Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=O.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:11](=[O:13])[CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc2ccccc2o1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc2ccccc2o1

Procedure:
Following General Procedure I′ above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, light brown solid (98 mg, 78%), MS (ISP) m/z=499.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:17]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([O:9][CH3:17])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (25.0 g, 106.3 mmol) was dissolved in methanol (60 mL) which was bubbled with hydrochloric acid gas for 1 h. The reaction was allowed to stir at room temperature overnight and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2×), brine (2×) dried over sodium sulfate and concentrated. Flash chromatography on silica gel afforded 23.4 g (88%) of the desired compound. 1H-NMR (CDCl3, 500 MHz) δ 9.02 (s, H), 8.66 (s, 1H), 8.61 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:19]2[CH2:18][C:17](=[O:23])[O:22][C:20]2=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)O1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)OC2=O)cc(C(C)(C)C)c1O
Yield: 56.5 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 9.8 grams of maleic anhydride, and 0.51 grams of triethylamine. The residue is recrystallized once from hexane-toluene mixture and once from cyclohexane to give 19.0 grams of a light yellow solid, m.p. 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:21]([NH:23][CH3:24])=[O:22]>>[CH2:25]([C:20]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21](=[O:22])[NH:23][CH3:24])[CH2:27][CH3:28])[CH3:26]
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(OC)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=390.2 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Yield: 105.1 %

Procedure:
A mixture of 1-benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (528 mg, 1.66 mmol) prepared in Reference Example 96 and 10% palladium/carbon (50 mg) in acetic acid (5 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, and the mixture was washed with water, 10% sodium hydroxide aqueous solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenyl)piperidine (400 mg, quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)C)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:10][C:2]=2[CH3:1])=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)N2CCCCC2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCCCC3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoic acid (100 mg, 0.40 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.1 mmol) and triethylamine (32 mg, 0.3 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative-TLC (silica gel, methanol/dichloromethane=1:15, 1% NH4OH) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(piperidin-1-ylmethyl)benzamide as a white solid (35 mg, 23%). LRMS (M+H+) m/z: calcd 381.51. found 381. HPLC purity (214 nm): 93%. 1H NMR (300 MHz, CD3OD): δ 7.42-7.32 (m, 3H), 6.11 (s, 1H), 4.85 (s, 2H), 4.79-4.72 (m, 1H), 2.94-2.79 (m, 4H), 2.40 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 1.83-1.63 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:10][CH:9]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1cc2[nH]cc(C(CN)c3ccccc3F)c2cc1Oc1cncnc1
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C)c(Oc3cncnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine (0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL, 1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 N HCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, the reaction was concentrated in vacuo and dissolved in water. Saturated aqueous NaHCO3 was added until pH ˜12 by litmus paper. The solution was extracted with EtOAc (2×). After separation of the layers, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction was refluxed for 45 min. After cooling to room temperature, the reaction was filtered through a pad of CELITE® and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[NH:36][N:35]=[N:34][N:15]=2)[N:6]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1nc(Cc2ccccc2F)n2ccccc12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccccc1Cc1nc(-c2nnn[nH]2)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 188 mg (0.75 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbonitrile from example 18A, 18.6 mg (0.075 mmol) of dibutyltin oxide and 172 mg (1.50 mmol) of trimethylsilyl azide in 5 ml of toluene is heated under reflux for 20 h. Cooling is followed by addition of 5 ml of ethanol and stirring at RT for 15 h. The mixture is then concentrated, mixed with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is purified by preparative HPLC. The product is taken up in ethyl acetate and clarified with activated carbon. The solid obtained after concentration is crystallized from dichloromethane. 40 mg (18% of theory) of the title compound are obtained as pale reddish crystals.
Reaction SMILES: [CH:1]([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH:1]([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC(C)C)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC(C)C)C(=O)CCl
Yield: 100.1 %

Procedure:
Ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer 35.4 g.), sulfuryl chloride (24.5 g.) and acetic acid (35.4 ml.) were treated in a similar manner to that of Example D-(2) to give ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:33]([C@@H:36]([OH:38])[CH3:37])=[N:34][N:35]=3)[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:39]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:42]([O:41][C:39]([NH:46][C@@H:47]([CH:48]([CH3:50])[CH3:49])[C:51]([O:38][C@H:36]([C:33]1[N:10]2[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]2=[N:35][N:34]=1)[CH3:37])=[O:52])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)O)n21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added (S)-8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (35 mg, 0.0648 mmol), Boc-L-Valine (15.5 mg, 0.0713 mmol), CH2Cl2(3 ml), DMAP (cat, 3 mg) and DIC (12.3 mg, 0.0973 mmol). The reaction was stirred at rt for 30 min. After this time, the solution was concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 0-50% EtOAc/Hex to give product (S)—((S)-1-(8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-7-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl) 2-(tert-butoxycarbonylamino)-3-methylbutanoate, as a white solid (39 mg, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 98.8 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (101 mg, 0.333 mmol) obtained in Example 5. After addition thereto of t-butyl acrylate (146 μl, 1.00 mmol) and 1,8-diazabicyclo[5,4,0]undece-7-en (151 μl, 1.00 mmol), stirring was conducted at room temperature for 1 week. The reaction mixture was then concentated. The residue thus obtained was subjected to flash chromatoraphy on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated, whereby the title compound (142 mg, 0.329 mmol, 99%) was obtained as a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:8]=1.[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH3:2][S:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12](=[NH:13])[O:16][CH2:14][CH3:15])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: CSc1cnn(C2(C#N)CC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1(n2cc(SC)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a saturated solution of hydrogen chloride in ethanol (3.5 mL) at 0° C. was added a solution of 1-(4-(methylthio)-1H-pyrazol-1-yl)cyclopropanecarbonitrile (125 mg, 0.697 mmol) in ethanol (0.5 mL). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under a stream of nitrogen to afford the title compound (210 mg). The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Yield: 44.9 %

Procedure:
A solution of 4-methyl-3-nitro-benzonitrile (3.0 g, 18.5 mmol), N-bromosuccinimide (4.12 g), and benzoyl peroxide (0.224 g) in carbon tetrachloride was refluxed overnight. The reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution and brine, dried, and concentrated. The residue was purified by silica gel chromatography in 10% ethyl acetate hexanes to give compound 65a (2.0 g, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[OH:25]
Reactant: COc1ccc(CN(C)C)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(CN(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 26.9 %

Procedure:
With 2.00 g of the compound obtained in Step 195-1 and 1.24 g of 5-chloroisatin as starting material, 637 mg of the title compound (pale red solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][N:8]([CH2:13][CH2:14][OH:15])[C:9](=[O:12])[CH2:10]Cl)=[O:4].[H-].[Na+]>O1CCCC1>[Cl:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:14][O:15][CH2:10][C:9]1=[O:12])=[O:4]
Reactant: O=C(CCl)OCCN(CCO)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCl)OCCN1CCOCC1=O
Temperature: 15 °C

Procedure:
A solution of 2-(2-chloro-N-(2-hydroxyethyl)acetamido)ethyl 2-chloroacetate (269 g, 1.05 mol) in tetrahydrofuran (250 ml) was added dropwise to a cooled (5° C.) slurry of sodium hydride (50.4 g, 2.10 mol) in tetrahydrofuran (250 ml). To the mixture was then added tetrahydrofuran (3 L). The resulting mixture was allowed to react overnight while the temperature was maintained at 15° C. The mixture was then filtered, and the filtrate was diluted with dichloromethane, washed one time with 500 ml of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19]([N+:20]([O-])=O)=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19]([NH2:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(c1ccc(F)cn1)c1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1c(C(=O)c2ccc(F)cn2)ccc2cccnc12
Yield: 49.5 %

Procedure:
In a similar fashion using route 22 general procedure 55, 7-[(5-fluoropyridin-2-yl)carbonyl]-8-nitroquinoline (Intermediate 358) (1.43 g, 4.9 mmol) and 10% Pd—C (200 mg) in THF (60 ml) gave the title compound (648 mg, 43%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[S:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[S:23][CH:24]=[N:25][CH:26]=1
Reactant: c1cscn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), thiazole (113 mg, 1.322 mmol), KOAc (130 mg, 1.322 mmol) and Pd(OAc)2 (0.297 mg, 1.322 μmol) were added to a vial, which was sealed and evacuated/purged with argon. DMA (0.81 mL) was added and the mixture was stirred at 130° C. for 20 h. The RM was diluted with THF (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 9.18 mg, 0.013 mmol) and filtered off. The filtrate was poured onto 1 M HCl (40 mL) and extracted 3 times with TBME. The combined extracts were washed 3 times with 1M HCl, sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 10% to 40% EtOAc) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.80 min, m/z=383.0 [M+H]+, m/z=381.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (m, J=8.31 Hz, 2H) 7.58 (dd, J=10.76, 8.80 Hz, 1H) 7.83-7.97 (m, 2H) 8.02 (ddd, J=8.62, 4.95, 2.32 Hz, 1H) 8.40 (dd, J=7.21, 2.32 Hz, 1H) 8.49 (s, 1H) 9.28 (s, 1H) 10.54 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:67]([O:69]C(C)(C)C)=O)[CH2:63][C:64]([OH:66])=[O:65])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:67]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:69])[CH2:63][C:64](=[O:65])[O:66][C:5]([CH3:10])([CH3:6])[CH3:3])=[O:60])([CH3:55])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 88 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 88%. [α]D =+13.8° (c=0.93, dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([O:32][CH3:33])[CH:3]=1.O.[OH-].[K+]>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([O:32][CH3:33])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CN
Yield: 93.1 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)-2,2,2-trifluoroacetamide (0.200 g), water (5 mL), KOH (0.200 g) and THF (10.0 mL) to afford 0.150 g of the desired product.