4-dichlorobenzyl)piperazine (0.058 g, 0.236 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.062 g, 0.322 mmol) in dichloromethane (0.5 mL) was allowed to stir at ambient temperature. After stirring overnight, the reaction was loaded directly onto a SF10-8 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes, maintaining 100% ethyl acetate for an additional 5 minutes (flow=20 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.42 (m, 2H), 7.17-7.34 (m, 6H), 4.45 (d, J=15.5 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 3.71 (dd, J=7.7, 6.0 Hz, 1H), 3.64 (t, J=4.9 Hz, 2H), 3.58 (s, 2H), 3.53-3.61 (m, 1H), 3.46-3.51 (m, 2H), 3.39-3.48 (m, 1H), 2.48-2.52 (m, 4H), 2.17-2.27 (m, 1H), 1.95-2.08 (m, 2H), 1.80-1.91 (m, 1H); MS (ESI+) m/z 460 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[O:9][N:8]=1.O.[OH-].[Li+].Cl>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[O:9][N:8]=1
Reactant: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (511 mg, 1.79 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added lithium hydroxide, hydrate (74.9 mg, 1.79 mmol). The reaction mixture was stirred for 1 hr. A 1N aqueous solution of hydrochloric acid (1.8 mL) was added, and the solvent were removed under reduced pressure to afford 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid+1LiCl (531 mg, 1.767 mmol, 99% yield) as a white solid. The compound had an HPLC ret. time=0.725 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.8. 1H NMR (400 MHz, CD3OD) δ ppm 7.59 (dd, J=7.03, 5.02 Hz, 1H), 7.82 (d, J=7.78 Hz, 1H), 8.01 (td, J=7.78, 1.76 Hz, 1H), and 8.73 (d, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=[O:38]>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH:23][C:37](=[O:38])[C:36]([F:41])([F:40])[F:35])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NNC(=O)C(F)(F)F)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (257 mg, 0.67 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (8.0 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.19 mL, 1.34 mmol). Thereafter, anhydrous trifluoroacetic acid (0.19 mL, 1.34 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and a 3 mol/L aqueous sodium hydroxide solution was added to the resulting residue to adjust the pH at 4. The precipitated white solid was then filtered off to obtain (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)-N′-(2,2,2-trifluoroacetyl)benzoic hydrazide (300 mg, 93%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[O:26])[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[O:26])[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)c2cccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (200 mg) in a mixture of tetrahydrofuran (12 ml) and methanol (12 ml) was added 1N sodium hydroxide solution (4 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (171 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]([O:21]C)=[O:20])=[O:16])[S:14][C:7]=12.[OH-].[Na+].O.Cl>C1COCC1.CO>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][C@H:18]([NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:32]=[CH:33][C:34]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=3[F:46])=[O:37])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16])[C:19]([OH:21])=[O:20])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate (260 mg, 0.40 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 1M HCl was added with stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as off-white solid. Yield: 230 mg, 91%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[NH2:16][C:17]([CH3:23])([CH3:22])[C:18]([NH:20][CH3:21])=[O:19]>>[CH3:22][C:17]([NH:16][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:18](=[O:19])[NH:20][CH3:21])[CH3:23]
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=318.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:40])[CH2:37][CH2:36][C:35]5=[O:41])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5C(=O)CCC5=O)cc4)c3Cl)cccn2c1Br
Yield: 11.2 %

Procedure:
A suspension of 3-bromo-8-[3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (110 mg) and anhydrous sodium acetate (16 mg) in acetic anhydride (1.1 ml) was refluxed for 5 hours. After cooling, the solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 ml) and washed with water, saturated sodium bicarbonate twice and brine. After dried over magnesium s the solvent was removed in vacuo. The residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(succinimido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (12 mg) as amorphous.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:32][CH3:33])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:34][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:32][CH3:33])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 140, 130 mg, 0.28 mmol), iron (94 mg, 1.68 mmol) and NH4Cl (10.48 mg, 0.20 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2.5 h. The mixture was allowed to cool to r.t., filtered and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column, eluting with 0.7M methanolic ammonia provided crude material as a brown gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (111 mg, 91%) as a brown gum; 1H NMR (CDCl3): 1.90-1.98 (2H, m), 2.04-2.12 (2H, m), 2.20 (6H, s), 3.08-3.16 (1H, m), 3.23 (2H, t), 3.35 (1H, s), 3.56 (2H, t), 3.84 (3H, s), 3.93 (2H, dd), 4.20 (2H, t), 6.37 (1H, s), 6.76 (1H, d), 7.35 (1H, s), 7.87 (1H, s), 7.95 (1H, s), 8.28 (1H, d); m/z: ES+ MH+ 435.58.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)([CH3:3])[CH3:2].[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(C)NCc1nc2c(c(=O)[nH]1)COCC2
Product: CC(C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (26.4 mg) from 2-((isopropylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C25H31FN4O4 470.5. found 471.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.91-8.18 (m, 2H) 7.19 (t, J=8.59 Hz, 2H) 4.53-4.69 (m, 2H) 4.50 (s, 1H) 4.24-4.43 (m, 1H) 4.19 (br. s., 1H) 3.86-4.08 (m, 3H) 3.80 (d, J=7.58 Hz, 1H) 3.58 (br. s., 2H) 3.33-3.50 (m, 1H) 3.28 (br. s., 1H) 2.74 (t, J=5.31 Hz, 2H) 2.19 (d, J=10.61 Hz, 2H) 2.13 (s, 1H) 1.11-1.33 (m, 5H) 1.07 (d, J=6.06 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1(C)CNc2ccccc21
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 175 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To 2c (317 mg, 2.12 mmol) was added 1-fluoro-2-nitrobenzene (200 mg, 1.42 mmol). The reaction mixture was stirred at 175° C. for 8 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl and dried over Na2SO4. The solvent was evaporated under reduced pressure and purified by column chromatography using 0 to 10% EtOAc in hexane over 30 min as eluting solvent to afford 2d (360 mg, 95%) as an oil. MS (ES) m/z 269 [M+H]+.