Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](=[CH:23]/C)/[CH3:22])=[CH:17][CH:16]=1.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: C/C=C(\C)c1ccc(OC)cc1
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0364 g (0.061 mmol) (S,S)-ethylene-1,2-bisη5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2×~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.075 mL, 1.58 M in hexanes, 0.118 mmol, 1.94 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.017 mL, 0.133 mmol, 2.4 equiv) and 0.189 g (1.17 mmol, 19.2 equiv) E-2-(4-methoxyphenyl)-2-butene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2100 psig with hydrogen and placed in an oil bath at 69° C. The reaction mixture was allowed to stir for 65 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.133g (0.811 mmol, 69%) of 2-(4-methoxyphenyl)propane with an ee of 96.2%.
Reaction SMILES: C(O)=O.[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7](=[O:15])[CH:6]=1.[CH:16]([C:18]1[CH:35]=[CH:34][C:21]([C:22]([O:24][CH:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.C(N(CC)CC)C>C(OCC)(=O)C>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7](=[O:15])[C:6]=1[CH2:16][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:25]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])[CH3:26])=[O:23])=[CH:34][CH:35]=1
Reactant: CC(OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(OC(=O)c1ccc(Cc2c(O)c3ccccc3oc2=O)cc1)C(F)(F)C(F)(F)F
Temperature: 140 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Formic acid (35.8 ml) was added to 4-Hydroxycoumarin (15.8 g, 97.5 mmol) and aldehyde 3 (28.9 g, 97.6 mmol). Triethylamine (43 ml) was added (exothermic) at 0° C. It was warmed to 140° C. and stirred for 4 h at this temperature. The yellow solution was cooled to rt, ethyl acetate was added, it was washed with 1 N HCl and brine, it was dried over Na2SO4 and the solvent was removed. The slightly yellow solid was recristallized from ethylacetate to yield the title compound as a white solid in 98% purity (60% yield).
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:51]4[C:46](=[N:47][CH:48]=[CH:49][CH:50]=4)[NH:45][C:44]3=[O:52])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:51]4[C:46](=[N:47][CH:48]=[CH:49][CH:50]=4)[N:45]([S:58]([CH3:57])(=[O:60])=[O:59])[C:44]3=[O:52])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ncccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one which was prepared by the method of Referential Example 7 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OC(OCC)CBr)[CH3:19]>CN(C=O)C.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[O:16][CH:18]=[CH:19][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=O)Cc1ccccc1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Oc2ccccc2Cc2ncco2)cc1
Yield: 41 %

Procedure:
A mixture of (2-phenoxyphenyl)acetamide (3.9 g) and bromoacetaldehyde diethyl acetal (3.1 ml) in DMF (100 ml) was heated for 2 hours. After cooling, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water then dried, concentrated and chromatographed using ethyl acetate: hexane (50:50) as eluant to give 2-(2-phenoxyphenylmethyl)oxazole (1.77 g, 41%) as a brown oil, 1H NMR (CDCl3): delta 4.20 (2H,s), 7.01 (1H,s) and 7.54 (1H,s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][CH:9]2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11](=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)[S:10][C:9]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1

Procedure:
3-(p-Chlorophenyl)-2,3-dihydro-3-hydroxy-thiazolo[3,2-a]-benzimidazole-2-acetic acid, (5.0 g.) is suspended in a solution of 100 ml. of a 6N NCl and 200 ml. of dioxane. The mixture is heated at reflux for 18 hours. The solution is concentrated in vacuo to 50 ml. To the concentrate is added 200 ml. of water, and sufficient 4N NaOH solution to dissolve all the solids. The alkaline solution is made acidic with acetic acid. The solid is collected, washed well with water and airdried. The crude material is recrystallized from dimethoxyethane. The product (2.0 g.) melts at 242°-243° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[C:33]([O:37][C:38]([NH:40][C@@H:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][N:10]([C:42](=[O:43])[C@@H:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To an iced slurry of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-2-carboxylate, TFA (255 mg, 0.543 mmol), (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (138 mg, 0.597 mmol), and HATU (309 mg, 0.814 mmol) in DCM (8 mL) was added N,N-diisopropylethylamine (0.285 mL, 1.629 mmol). The formed colorless slurry was stirred at room temperature overnight. Diluted with DCM, quenched with 5% citric acid. The organic layer was washed with 0.1 M NaOH and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with 5˜35% EtOAc-hexane to yield the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate (240 mg, 0.380 mmol, 69.9% yield) as a white foam. 1H NMR (500 MHz, MeOD) ppm 1.06 (d, 3H), 1.09-1.13 (m, 12H), 1.48 (s, 9H), 2.48 (dd, J=12.82, 8.24 Hz, 1H), 2.53-2.62 (m, 1H), 2.97 (dd, J=12.51, 7.63 Hz, 1H), 3.73 (s, 3H), 4.03 (d, J=11.29 Hz, 1H), 4.25 (t, J=7.93 Hz, 1H), 4.45 (s, 1H), 4.88-4.91 (m, 1H), 7.36 (t, J=7.32 Hz, 1H), 7.45 (t, J=7.78 Hz, 2H), 7.58-7.73 (m, 6H). LC-MS (retention time: 3.50 min, method B), MS m/z 569 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)CS(=O)(=O)c1ccc(OC)c(OC)c1
Reactant: BrCCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a suspension of 60% NaH (0.23 g, 5.84 mmol) in anhydrous DMF (15 mL) is added a solution of methyl (3,4-dimethoxyphenylsulfonyl)acetate in 20 mL of DMF (1.6 g, 5.84 mmol) dropwise over 10 minutes. The mixture is stirred at room temperature for 20 minutes. 1-Bromo-4-phenylbutane (1.6 g, 5.84 mmol) is added and the mixture is stirred at room temperature for 24 hours. The mixture is added to 5% HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (7:3 hexane:ethyl acetate) to afford methyl 2-[(3,4-dimethoxyphenyl)sulfonyl]-6-phenylhexanoate (1.3 g, 55%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.30-1.42 (m, 2H), 1.52-1.68 (m, 2H), 1.95-2.12 (m, 2H), 2.48-2.68 (m, 2H), 3.64 (s, 3H). 3.92 (d, 7H), 6.95 (d, 1H), 7.07-7.18 (m, 2H). 7.20-7.30 (m. 4H), 7.44 (d, 1H); MS (EI) m/e 406 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:7]=12.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[ClH:1].[CH3:12][C:9]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]2=[C:2]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([CH3:21])=[CH:23][CH:24]=3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH3:11]
Reactant: Cc1ccc(Cn2c(C)c(C)c3ccnc(Cl)c32)cc1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNc2nccc3c(C)c(C)n(Cc4ccc(C)cc4)c23)cc1
Product: Cl
Yield: 31 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 31%)
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:20]N1C(=O)CCC1=O.O>ClCCl>[Br:20][C:10]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCN(c2ncc3c(C)nccn23)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(c2nc(Br)c3c(C)nccn23)CC1
Yield: 88.1 %

Procedure:
To 1-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (0.208 mmol, 54 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.208 mmol, 37.1 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (62 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[OH2:17].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:20]([O:21][C:22](=[O:17])[CH:18]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1 eq) in THF (50 ml) was slowly added dropwise to an ice-cold (0° C.) suspension of NaH (1.56 g, 65.32 mmol, 1.3 eq) in THF (50 ml), and stirring was carried out for 30 min. Triethyl phosphonoacetate (12.96 ml, 65.32 mmol, 1.3 eq), dissolved in THF (50 ml), was added and stirring was carried out for 2 h at RT. The reaction mixture was hydrolyzed with water (5 ml) and concentrated. The residue was taken up in water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% ethyl acetate in hexane), the desired product was obtained in the form of a white solid. Yield: 78% (10.5 g, 39.03 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([CH:19]2[CH2:24][CH:23]3[CH:25]([OH:26])[CH:20]2[CH2:21][CH2:22]3)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH2:29]O.C([O:34][CH2:35]C)(=O)C>C(O)C.C(OC(OCC)OCC)C>[O:34]1[CH:35]=[N:29][C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH:19]3[CH2:24][CH:23]4[CH:25]([OH:26])[CH:20]3[CH2:21][CH2:22]4)[S:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)(=[O:11])=[O:10])=[CH:27][CH:28]=2)=[N:2]1
Reactant: N#Cc1ccc(CN(C2CC3CCC2C3O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: NO
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)C1CC2CCC1C2O
Yield: 44 %

Procedure:
A mixture of N-(4-cyanobenzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (380 mg, 0.91 mmol) and hydroxylamine (500 up was refluxed in 20 mL ethanol for 2 h. The reaction was concentrated and dried under high vacuum. A portion of the crude amide oxime (25 mg) which was obtained was refluxed in triethylorthoformate (2 mL) for 5 h. The reaction was diluted into 20 mL ethyl acetate, washed with brine, and purified by flash chromatography on 4 g silica gel with 0 to 30% ethyl acetate in hexane to yield N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (11 mg, 44%). 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (1H, s), 8.00-8.08 (2H, m), 7.68-7.79 (2H, m), 7.40-7.49 (4H, m), 4.83 (2H, q, J=17.54 Hz), 4.02-4.11 (1H, m), 3.83 (1H, s), 1.88 (1H, br. s.), 1.58-1.68 (2H, m), 1.43-1.55 (3H, m), 1.06-1.16 (2H, m). LC/MS R.T.=2.35 min; [M+H]+=460.13.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:14]([C:17]1OC(C=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O[BH-](O[C:34](=[O:36])[CH3:35])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:14]([CH:17]([C:18]1[O:36][CH:34]=[CH:35][CH:19]=1)[C:11]1[CH:12]=[CH:13][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([NH2:9])[CH:10]=1)([O-:16])=[O:15]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccccc1N1CCCCC1
Agent: [Na+]
Solvent: ClCCl
Product: Nc1cc(C(c2ccco2)[N+](=O)[O-])ccc1N1CCCCC1

Procedure:
A solution of 2-piperidinoaniline (1 mmol), 5-nitro-furan-2-carbaldehyde (1.1 mmol) and sodium triacetoxyborohydride (“NaBH(OAc)3”) (2 mmol) in anhydrous DCM (10 mL) was stirred 16 h at room temperature. The mixture was then washed successively with water, dilute aqueous sodium hydroxide (“NaOH”), water and brine before being dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residual oil by flash silica gel chromatography yielded the product. MS: 301 (M+1). LC/MS purity: 100%. 1H NMR (CDCl3, 300 MHz): δ 7.25 (d, 1H), 7.15-6.95 (m, 2H), 6.75 (t, 1H), 6.55 (d, 1H), 5.4 (bs, 1H), 4.45 (s, 2H), 2.8 (bm, 4H), 1.8-1.5 (bm, 6H).
Reaction SMILES: [C:1]([CH:9]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].[CH3:28]CO>CC(O)=O.O>[C:24]([O:23][C:19](=[O:22])[NH:20][N:21]1[C:12]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:28]=2)=[CH:11][CH:9]=[C:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCO
Reactant: CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of dibenzoylethane (5 g, 21.0 mmol) and t-butyl carbazate (3.98 g, 30.1 mmol) in EtOH (170 mL) and AcOH (21 mL) was heated to reflux under Ar for 4.5 h, cooled to rt and diluted with water (400 mL). The resulting suspension was stirred under Ar at rt for 3 h, and then allowed to settle overnight at rt. The solid was filtered, washed with small portions of water and dried in vacuo to afford (2,5-Diphenyl-pyrrol-1-yl)-carbamic acid tert-butyl ester (6.72 g, 96%) as a white solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.14 (s, 3H), 1.38 (s, 6H), 6.35 (s, 2H), 6.84 (bs, 2H), 7.29-7.53 (m, 10H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([OH:10])=O)(=[O:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.C(Cl)Cl>[C:1](=[O:3])([S:4][CH2:5][CH2:6][C@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:10])[CH3:2]
Reactant: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCCCCO
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a round bottom flask was added (S)-4-(acetylthio)-2-(benzyloxycarbonylamino)butanoic acid (312 mg, 1.00 mmol), 5-aminopentan-1-ol (119 mg, 1.15 mmol), DCM (5 mL), EDC (211 mg, 1.10 mmol) and HOBt (184 mg, 1.20 mmol). The light yellow mixture was stirred at rt for 16 hr. The reaction mixture was diluted with EtOAc (60 mL), washed with 5% aqueous KHSO4 (2×), saturated aqueous NaHCO3 (2×), water, and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)—S-3-(benzyloxycarbonylamino)-4-(5-hydroxypentylamino)-4-oxobutyl ethanethioate (311 mg, 0.784 mmol, 78% yield) as a white solid. Anal. Calcd. for C19H28N2O5S m/z 396.5. found: 397.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.28 (m, 5H), 6.41 (s, 1H), 5.59 (d, J=6.7 Hz, 1H), 5.11 (s, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.63 (dd, J=11.6, 6.1 Hz, 2H), 3.28 (dd, J=12.7, 6.3 Hz, 2H), 2.97 (dt, J=14.5, 7.4 Hz, 1H), 2.91-2.75 (m, 1H), 2.34 (s, 3H), 2.21-2.00 (m, 1H), 1.91 (dt, J=14.4, 7.2 Hz, 1H), 1.72-1.48 (m, 5H), 1.48-1.34 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=O)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (125 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH2:33][CH3:34]>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([CH2:33][CH3:34])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=3)=[N:14][CH:13]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: N#Cc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1F
Reactant: CCC(=N)NO
Product: CCc1noc(N2CCC(N(C(=O)c3cnc(-c4ccc(C#N)c(F)c4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 2-(4-cyano-3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=1.94 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH:35]([CH3:37])[CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH:35]([CH3:36])[CH3:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 129.7 %

Procedure:
13.2 g of trityl chloride were slowly added to a cooled mixture of 11 g of the product of Step C, 20 ml of dry dimethylformamide, 40 ml of methylene chloride and 6.2 ml of triethylamine and the mixture was stirred for 21/2 hours. 43 ml of N hydrochloric acid were added thereto and the mixture was stirred and decanted. The organic phase was washed with 40 ml of water and was extracted with methylene chloride. The extracts were dried and vacuum filtered. The filtrate was evaporated to dryness to obtain 27.7 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate in the syn configuration.