Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[CH2:38][CH2:37]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:47]=[CH:48][CH:49]=[C:43]([CH2:42][N:39]6[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]6)[CH:44]=5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Product: COc1cc(C(=O)Nc2cccc(CN3CCN(C)CC3)c2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 3-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride with yield 43 mg (33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s., 6 H) 1.99 (br. s., 2 H) 2.14 (s, 3 H) 2.33 (br. s., 8 H) 3.43 (s, 2 H) 3.94 (s, 3 H) 4.09 (t, J=13.89 Hz, 2 H) 4.84 (br. s., 1 H) 7.01 (d, J=7.58 Hz, 1 H) 7.20-7.35 (m, 2 H) 7.61 (br. s., 1 H) 7.67 (br. s., 1 H) 8.10 (s, 1 H) 8.23-8.40 (m, 2 H) 10.14 (s, 1 H). [M+H] calc'd for C33H39F3N8O3, 653; found 653.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:20][S:19][CH:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:17]2)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([CH3:35])[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:14]([CH:16]3[CH2:20][S:19][CH:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:17]3)=[O:15])[CH:35]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCNCCCc1ccccc1)C1CSC(c2cccnc2)N1
Reactant: Cc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2N(CCCc3ccccc3)CCN2C(=O)C2CSC(c3cccnc3)N2)cc1
Temperature: 120 °C
Yield: 5.2 %

Procedure:
A mixture of 50 mg of N-(3-phenylpropylaminoethyl)-2-(3-pyridyl)thiazolidine-4-carboxamide, 17 mg of p-tolualdehyde, 100 mg of molecular sieve (4A) and 2 ml of toluene was heated in a sealed tube at 120° C. for 8 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (development with 2% methanol-ethyl acetate being made twice; Rf value=0.15) to give 3.3 mg of 1-(3-phenylpropyl)-3-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]-2-(4-tolyl)imidazolidine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]CC)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br.O>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)cc2s1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
A solution of 2-amino-6-ethoxybenzothiazole (5 g, 25.74 mmol) and of 48% hydrobromic acid in water (130 ml, 1.141 mol) in 65 ml of acetic acid is distributed in ten 20 ml microwave tubes, and then heated at 150° C. by microwave for 200 seconds. The reaction medium is concentrated. The residue is taken up in 200 ml of water, basified to pH 8 by addition of 75 ml of saturated NaHCO3 solution and extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness to give 3.4 g of 2-aminobenzothiazol-6-ol (gray powder).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([Cl:22])=[CH:4][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a stirring dichloromethane solution (40 mL) containing 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid (2.3 g, 5.9 mmol) and 2-(trimethylsilyl)-ethanol (1.8 g, 8.9 mmol), dicyclohexyl-carbodiimide (1.83 g, 8.9 mmol) and DMAP (108 mg, 0.9 mmol) were added. The mixture was stirred at rt for 16 hrs and was concentrated. The residue was purified via silica gel flash chromatography (eluting with 20% ethyl acetate in hexane) to afford 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCl): 482.0, 441.0, 410.9. tR=3.61 min (method 1)
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][OH:22])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41](=[O:45])[CH:42]=[N+]=[N-])[CH3:39].C(O)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:45])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2CCO)O[Si](C)(C)C(C)(C)C)cc1F
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)COCCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-{2-[(1R)-1-({(2R)-2-{[Tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}ethanol (545 mg, 1.03 mmol), which had been obtained in Example 180 (180d), was dissolved in methylene chloride (5 mL), added with rhodium diacetate dimer (46 mg, 0.10 mmol) and ethyldiazoacetate (267 μL, 2.58 mmol) at 0° C., and stirred for 1.5 hours. Ethanol was added to the reaction solution to terminate the reaction. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (565 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH2:11]([Mg]Br)[CH3:12]>>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:11][CH3:12])=[CH:3][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC[Mg]Br
Product: CC=Cc1ccc(Cl)c(Cl)c1

Procedure:
With the exception of three compounds, the styrene compounds herein utilized for preparing the α-chloro oximes are known and their preparations are published in the prior art. The compounds not previously known are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1-(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of p-toluenesulfonic acid catalyst to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl)benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](Cl)=O)=[CH:57][CH:56]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:63]=[CH:62][C:58]([CH3:59])=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Prepared using General Procedures 20 and 8: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (128 mg, 0.21 mmol) and DIEA (0.058 mL, 0.31 mmol) in dioxane (4 mL) was added a solution of 4-methylbenzoyl chloride (0.028 mL, 0.21 mmol) in dioxane (1 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), shaken with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h then evaporated and re-slurried from acetonitrile (6 mL) to afford 77 mg (56%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 355 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=7.97 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 10.34 (s, 1H), 8.10 (d, J=6.1 Hz, 2H), 8.09-8.05 (m, 2H), 7.70-7.56 (m, 3H), 7.53-7.41 (m, 4H), 7.38 (d, J=8.0 Hz, 2H), 7.26-7.14 (m, 2H), 4.76 (s, 1H), 4.68 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 3.91-3.79 (m, 5H), 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[H][H].[ClH:38]>C(O)C.[Pd]>[ClH:38].[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of 6 (0.111 g, 0.232 mmol) in 2% HCl in ethanol (60 mL) was added palladium on activated charcoal (0.025 g) under an atmosphere of argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 4 h, the mixture was flushed with argon, filtered using ethanol and methanol. Preparative HPLC afforded 7 (0.055 g, 69%) as a bright yellow solid. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.52-7.34 (m, 1H), 6.94 (m, 2H), 6.53 (br s, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.65 (m, 1H), 2.63-2.56 (m, 1H), 2.54 (m, 1H), 2.44 (m, 1H), 2.31 (m, 1H), 2.21 (m, 1H), 2.02 (m, 1H), 1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.26 (m, 2H). MS (ESI) m/z calcd for C17H21N4O4 [M+H]+345.4. found 345.7.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(C2CCNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N:28]([CH3:52])[CH:29]2[C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][C:32]=3[CH2:31][CH2:30]2)[N:39]=[C:38]([CH3:42])[N:37](COC(=O)C(C)(C)C)[C:36]4=[O:51])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH2:13][C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]C)=[O:21])[N:18]=1)[C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:27]=[C:26]([N:28]([CH3:52])[CH:29]2[C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][C:32]=3[CH2:31][CH2:30]2)[N:39]=[C:38]([CH3:42])[NH:37][C:36]4=[O:51])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH2:13][C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)Cn1nnc(CC[C@H](NC(=O)c2ccc(N(C)C3CCc4cc5nc(C)n(COC(=O)C(C)(C)C)c(=O)c5cc43)cc2F)C(=O)OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)N[C@@H](CCc2nnn(CC(=O)O)n2)C(=O)O)c(F)c1)CC3
Reaction time: 1 h

Procedure:
To a solution of methyl (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzamido}-4-(2-methoxycarbonylmethyltetrazol-5-yl)butyrate (87 mg) in methanol (2 ml) was slowly added an aqueous solution of NaOH (1N, 0.72 ml). The resultant solution was stirred at room temperature for 4 hours then more aqueous 1N NaOH (0.36 ml) was added and stirring was continued at room temperature for 1 hour. Next the solution was diluted with water (3 ml) and acidified to pH 4 with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water (15 ml), and dried in vacuo over phosphorus pentoxide. There was thus obtained (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-amino]benzamido}-4-(2-carboxymethyltetrazol-5-yl)butyric acid (57 mg) as a pale yellow solid, m.p. 196°-199° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(F)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)c(F)cc2N1
Yield: 63.7 %

Procedure:
A crude of 2-amino-4,5-diflourophenol (2.67 g, 18.4 mmol), 2-chloroacetyl chloride (2.28 g, 20 mmol) and K2CO3 (5.34 g, 38.6 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; heptanes/EtOAc 4:1 to 1:1) to give the title compound (2.17 g, 64%). Rf=0.43 (heptanes/EtOAc 1:1); Mp=214.5-219.2° C.; 1H NMR (CD3OD) d 6.90 (dd, J=11.4 Hz, J=7.2 Hz, 1H), 6.80 (dd, J=11.0 Hz, J=7.7 Hz, 1H), 4.56 (s, 2H); 13C NMR (CD3OD) d 167.0, 147.0 (dd, J=243.5 Hz, J=13.8 Hz), 146.9 (dd, J=240.0 Hz, J=13.8 Hz), 141.2 (dd, J=9.8 Hz, J=3.0 Hz), 124.8 (dd, J=8.7 Hz, J=3.0 Hz), 106.9 (dd, J=22.0 Hz, J=6.9 Hz), 105.5 (dd, J=23.1 Hz, J=4.6 Hz), 68.1 (t, J=6.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:21][C:22]1[N:27]=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2cncc(F)c2)c1C#N
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamine.2HCl (165 mg, 0.48 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (60 mg, 0.36 mmol) and DIPEA (315 μL, 1.82 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 364 as a white solid (21 mg, 15%). LCMS (Method K): RT 3.04 min [M+H]+ 407.04. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.61 (1H, d, J=1.63 Hz), 8.02 (1H, d, J=9.22 Hz), 7.77 (1H, dd, J=8.80, 4.84 Hz), 7.55 (1H, d, J=7.75 Hz), 7.15 (1H, ddd, J=9.84, 8.79, 2.50 Hz), 7.07 (1H, dd, J=8.96, 2.48 Hz), 7.05-6.58 (2H, m), 5.53 (1H, m), 2.18 (3H, s), 1.54 (3H, d, J=6.75 Hz)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH:19]=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc(F)cc(F)c2)CC1

Procedure:
The title compound was prepared (3.3 g, 100%) from tert-butyl piperidin-4-ylcarbamate (2 g, 10 m. mol) and 3,5-difluorobenzaldehyde (1.42 g, 10 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3): δ 6.85 (m, 2H), 6.65 (m, 1H), 4.45 (bs, 1H), 3.50 (m, 1H), 3.05 (s, 2H), 2.75 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.45 (m, 11H). MS (ESI) m/z: Calculated: 326.38; Observed: 327.0 (M++1).
Reaction SMILES: [C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([O:26]CC2C=CC=CC=2)=[CH:24][CH:25]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>C1COCC1.C(OCC)(=O)C>[C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CNc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc(O)cc1C(=O)O
Yield: 100.4 %

Procedure:
N-(Carbo-t-butoxymethyl)-5-benzyloxyanthranilic acid, benzyl ester (45.0 g, 101 mmol) was dissolved in 1:1 THF/ethyl acetate (1200 mL) in a 2 liter round bottom flask. The atmosphere was flushed with argon and 10% Pd/C (4.0 g) was added. The reaction atmosphere was replaced with hydrogen gas (4 purge-fill cycles) and the reaction mixture stirred under a balloon of hydrogen for 23 hours. The atmosphere was replaced with argon and the reaction mixture filtered through a pad of Celite, washing the Celite pad with methanol (250 mL). The solvents were removed in vacuo and the resulting yellow solid placed under high vacuum overnight to yield N-(carbo-t-butoxymethyl)-5-hydroxyanthranilic acid (27.1 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH2:20]([N:22]([CH2:25][C:26]([NH:28][NH2:29])=O)[CH2:23][CH3:24])[CH3:21]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:26]([CH2:25][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:28][N:29]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CCN(CC)CC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione and (diethylamino)acetic acid hydrazide in n-butyl alcohol was refluxed to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, which was recrystallized from ethyl acetate-Skellysolve B hexanes and was identical to the compound obtained in Example 4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[C:42]([NH:50][NH2:51])(=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[CH:19][C:18]([C:21]([NH:51][NH:50][C:42](=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:23])=[CH:17][N:16]=3)=[CH:11][CH:10]=2)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C(=O)O)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCC(=O)NN
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCC(=O)NNC(=O)c1cnc(-c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
Prepared using General Procedure 7. Into a stirring solution of (S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DCM (2 mL) were added EDC (34 mg, 0.20 mmol), DMAP (3 mg, 0.02 mmol) and heptanehydrazide (16 mg, 0.11 mmol). After 18 h, the reaction mixture was diluted with NaHCO3 and extracted with DCM (2×). The organic layers were combined, dried (Na2SO4), concentrated and purified by chromatography (EA/Hexane) to provide 38 mg (61%) of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C36H47BN5O5: 629.8; no m/z observed, tR=3.84 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 5.01 (dd, J=12.6, 5.8 Hz, 1H), 3.41-3.20 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.81-1.61 (m, 2H), 1.59 (d, J=14.0 Hz, 2H), 1.45 (s, 4H), 1.42-1.22 (m, 18H), 0.88 (t, J=6.8 Hz, 3H).