Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.I[CH:30]([CH3:32])[CH3:31]>C(#N)C.C(Cl)Cl>[CH:30]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][CH2:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:28])[N:9]3[CH3:27])=[CH:4][C:3]=2[O:2][CH3:1])[C@@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:32])[CH3:31]
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CC(C)I
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(C)C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Yield: 34.7 %

Procedure:
6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.26 mmol) and 2-iodopropane (0.058 mL, 0.58 mmol) were stirred in acetonitrile at 60° C. for 2 days. The reaction was diluted with methylene chloride, washed once with satd. NaHCO3, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (9.1 ethyl acetate/methanol) gave 38 mg (34%) of the title compound, a yellow oil. Rf=0.08 (9:1 ethyl acetate/methanol). MS (M+H)+=422.1; 1H NMR (400 MHz, CDCl3): δ 0.66–0.68 (d, J=6.5 Hz, 3H), 1.00–1.02 (d, J=6.5 Hz, 3H), 1.35–1.42 (m, 1H), 1.50–1.53 (bd, J=13.0 Hz, 1H), 1.91–1.97 (m, 1H), 2.02–2.07 (m, 1H), 2.22–2.28 (t, J=11.5 Hz, 1H), 2.53–2.57 (t, J=7.4 Hz, 2H), 2.64 (s, 1H), 2.75–2.79 (t, J=7.4 Hz, 2H), 2.94–3.02 (m, 2H), 3.12 (s, 3H), 3.38–3.42 (d, J=14.6 Hz, 1H), 3.54 (s, 3H), 3.60 (s, 1H), 3.66–3.69 (d, J=14.6 Hz, 1H), 6.49 (s, 1H), 6.66 (s, 1H), 7.19–7.29 (m, 3H), 7.36–7.38 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 12.0, 20.3, 21.1, 25.5, 27.7, 29.6, 31.8, 44.1, 45.0, 48.5, 55.5, 56.3, 109.8, 112.8, 116.0, 124.9, 126.7, 127.8, 129.2, 133.5, 141.5, 152.9, 170.0. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:26])[C:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Yield: 88.2 %

Procedure:
A suspension of 7-hydroxy-2-(3-trifluoromethyl-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 24.b, 120 mg, 0.32 mmol), N-bromosuccinimide (60 mg, 0.34 mmol), and benzoyl peroxide (7.3 mg, 0.03 mmol) in 0.8 mL of carbon tetrachloride was heated at reflux temperature for 5 hours. The reaction mixture was cooled and chromatographed on silica gel, eluting the desired product with 30% ethyl acetate in hexanes to provide 126 mg of a white solid: MS: (+) m/z 445.9, 447.9 (M+1, 79Br/81Br)
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][C@@H:24]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:25][C@H:26](O)[C@@H:27]([NH:35][C:36]([O:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][CH:41]=3)=[O:37])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N[C@@H](CC1C=CC=CC=1)C[C@H](O)[C@@H](NC(OCC1SC=NC=1)=[O:67])CC1C=CC=CC=1.N[C@H]([C@@H](O)C[C@@H](NC(OCC1SC=NC=1)=O)CC1C=CC=CC=1)CC1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C@@H:25]([OH:67])[CH2:26][C@@H:27]([NH:35][C:36]([O:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][CH:41]=3)=[O:37])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[N:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)[C@H](NC(=O)OCc1csc(N2CCOCC2)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OCc1csc(N2CCOCC2)n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1

Procedure:
Using the procedure of Example 1 U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with the resultant compound of Example 11 E and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 2% methanol in chloroform, 196 mg (90%) of the desired compound (Rf 0.19, 4% methanol in chloroform), mp. 146°-148° C. Mass spectrum: (M+H)+ =751.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C(C)C)N=NN=2)C(OCC)=O)=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[C:38]([C:44]2[N:45]=[N:46][N:47]([CH:49]([CH3:51])[CH3:50])[N:48]=2)[C:39](OCC)=[O:40])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[C:38]([C:44]2[N:45]=[N:46][N:47]([CH:49]([CH3:51])[CH3:50])[N:48]=2)[CH:39]=[O:40])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)C)n1
Agent: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Product: CC(C)n1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 88 %

Procedure:
The general procedure of Example 21, Steps A, B, C, and D were repeated, except that the ethyl 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate utilized therein was replaced by ethyl 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenoate and there was thereby produced in 88% yield the title compound.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:29])=[O:30])[CH:19]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1cccc(C#N)c1
Agent: Cl
Product: N#Cc1cccc(C[C@H](NC(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cccc3nccnc23)C(=O)O)c1

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(3-cyano-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(3-cyano-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=8.94 min. MS (ESI−): mass calcd. for C25H18ClN5O5S, 535.07; m/z found, 534/536 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.01 (s, 1H), 9.03 (d, J=1.7, 1H), 8.94 (d, J=1.7, 1H), 8.57 (d, J=7.4, 1H), 8.33 (d, J=8.5, 1H), 7.90 (t, 7.5, 1H), 7.74 (d, J=1.9, 1H), 7.57-7.55 (m, 1H), 7.47-7.41 (m, 3H), 7.12 (d, J=8.4, 1H), 6.93 (dd, J=5.6, 1.9, 1H), 6.40 (d, J=7.3, 1H), 5.02-4.98 (m, 1H), 3.36 (dd, J=14.1, 6.0, 1H), 3.25 (dd, J=14.2, 5.6, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C.C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:6]([C:5]1[S:1][C:2]2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]=2[CH:4]=1)=[O:7]
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2c(s1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5 mmol), methylene chloride (80 mL), and DMF (60 mg, 0.825 mmol) and cooled to 0° C. To the resulting solution, oxalyl chloride (2.31 g, 18.2 mmol) was added dropwise. After this addition was complete, the reaction was warmed to room temperature and stirred for 2 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting white solid was dissolved in methylene chloride (80 mL) and the solution cooled to 0° C. Triethylamine (5.00 g, 49.5 mmol) and N,O-dimethylhydroxylamine (1.61 g, 16.5 mmol) were then added. After the addition was complete, the cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (100 mL), followed by brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford an 88% yield of 103a (3.29 g) as a white solid: mp 36-37° C.; 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 3.76 (s, 3H), 3.34 (s, 3H), 2.78 (t, 2H, J=6.0 Hz), 2.62 (t, 2H, J=6.0 Hz), 1.82 (m, 4H); MS (APCI+) m/z 226.3 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1/[C:36](/[NH:39]O)=[N:37]/[H])[NH:32][CH:31]=[C:30]2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:37]=[C:36]([C:35]3[CH:34]=[C:33]4[C:29]([C:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][NH:32]4)=[CH:28][C:27]=3[F:26])[N:39]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)cc12
Temperature: 120 °C
Yield: 55.5 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (200 mg) in tetrahydrofuran (THF) (10 mL) was added EDC (374 mg) and HOBt (299 mg). The mixture was stirred for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (286 mg) was then added and the resulting mixture was stirred further for 1 hour. Finally, TBAF (1019 mg) was added to the solution and the reaction vessel was sealed and heated in macrowave at 120° C. for two hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel to give the designed product ethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D157) (250 mg). MS (ES): C25H23FN4O4 requires 462.2; found 463.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:37][CH:38]=1)[CH3:23]
Reactant: CN(C)Cc1ccccc1-c1ccc(N)cc1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1ccccc1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (60 mg, 0.19 mmol) and 4-(2-dimethylaminomethyl-phenyl)phenylamine (50 mg, 0.22 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.034 mL, 0.37 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (8 mg). MS 531.1 and 533.1 (M+H, Cl pattern).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C([N:16]([CH2:19]C)[CH2:17][CH3:18])C.ClC(OCC)=O.FC(F)(F)C([N:31](CNC)[C:32]1[CH:37]=C[CH:35]=[CH:34][CH:33]=1)=O.[Cl-].[NH4+]>CN(C)C=O>[CH3:19][NH:16][CH2:17][C:18]1[CH:37]=[C:32]([NH:31][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: CNCN(C(=O)C(F)(F)F)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNCc1cccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (100 mg, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (5 mL) at 0° C. is added ethyl chloroformate (0.1 mL, 1.1 mmol). After stirring an additional 1 hour, 3-(N-trifluoroacetyl-(methylaminomethyl)aniline (0.3 g, 1.3 mmol) is added. The reaction mixture is stirrred for 4 hours, then poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers are washed sequentially with brine, aqueous 2N hydrochloric acid, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue is added 15% aqueous potassium bicarbonate (5 mL) and methyl alcohol (3 mL), then heated at reflux for 3 hours. After cooling, the reaction mixture is extracted with ethyl acetate, the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo to give N-[3-(methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (Compound 1) m.p. 130-132° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[F:10].N1C=CC=CC=1.[C:53](OC(=O)C)(=[O:55])[CH3:54].Cl>C(Cl)Cl>[C:53]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[F:10])(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of (R)—N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide hydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt was added pyridine (7.8 μL, 0.1 mmol) followed by acetic anhydride (4.6 μL, 0.05 mmol). The reaction mixture was stirred at rt for 1 h, then poured into 1N HCl and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by ISCO column chromatography (4 g, 0-50% EtOAc/hexane) to yield (R)—N-(1-(3-(acetamidomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 270) as a white foam (21 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (dt, J=8.53, 2.18 Hz, 1H), 7.25 (m, 2H), 7.13 (m, 3H), 6.99 (m, 5H), 6.81 (s, 1H), 6.69 (m, 2H), 5.87 (m, 2H), 4.38 (m, 2H), 4.04 (d, J=13.14 Hz, 1H), 3.75 (d, J=13.14 Hz, 1H), 1.92 (s, 3H).
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@:7]([CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])([CH3:12])[N:6]1C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[C:1]([CH:5]1[N:9]([CH3:10])[C:8](=[O:11])[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])([CH3:12])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)[C@@](C)(CCCCCl)N(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)C(C)(CCCCCl)NC1C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
To an ice cooled of (2S,5R)-tert-butyl 2-(tert-butyl)-5-(4-chlorobutyl)-3,5-dimethyl-4-oxoimidazolidine-1-carboxylate (D44) (465 mg, 1.28 mmol) in dry DCM (2 ml), TFA (1 ml, 12.8 mmol) was added and the solution stirred for 12 hrs at RT. The reaction mixture was treated with NaHCO3 sat sol with vigorous stirring until pH˜7. The resulting mixture was poured into water and the aqueous phase extracted with DCM (3×10 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D45) (310 mg).
Reaction SMILES: C([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:5](C(O)=O)[C:4]=1[CH2:16][CH3:17])#N.[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:16]([C:4]1[CH:3]=[C:12]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11]2)[CH:5]=1)[CH3:17]
Reactant: CCc1c(C#N)c2cccccc-2c1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc2cccccc-2c1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
3.7 g (16.4 mmol) of the above-obtained 1-cyano-2-ethylazulene-3-carboxylic acid was separated into two parts, i.e., about 1 g and a remaining part. 30 ml of 75% sulfuric acid was added to the first part, i.e., about 1 g of 1-cyano-2-ethylazulene-3-carboxylic acid and heated to 90° C., and thereafter gradually supplied with the remaining part of 1-cyano-2-ethylazulene-3-carboxylic acid. The mixture was heated at 90° C. for 2 hours and further at 120° C. for 2 hours. The obtained reaction solution was added to an aqueous solution containing 35 g of sodium hydroxide and extracted with a mixed solution of hexane and ethyl acetate. An organic phase of the extract was removed under a reduced pressure. The resultant crude product was purified by silica gel column chromatography, to obtain 1.71 g of 2-ethyl azulene (yield: 67%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CN(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(C)CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 17.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.73 g) and 5-amino-2-[4-[N-(2-hydroxyethyl)-N-methylamino]piperidin-1-yl]benzonitrile (0.65 g), the title compound (0.2 g) was obtained, melting point: 186° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Sc2ccccc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(Sc2ccccc2)nc1-c1ccc(C)cc1
Yield: 63.7 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(phenylthio)-6-p-tolylpyrimidin-5-yl)pentanoate (0.057 g; 0.140 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.035 g (64%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]([F:16])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[C:10]([CH3:15])=[N:9]2)[CH:7]=1.CCO[C:21]([S-:23])=[S:22].[K+].Cl>CN(C)C=O>[F:16][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[C:10]([CH3:15])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:21]([SH:23])[S:22][C:3]=2[CH:4]=1
Reactant: Cc1nn(-c2cc(N)c(Br)cc2F)c(=O)n1C
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2F)c(=O)n1C
Temperature: 140 °C
Yield: 75 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-4-bromo-2-fluorophenyl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 6 h, cooled, and poured into 100 mL ice water slurry. The mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solid materials crushed out. The title compound was obtained in a 75% yield as a white solid after filtration.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24]
Reactant: C=CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To 11.0 g (31 mmol) of 25 was added 124 mL of a 1 M solution of TBAF in THF and the reaction was stirred for 16 h at room temperature. The reaction mixture was then quenched with saturated solution of aq. NH4Cl and THF was evaporated under reduced pressure. The aq. solution was then diluted with 200 mL of water and the target product was extracted with Et2O (3×), the combined organic layers were then washed with brine (1×), dried over MgSO4 and the solvent was removed under reduced pressure. The crude was then purified by combiflash using hexane/ethyl acetate as eluent to furnish 5.7 g of target product 26 in 77% yield as colorless oil.