Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@H:11]([OH:12])[C:13]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[O:17][CH2:16][C:15]=3[C:14]=2[CH3:23])[CH2:6][CH2:5]1
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 24)(110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one as a diastereomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:36][CH3:37])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:33]4[CH2:34][CH2:35][CH:31]([N:30]([CH2:36][CH3:37])[CH2:28][CH3:29])[CH2:32]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Reactant: CCN(CC)C1CCNC1
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCC(N(CC)CC)C1

Procedure:
In analogy to the procedure described for example 2, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and [rac]-diethyl-pyrrolidin-3-yl-amine gave the title compound as colorless oil. MS: 505.3 (MH+, 1 Cl).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[C:13]([CH:14]=O)[C:12]([OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[CH2:1]([C:9]1[CH:16]=[C:13]([CH:14]=[N:20][CH2:19][CH2:18][N:21]=[CH:14][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:16]=2)[OH:17])[C:12]([OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCN
Reactant: CCCCCCCCc1ccc(O)c(C=O)c1
Product: CCCCCCCCc1ccc(O)c(C=NCCN=Cc2cc(CCCCCCCC)ccc2O)c1

Procedure:
NN1 -di(5-octylsalicylidene) ethylene diamine was prepared by codissolving stoichiometric quantities of 5-octylsalicylaldehyde (prepared as described above) and ethylene diamine in hot absolute alcohol. After heating for 15 minutes the mixture was cooled to precipitate the Schiff's base (ketimine) in the form of yellow plates m p 157°-158° C.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)=[N+:2]=[N-:3].Cl.[NH2:20][OH:21]>N1C=CC=CC=1.C(O)C>[N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6](=[N:20][OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: NO
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Reaction time: 5 h

Procedure:
25.8 G (0.100 mol) of 2-azido-5-chlorobenzophenone [compare Example 1a] are dissolved in 500 ml of pyridine/ethanol (1:1). 14.0 G (0.200 mol) of hydroxylamine hydrochloride are added to the solution and the mixture is boiled for 5 hours under reflux and evaporated in vacuo at 60°C. The residue is taken up in 250 ml of methanol and the solution is poured into 250 ml of 2 N hydrochloric acid. The crude product which precipitates is filtered off, suspended in 250 ml of 75% strength methanol, again filtered off and dried in vacuo. 2-Azido-5-chloro-benzophenone-oxime of melting point 125°-132°C is obtained. A sample of the crude product is recrystallised from benzene/cyclohexane, after which the pure compound melts at 135°-137°C.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][CH:19]=1>[Cu]I>[N:21]1[N:20]([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[CH:19][CH:18]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1ccc(-n2cccn2)s1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-n2cccn2)s1

Procedure:
The compound was prepared by a method analog to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-(2-pyrazolyl)thiophene using 3.6 equivalents of copper (I) iodide. The title compound was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25](Br)[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(#N)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 118 (69.3 mg, 0.16 mmol) and bis(triphenylphosphine) palladium (II) acetate (11.68 mg, 0.015 mmol) was dissolved in a mixed solvent system of acetonitrile (120 mL) and TEA (80 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (0.044 mL, 0.31 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 118 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). The conditions for TLC were EtOAc on silica gel. A white solid 119 (58.1 mg, 7 9%) was obtained. mp 186-187° C.; IR (KBr, cm−1) 2410, 2358, 1716, 1497, 1253; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H), 0.24 (s, 9 H). MS (EI) m/e (relative intensity) 459 (M+, 28), 445 (32), 399 (51), 371 (100), 235 (71), 178 (75); [α]26D=−27.8 (c 0.46, EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:12]([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1nccn1-c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene 1.01 g, 2-isopropylimidazole 634 mg, N,N-diisopropylethylamine, 1.46 mL and acetonitrile 12 mL was heated under reflux for 15 hours. The solvent was distilled off and water was added to the residue which was then rendred acidic with diluted hydrochloric acid. After washing the same with diethyl ether, the aqueous layer was rendered alkaline with aqueous sodium hydroxide solution and extracted twice with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and removed of the solvent by distillation to provide 0.98 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[N:27]=[C:26](O)[CH:25]=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:30]>>[Br:30][C:26]1[N:27]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: BrP(Br)Br
Reactant: Oc1cccc(-c2cnc3ccc(N4CCC[C@@H]4c4cccc(F)c4)nn23)n1
Product: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(Br)n4)n3n2)c1
Temperature: 175 °C

Procedure:
In step 16-2, a suspension of crude (R)-6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-ol (16-1) (13.3 g, 35.4 mmol) in PBr3 (25 mL) was heated to 175° C. for 35 minutes. While the mixture was hot, it was poured into ice-cold 2N NaOH (1.2 L). The solid was collected by filtration and washed with H2O. The final product was dried under high vacuum overnight to give (R)-3-(6-bromopyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-2) as a light-yellow solid which was used in the next step without further purification. LC/MS: 438.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Br-:8].[Br-:9].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:8][CH:4]([Br:9])[C:3](=[O:5])[C:2]([OH:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)O
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)C(=O)C(Br)Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 30.8 %

Procedure:
To a stirred solution of 3-methyl-3-hydroxy-2-butanone (40 g, 0.392 mol) in anhydrous dichloromethane (2.2 l) under nitrogen was added solid pyridinium tribromide (250.4 g, 0.784 mol) in portions and the mixture was stirred at room temperature for 14 h. The mixture was then washed with dilute aqueous sodium hydrogensulphite (500 ml), then saturated aqueous NaCl (500 ml), dried (Na2SO4), and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2) to afford 31.4 g (31%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ 1.54 (6H, s), 2.45 (1H, br s), 6.62 (1H, s).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[N:27]1([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCCCCCCCC(CCCCCCCCCOCc1ccccc1)n1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(CCCCCCCCCO)n1ccnc1
Yield: 81 %

Procedure:
1-(18-(benzyloxy)octadecan-9-yl)-1H-imidazole (1.5 g, 3.52 mmol) was dissolved in EtOH, then 10% Pd on carbon (200 mg) was added and the reaction mixture hydrogenated under hydrogen balloon at reflux for 2 days. The reaction was filtered off to remove Pd carbon, then the filtrate was concentrated. The crude product was purified by silica gel column (3% MeOH in DCM) to give 10-(1H-imidazol-1-yl)octadecan-1-ol as a gummy liquid (0.96 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[O:18]=[C:19]1[O:23][CH:22]([C:24](Cl)=[O:25])[CH2:21][CH2:20]1>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][C:24]([CH:22]1[CH2:21][CH2:20][C:19](=[O:18])[O:23]1)=[O:25]
Reactant: O=C1CCC(C(=O)Cl)O1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: O=C1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)O1

Procedure:
In substantially the same manner as in Example 8 (1), 15 g of 2-amino-2',5-dichlorobenzophenone was allowed to react with 5-oxotetrahydrofuran-2-carbonyl chloride to afford 18.1 g of 2',5-dichloro-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenone, m.p. 170° C.-173° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[NH:14][C:15](=[O:22])[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1.Cl[CH2:24][C:25]1[N:26]=[N:27][N:28]([CH3:30])[CH:29]=1.O>CN(C=O)C>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:24][C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1
Reactant: Cc1cc(-c2nnc3c4ccncc4c(=O)[nH]n23)no1
Reactant: Cn1cc(CCl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccncc4c(OCc4cn(C)nn4)nn23)no1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
Sodium hydride (42 mg of a 60% dispersion on oil, 1.1 mmol) was added to a stirred solution of 3-(5-methylisoxazol-3-yl)-1,2,3a,4,7-pentaazacyclopenta[a]naphthalen-5(4H)-one (200 mg, 0.75 mmol) in DMF (6 ml) at room temperature under nitrogen, and the mixture was heated at 60° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, treated with 4-chloromethyl-1-methyl-1,2,3-triazole (108 mg, 0.82 mmol) and heated at 60° C. for 1.5 h. On cooling to room, water was added. The mixture was extracted with ethyl acetate, the organics separated, dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from methanol to afford the title product as a white solid (39 mg, 14%), 1H NMR (360 MHz, d6 DMSO) δ 2.60 (3H, s, Ar—CH3), 4.08 (3H, s, N—CH3), 5.73 (2H, s, OCH2), 7.21 (1H, d, J=0.8 Hz, Ar—H), 8.45 (2H, m, Ar—H), 9.15 (1H, d, J=5.3 Hz, Ar—H)), 9.41 (1H, s, Ar—H); MS (ES+) m/e 364 [MH]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=3)[C:17](O)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:35]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:58]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([O:60][CH2:61][C:62]([NH2:65])([CH3:64])[CH3:63])=[O:59].C(N(CC)C(C)C)(C)C>CS(C)=O>[C:72]([O:71][P:58]([O:60][CH2:61][C:62]([NH:65][C:17]([C:16]1[CH:20]=[CH:21][C:22]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:32])[O:33][CH3:34])=[CH:28][CH:29]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:15]=1)=[O:18])([CH3:64])[CH3:63])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:59])([CH3:75])([CH3:74])[CH3:73]
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 79.4 %

Procedure:
To a suspension of the product from Example 441D (200 mg, 0.41 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (187 mg, 0.57 mmol) in DMSO (2 mL) was added the product of Example 438C (178 mg, 0.57 mmol) then N,N-diisopropylethylamine (0.220 mL, 1.10 mmol) dropwise at room temperature under N2. After 2 hours the reaction was quenche with water (20 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed sequentially with water (3×) and saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound as a pale yellow amorphous solid (245 mg., 79%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=O)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:29]=[CH:30][CH:31]=1)#[N:22]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: N#Cc1cccc(C(=O)O)c1
Product: N#Cc1cccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)c1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-cyanobenzoic acid: MS (ESI): m/z 392 (M−1).
Reaction SMILES: C(O[C:9]([N:11](C)[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=O)C1C=CC=CC=1.[CH2:34]1[CH2:39][CH2:38][CH:37]([CH2:40]O)[CH2:36][CH2:35]1>>[CH:37]1([CH2:40][O:24][C:22]([C:21]2[N:12]([NH:11][CH3:9])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:23])[CH2:38][CH2:39][CH2:34][CH2:35][CH2:36]1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: OCC1CCCCC1
Product: CNn1c(C(=O)OCC2CCCCC2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 207 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-cyclohexylmethylalcohol.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([OH:18])[C:13](OCC)=[O:14])[CH2:3][CH2:2]1.[CH3:25][NH2:26]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([OH:18])[C:13]([NH:26][CH3:25])=[O:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Reactant: CN
Product: CNC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of ethyl (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoate (283 mg, 0.864 mmol) and ethanolic methylamine solution (5 mL, 33% in ethanol) was stirred at 70° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow solid was purified via Biotage Horizon (FLASH 12 S, silica, 20%, 35%, 50% EtOAc/hexane) to yield 235 mg (87%) (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3 phenylpropanamide as a white solid. MS (ESI) m/z 311.0 ([M−H]−).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F.F.F.C(N(CC)C(C)C)(C)C.[F:59]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34][F:59])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CO)nn2)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CF)nn2)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:35])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:35][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 451.55 [M+H]+; tR=1.55 min (System 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20]([C:22]([O:24][CH3:25])=[O:23])#N>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:20][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)C#N
Reactant: N#Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-{5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl}-3-chlorobenzonitrile (1.7 g, 4.52 mmol) is dissolved in anhydrous THF (30 mL) and stirred at −78° C. before a THF solution of LHMDS (8.1 mL, 1.0 M) is added. After 15 min, methyl cyanoformate (0.38 mL, 4.74 mmol) is added and the solution is left at −78° C. for 2 h. The excess LHMDS is quenched with aqueous saturated NH4Cl and the mixture is allowed to warm to room temperature. The mixture is then diluted with EtOAc and washed with aqueous saturated NH4Cl (2×). Organic is dried (Na2SO4) and evaporated. The crude residue is purified via flash column chromatography (EtOAc/hexanes 1:1→EtOAc) to give {5-[2-tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(2-chloro-4-cyanophenyl)acetic acid methyl ester as an oil. MS (ESI) m/z 434.3, 436.3 (M+H).