Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=3)[N:19]([CH3:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C=O)C>[OH:46][NH:47][C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:29])[CH:18]=[C:17]2[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)=[O:27]
Reactant: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)NO)ccc21
Yield: 34.4 %

Procedure:
A solution of 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid (64 mg, 0.16 mmol), DIPEA (0.14 mL, 0.8 mmol), HATU (68 mg, 0.18 mmol), hydroxylamine hydrochloride (56 mg, 0.8 mmol) and DMF (4 mL) was stirred for 19 hr at room temperature. The reaction mixture was then subjected to HPLC purification to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid hydroxyamide (22 mg, 34% yield). 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.18 (s, 1H), 7.99 (s, 1H), 7.93 (d, 2H, J=7.2 Hz), 7.67 (d, 2H, J=8.7 Hz), 7.57 (m, 2H), 7.53 (d, 2H, J=7.7 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.27 (d, 2H, J=8.2 Hz), 7.19 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:68])[C:59]2[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=2[Br:67])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Br:67][C:60]1[CH:61]=[CH:62][C:63]([O:65][CH3:66])=[CH:64][C:59]=1[C:58]([N:55]1[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:32]([C:29]2[CH:28]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:31][N:30]=2)=[O:34])[CH2:57][CH2:56]1)=[O:68]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
HOBt (22 mg, 0.16 mmol) and DIPEA (66 mg, 0.51 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (29 mg, 0.13 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (30.5 mg, 0.16 mmol) followed by 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.13 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration. The crude product was washed with hexane and diethyl ether to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 59% yield. LC-MS purity: 89.83%, 1H-NMR (DMSO): δ 8.62 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.58 (m, 1H), 7.5 (m, 2H), 7.4 (m, 1H), 7.1 (s, 1H), 7.0 (m, 2H), 4.2 (m, 2H), 3.8 (s, 3H), 3.75 (m, 2H), 3.6 (m, 2H), 3.55 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(C(F)(F)F)cnc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (500 mg, 2.21 mmole, available from Apollo #PC9219) in a mixture diethyl ether/methanol (5 ml)/(15 ml) was cooled to −20° C. then trimethylsilyldiazomethane (2M solution in diethyl ether) (2.15 ml, 4.43 mmol) was added dropwise. The reaction mixture was stirred at −20° C. for 1 h then allowed to warm to room temperature. After solvent evaporation, the obtained residue was loaded on SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/dichloromethane from 80/20 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D66) (300 mg)
Reaction SMILES: [C:1]([C:5]1[CH2:12][N:11]2[N:7]([C:8](=[O:21])[CH:9]([NH:13]C(OC(C)(C)C)=O)[CH2:10]2)[C:6]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])(=[O:4])[CH2:2][CH3:3].[ClH:28]>C(O)(=O)C>[ClH:28].[C:1]([C:5]1[CH2:12][N:11]2[N:7]([C:8](=[O:21])[CH:9]([NH2:13])[CH2:10]2)[C:6]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])(=[O:4])[CH2:2][CH3:3]
Reactant: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(NC(=O)OC(C)(C)C)C(=O)N12
Agent: Cl
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere, allyl 3-(propionyl)-7-(R,S)-(t-butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate (330 mg, 0.87 mmol) was combined with 3N hydrochloric acid in glacial acetic acid (15 ml). The solution was stirred for 25 minutes at room temperature then concentrated in vacuo. The remaining volatiles on the concentrate were removed by azeotropic distillation with methylene chloride (2×) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]([C:9]3[CH:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:26][C:25]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[CH:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=3)=[N:6][C:5]=2[CH:24]=1
Reactant: CSc1cc(-c2nc3cc(C)c(C)cc3n2COCC[Si](C)(C)C)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(-c2nc3cc(C)c(C)cc3[nH]2)n[nH]1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [90 mg, Reference Example 1(a)], hydrochloric acid (2 mL, 4N) and ethanol (4 mL) was heated at reflux temperature for 16 hours then cooled to room temperature. The pH of the reaction mixture was adjusted to 7 by addition of saturated sodium bicarbonate solution. The resulting solid was filtered, then washed with water and then dried in a vacuum oven to give 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole (38 mg). LC-MS (METHOD A): RT=2.22 minutes; 259 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[OH:16])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
A Grignard reagent was prepared from magnesium (0.14 g, 5.76 mmol) (Wako Pure Chemical Industries, Ltd.) and p-bromotoluene (0.48 g, 5.45 mmol) (Wako Pure Chemical Industries, Ltd.). 4,4′-dimethylbenzophenone (0.60 g, 2.85 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in tetrahydrofuran (5 mL) (KANTO CHEMICAL CO., INC.), and it was added dropwise to the Grignard reagent while cooling with ice, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution while cooling with ice, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.):ethyl acetate (Wako Pure Chemical Industries, Ltd.)=19:1 as an eluent), to thereby obtain the title compound (0.74 g, 86% yield).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][CH2:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([C:13](=[O:19])[CH2:12][CH3:11])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCC(=O)CC(=O)CC
Product: CCC(=O)C(=Cc1ccc(C#N)cc1)C(=O)CC

Procedure:
The produre described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 5.0 g 3,5-heptanedione. Yield 2.8 g, mp 59°-60° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH:18]=[CH2:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:4][C:3]([CH3:5])=[CH2:2])[CH2:17][CH:18]=[CH2:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: C=CCNS(=O)(=O)c1ccc(C)cc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(CC(=C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chloro-2-methylpropene (20 mL, 0.20 mol) is added over a period of 5 minutes to a suspension of 4-methyl-N-(prop-2-en-1-yl)benzene-1-sulphonamide (27.9 g, 0.13 mol) and potassium carbonate (28.1 g, 0.20 mol) in N,N-dimethylformamide (200 mL) cooled in an ice bath. After 20 minutes, the suspension is stirred at ambient temperature for 18 hours. The suspension is concentrated to dryness. The residue is taken up in ethyl acetate (250 mL) and water (110 mL). The aqueous phase is extracted with ethyl acetate (2×50 mL). The combined organic phases are washed successively with aqueous 3N HCl solution (50 mL), water (3×50 mL), aqueous 5% potassium bicarbonate solution (50 mL), and finally brine (50 mL). The organic phase is dried over Na2SO4, filtered and concentrated to obtain the expected compound in the form of an oil.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.Cl.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:26]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
18.68 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt was added to 80 ml of ethanol, and 18.39 g of benzylhydrazine dihydrochloride was added. The mixture was stirred at 70° C. for 7 hours and then cooled to room temperature. After 100 ml of water was added, the mixture was concentrated to 100 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.39 g of methyl 1-benzyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Br[C:10]1[S:14][N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=1.C(N(CC)CC)C.C(Cl)Cl>O>[CH3:16][CH:15]([C:12]1[N:11]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[S:14][N:13]=1)[CH3:17]
Reactant: OCC1CCNCC1
Reactant: CC(C)c1nsc(Br)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)c1nsc(N2CCC(CO)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 4-piperidinylmethanol (115 mg, 1 mmol), 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole (Example 182, Step 6, 207 mg, 1 mmol), triethylamine (0.42 mL, 3 mmol) and CH2Cl2 (3 mL) was stirred at ambient temperature overnight. The mixture was charged with additional 4-piperidinylmethanol (58 mg, 0.5 mmol) and was stirred at ambient temperature for 3 h. The mixture was charged with water, and extracted with CH2Cl2. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 159 mg (66%) of {1-[3-(1-methylethyl)-1,2,4-thiadiazol-5-yl]-4-piperidinyl}methanol as a golden oil. 1H NMR (400 MHz, CDCl3): δ 3.98-3.88 (m, 2H), 3.54 (d, 2H, J=6.3 Hz), 3.20-3.05 (m, 2H), 3.02 (septet, 1H, J=6.9 Hz), 1.90-1.80 (m, 2H), 1.82-1.70 (m, 1H), 1.42-1.25 (m, 8H); LRMS (ESI), m/z 242 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (54 mg, 62%), MS (ISP) m/z=352.5 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22]>[Pd].C(OCC)(=O)C>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(N)cc2C(F)(F)F)c(C(F)(F)F)c1
Yield: 89.6 %

Procedure:
A hydrogenation bottle was charged with 40.0 g of 2,2′-bis(trifluoromethyl)-4,4′-dinitrobiphenyl, 0.6 g of 5% palladium on activated carbon and 200 ml of ethyl acetate. The bottle was secured on a Parr hydrogenation apparatus, flushed five times with hydrogen, and then pressurized with hydrogen to 56 psi. The pressure was maintained, and the vessel was agitated for several hours. After the reaction mixture was filtered and about 200 ml of hexanes were added. The crystals that formed were filtered to afford 30.2 g (90%) of product.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[C:50]([N:54]=[C:55]=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([NH:45][C:55]([NH:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: CC(C)(C)N=C=O
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](NC(=O)NC(C)(C)C)C2)C2CC2)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of (3S,5R)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (115 A.) (374 mg, 0.62 mmol), dichloroethane (5 mL) and tert-butyl isocyanate (142 μl, 1.24 mmol) is shaken for 14 h at 50° C. The mixture is diluted with CH2Cl2 and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (6 ml) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 484.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+]>CC1C=CC=CC=1C.O.[Pd]>[N:11]1([C:2]2[C:10]3[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Brc1cccc2nc[nH]c12
Reactant: C1CNCCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: c1cc(N2CCCNCC2)c2[nH]cnc2c1
Temperature: 120 °C

Procedure:
A suspension of 4-bromobenzimidazole (42 mmol), homopiperazine (256 mmol) and NaOt-Bu (59 mmol) in dry o-xylene, under N2, is treated with a catalytic amount of Pd (OCOCH3)2·P(t-Bu)3 (P/Pd=4), heated at 120° C. for 3 hr, cooled to room temperature and diluted with water. The aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography to give 4-(homopiperazin-1-yl)benzimidazole.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:11][C:13](=[O:14])[CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1CCCC1=O
Reactant: C=CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(CCC(C)=O)CCCC1=O
Yield: 67 %

Procedure:
A solution of methyl 2-oxocyclopentanecarboxylate (2.000 ml, 14.07 mmol), methyl vinyl ketone (1.381 ml, 16.88 mmol) and triethylamine (2.94 ml, 21.10 mmol) in toluene (20 mL) was heated at 40° C. for 24 h. The reaction was brought to room temperature, diluted with EtOAc, washed with sat. NH4Cl, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% heptane/EtOAc to afford a colorless oil as methyl 2-oxo-1-(3-oxobutyl)cyclopentanecarboxylate (2.0 g, 9.42 mmol, 67.0% yield).
Reaction SMILES: C(O)[CH2:2][CH2:3][OH:4].N(CCC[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=C=O>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH3:15][CH2:14][O:13][Si:12]([O:4][CH2:3][CH3:2])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: OCCCO
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCO[Si](OCC)(OCC)OCC
Reaction time: 0.25 h

Procedure:
1,3-Propanediol (2.9 g, 38.0 mmol) is reacted with 3-isocyanatopropyltriethoxy silane (16.4 g, 76.0 mmol) and 0.2% dibutyltin dilaurate catalyst. The reaction is conducted under nitrogen at room temperature in a glass vessel with mechanical stirring. An exotherm occurs after 15 minutes and the reaction is complete after 2 hours as evidenced by infrared spectroscopy. The following TEOS macromer is obtained ##STR9## as a low viscosity liquid, MW 508.72, which is stable at room temperature.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([CH:32]1[CH2:35][CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:26][N:29]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC(=NO)C1CCC1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CCC3)no2)C1

Procedure:
150 mg (0.388 mmol) of the compound from Example 81A and 88 mg (0.776 mmol) of N′-hydroxycyclobutanecarboximidamide were reacted according to the General Method 2. Yield: 124 mg (65% of theory)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(CCOc2ccc(N)cc2)nc1

Procedure:
A solution of 4-(2-(5-ethyl-2-pyridyl)ethoxy)nitrobenzene (23 g) in methanol is hydrogenated under atmospheric pressure in the presence of 10% Pd on carbon (50% humid, 2.5 g). The catalyst is removed by filtering. Distilling the solvent off under reduced pressure gives 4-(2-(5-ethyl-2-pyridyl)ethoxy)aniline as crude oil (20 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1>[Pd].C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1
Reactant: O=C(O)C=C1CCC(c2ccc(O)cc2O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added {4-[2,4-dihydroxyphenyl]cyclohexylidene}acetic acid (50 mg, 0.20 mmol) and ethanol (15 ml). To the stirred solution was added palladium (catalytic amount, 10% on activated carbon) in one portion. The reaction vessel was evacuated and then placed under an atmosphere of hydrogen. This was repeated ten times and then stirred for 17 hr under a hydrogen atmosphere at room temperature. The reaction mixture was filtered through a celite plug, washing with ethanol. The solvent was removed in vacuo to give the title compound (50 mg, 100%) as a pale yellow oil. m/z (ES+) 251 (M+H+); δH(CD3OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.81 (1H, m), 6.28 (2H, m), 6.94 (1H, m).