Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[C:22]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[S:11][C:12]=2[CH:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccc(O)cc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Under N2, 24 (4.0 mmol) was dissolved in THF (100 ml) and, at 0° C., NaH (8.2 mmol) was slowly added. The mixture was stirred for 30 min at 0° C. and acetyl chloride (6.0 mmol) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The reaction was hydrolyzed and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 7:3 hexane/ethyl acetate as the eluent to yield 1.24 g (74%) of 25 as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([OH:11])=O)[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>S(Cl)(Cl)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH:23]=2)=[O:11])[C:6]=1[O:7][CH3:8]
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: COc1c(C(=O)O)csc1Br
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2csc(Br)c2OC)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
2-Bromo-3-methoxythiophene-4-carboxylic acid (0.429 g; 1.81 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (5 ml) and treated with dry triethylamine (0.25 ml;1.81 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.4 g; 1.8mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as white powder after trituration with Et2O (0.43 g;54%), mp=120-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: Cc1ccc(C(=O)N(C)[C@@H]2CCNC[C@H]2c2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(C)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 23 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][O:16]C(=O)C)[CH2:10][CH2:9]1.N>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(=O)OCC(=O)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CO)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 90.7 %

Procedure:
(5RS)-3-(3-Fluoro-4(4-(2-acetoxyacetyl)piperazin-1-yl)phenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (112 mg, 0.25 mM) was suspended in a saturated solution of ammonia in methanol (8 ml), diluted with tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 40 hours. The residue after evaporation was chromatographed on a 5 g silica Mega Bond Elut® column, eluting with a gradient from 0–5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (92 mg).
Reaction SMILES: C([O:8][C:9]1[C:34]([O:35][CH3:36])=[CH:33][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[C:11]([F:37])[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[F:37][C:11]1[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[CH:33][C:34]([O:35][CH3:36])=[C:9]([OH:8])[CH:10]=1
Reactant: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (657, 0.831 g, 1.60 mmol) was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL). 10% Palladium on carbon (3.41 g) was added. The reaction was shaken at 50 psi for 1 hour. The reaction was filtered through Celite and washed with methanol. The organic portion was passed through celite several times until a clear solution was obtained. The organic portion was concentrated under reduced pressure to provide the desired compound as an off-white solid (649, 587 mg, 86%). MS (ESI) [M+H+]+=429.5.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C)C=O.O>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It is extremely important to make sure the reaction initiates after the addition of the first ˜1/5 of the NCS; an ice-bath was readily available.). After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)—N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]([CH2:16][NH:17]CC2C=CC=CC=2)[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:15]([CH2:16][NH2:17])[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Reaction time: 16 h

Procedure:
A solution of (1S,3S,5S)-3-(benzylamino-methyl)-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester (9.0 mmol) in ethanol (10 mL) is added to a suspension of Pd/C (1.9 g, 10%) in ethanol (40 mL) and stirred under a hydrogen atmosphere (1 bar) for 16 h. After filtration through celite, washing with ethanol and removal of the solvents the desired amine is obtained which is used without further purification. LC-MS: tR=0.73 min; [M+H]+=241.4.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16]I)[CH2:12][CH2:13][CH3:14].O>C1COCC1>[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: c1ccsc1
Reactant: CCCCCCC(CI)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(CCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (5.71 g, 67.9 mmol) in dry THF (60 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (26.0 mL, 2.5 M, 65.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of 2-butyloctyliodide (16.0 g, 54.0 mmol) in dry THF (30 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature for 38 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ether. The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (4.95 g, 36.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=O)[N:12]([C:16]3[C:17]([CH3:36])=[C:18]([CH3:35])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[C@H:21]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[C:20]=4[C:33]=3[CH3:34])[C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:16]3[C:17]([CH3:36])=[C:18]([CH3:35])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[C@H:21]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[C:20]=4[C:33]=3[CH3:34])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CC(=O)N(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)C(=O)C2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 59 %

Procedure:
Using (3R)-4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperidine-2,6-dione obtained in Example 26, the title compound was synthesized in the same manner as in Example 28. Yield 59%. mp. 183–185° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[C:6]2[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1sc2c(Cl)c(Cl)c(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(C)c(C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of 22.4 g of 6,7-dichloro-5-hydroxy-2,3-dimethylbenzo[b]thiophene is added a mixture of 18.23 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 15 g of potassium carbonate and 7.5 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 21/2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are separated, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. The solid is recrystallized from acetone-hexane to give 25.8 g of ethyl[ (6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetate, mp 102°-104°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[NH2:25])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]1=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[NH:25][C:27]2([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)cc2N)CC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
The mixture of 4-(2-Amino-4-chloro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.051 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (30 mg, 0.081 mmol) and K2CO3 (30 mg, 0.22 mmol) in DCM (1 mL) was stirred at room temperature overnight. The mixture was purified by column chromatography to give 22 mg rac-4-{4-Chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzenesulfonylamino}-piperidine-1-carboxylic acid tert-butyl ester. MS: [M+H]+=679
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>CCCCC>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(F)c(F)c2)C1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To sodium hydride (60% w/w dispersion in oil, 0.62 g, 16.4 mmol) washed in pentane was added N,N-dimethylformamide (20 ml) and then 1,1-dimethylethyl 3-hydroxypiperidine-1-carboxylate (Preparation 117, 3.0 g, 14.9 mmol). The reaction mixture was stirred for 1 h, before adding 3,4-difluorobenzyl bromide (2.0 ml, 16.4 mmol) and stirring the reaction mixture for 18 h. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in dichloromethane and washed with brine and dried (MgSO4) before concentrating in vacuo. The crude residue was purified by flash chromatography to give the title compound (4.58 g, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:34][NH2:35]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:28][CH2:29]4)=[C:21]([CH:26]=3)[C:22]([NH:34][NH2:35])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: CCO
Product: CCc1cc(C2CC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in ethanol (15 mL) was added hydrazine hydrate (80%, 5 mL). The resulting solution was stirred at 80° C. for 15 h. After cooling to ambient temperature, the reaction was quenched with 50 mL of water, then extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 150 mg (75%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.C(O)(=O)C>C(O)C>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:24]=[N:23][NH:22][C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=2)=[CH:27]1
Reactant: NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of (7-morpholin-4-yl-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25 mg, 0.080 mM) in ethanol (1.5 mL), there were added 3-formyl-indole (18 mg, 0.12 mM) and acetic acid (3 μL) and then the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol to thus give the title compound (18 mg, yield: 51%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a stirred solution of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol) in DMF (60 mL) is added tert-butyldimethylsilyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol). The reaction is stirred at room temperature for 18 h, diluted with 1 L of water and extracted with a 1:1 (2×200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine, dried with NaSO4, and concentrated under vacuum. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S, 6R)-3-(tert-butoxycarbonyl) aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one as a white solid, melting point: 65-66° C.; 1H NMR (CDCl3) δ 5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:16]1([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([N:16]2[CH2:21][CH2:20][N:19]([C:10](=[O:12])[CH2:9][CH2:8][C:6]3[CH:7]=[C:2]([Br:1])[C:3]([Cl:15])=[CH:4][C:5]=3[O:13][CH3:14])[CH2:18][CH2:17]2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(Br)cc1CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cc1CCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 3-(5-bromo-4-chloro-2-methoxyphenyl)propanoic acid (350 mg, 1.2 mmol) in DMF (30 mL) at RT, tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (317 mg, 1.3 mmol), BOP (731 mg, 1.4 mmol) and DIEA (461 mg, 3.6 mmol) were added and the mixture was stirred at RT for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (285 mg, 46% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: N#CC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: N#CC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperidine-4-carbonitrile were reacted to give 220. MS: (ESI+)=406.0
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:7]([N:19]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CCCO1
Product: CCCCCCCCCCCCN1CCCC1=O
Yield: 80.5 %

Procedure:
Following Example 5, 18.8 g (0.22M) of butyrolactone and 37 g (0.2M) of n-dodecylamine was heated for 24 hours. Distillation of the residue gave 40.7 g (80.3%) of 1-n-dodecylazacyclopentan-2-one; b.p. 165°-170°/0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (103 mg, 36.3%)