Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:25]>CS(C)=O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[O:25])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CCc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1
Reactant: O
Solvent: CS(C)=O
Product: CCc1ccc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc1
Reaction time: 24 h
Yield: 10 %

Procedure:
A light brown solution of 3-(cyclopentylamino)-2-(4-ethylphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (56.4 mg, 0.177 mmol) in DMSO (17.7 mL) was stored for 35 days at RT. Within 24 h, it became a dark brown solution. After 35 days, LCMS analysis indicated the absence of starting material and the presence of a strong desired peak. Then, it was poured into water (1 L) and the resulting cloudy brown solution was extracted with EA (2×200 mL). Then, the combined extracts were washed with water and brine solution (2 L) to wash the DMSO. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the red brown paste which was purified using an ISCO (120 g) column chromatography eluting with 0-40% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 5.9 mg (10% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-ethylphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 1.28 (t, J=7.7 Hz, 3H), 1.40-2.00 (br m, 8H), 2.75 (q, J=7.7 Hz, 2H), 3.78 (p, J=6.1 Hz, 1H), 6.78 (br s, 2H), 7.36 (d, J=8.3 Hz, 2H), 7.42 (s, 1H), 7.81 (d, J=8.3 Hz, 2H). LC/MS calcd. for C19H21N5O3 (m/e) 367.4, obsd. 368.0 (M+H, ES+).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42].[Cl-].[Na+]>ClCCl>[CH2:2]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([OH:11])=[N:9][C:7](=[O:8])[N:6]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:4]1=[O:5])[CH3:1]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: COC(=O)CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(c2ccccc2)C(=O)N(CCCCC(=O)OC)C(=O)N=C1O
Reaction time: 20 h

Procedure:
A mixture of phenobarbital (46.5 g, 0.2 mole) and tetrabutylammonium hydroxide (500 mL, 0.2 mole of 0.4M in water) in dichloromethane (500 mL) was prepared and to it was added methyl 5-bromovalerate (39.0 g, 0.2 mole). The reaction mixture was stirred vigorously overnight (20 hrs). To this mixture was added saturated sodium chloride solution (100 mL), the organic layer was separated, and the aqueous solution was washed with dichloromethane (2×100 mL). The combined organic solution was washed with saturated sodium chloride solution (100 mL), dried over anhydrous MgSO4, filtered, and the solvent removed.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]2[CH2:21][N:22]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:43])[C@@H:32]([N:34](C)[C:35](=O)OC(C)(C)C)[CH3:33])[CH2:26][O:25][C:24]2[CH:44]=[CH:45][CH:46]=[CH:47][C:23]1=2>C([O-])(O)=O.[Na+]>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]2[CH2:21][N:22]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:43])[C@@H:32]([NH:34][CH3:35])[CH3:33])[CH2:26][O:25][C:24]2[CH:44]=[CH:45][CH:46]=[CH:47][C:23]1=2
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2cc(=O)n(C)c3ccc(F)cc23)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2cc(=O)n(C)c3ccc(F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A mixture of 3 M HCl in dioxane (36.0 g, 30 mL, 120 mmol, Eq: 1660) and tert-butyl (S)-1-((S)-5-((6-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (40 mg, 72.4 μmol, Eq: 1.00) were stirred at RT overnight. The mixture was diluted with sat. NaHCO3 and extracted with DCM The combined extracts were washed with H2O and concentrated. The residue was purified was purified by preparative TLC to give the title compound (26 mg, 95%) as a white solid. MS m/z 453 (MH+)
Reaction SMILES: [C@@H:1]1([CH2:10][OH:11])[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.O>[CH3:23][C:22]([Si:19]([CH3:21])([CH3:20])[O:11][CH2:10][C@@H:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12)([CH3:25])[CH3:24]
Reactant: OC[C@@H]1NCCN2CCC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1NCCN2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of cis-Octahydropyrrolo[1,2-a]pyrazin-1-ylmethanol (D72, 198 mg) in anhydrous DCM (10 mL) under a Nitrogen atmosphere at room temperature, triethylamine (350 microL) and t-butyldimethylsilylchloride (286 mg) were added. The resulting solution was stirred at room temperature overnight then diluted with water (5 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (DCM/0.5M NH3 in MeOH from 100/0 to 90/10) to give the desired compound (195 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3CCO[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(N2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.Cl.C(N)C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][NH:32][CH2:33][CH3:34])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Agent: Cl
Product: CCNCCc1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and ethylamine hydrochloride (0.55 mg). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.8, 159.4 (dd), 155.8 (dd), 148.6, 144.7, 140.8, 138.3, 135.4, 134.6, 133.9, 132.6, 128.2, 124.9 (dd), 124.1 (dd), 122.2, 120.8, 120.4, 116.1, 112.7, 111.7 (dd), 105.0 (dd), 46.5, 42.8, 23.2, 19.9, 12.1
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:20](=O)C>C(O)C>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:20][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: CC=O
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2

Procedure:
0.01 mole (2.67 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 30 ml of ethanol, and the solution is stirred with 0.015 mole of acetaldehyde for one hour. The reaction mixture is evaporated to dryness to yield the aimed compound in a crystalline form.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:15]=[CH:14][C:13]=1[C:32]([F:35])([F:34])[F:33].[O-]CC.[K+].C(O)(=O)C>O1CCCC1.O>[CH3:31][N:21]([C:16]1[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH2:11][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:13]([C:32]([F:34])([F:35])[F:33])=[CH:14][CH:15]=1)[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diethyl oxalate (1.94 g, 13.2 mmol) and then a solution of 2-methyl-4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride (2.40 g, 6.62 mmol) in tetrahydrofuran (40 ml) were added dropwise to a mixture of potassium ethoxide (1.11 g, 13.2 mmol) and tetrahydrofuran (60 ml) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and then cooled to 3° C., and acetic acid (1.59 g, 26.5 mmol) was added dropwise. The reaction mixture thus obtained was poured into cold water and extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/9) to obtain an oil of ethyl [3-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]-amino]-2-nitro-6-trifluoromethylphenyl]pyruvate.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23].[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:16][C:15]=1[CH3:23]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.68 g) was added to a solution of 4-bromo-3-methyl benzoic acid (3.0 g), 1-(2-aminoethyl)pyrrolidine (1.78 ml) and 1-hydroxybenzotriazole hydrate (1.89 g) in dry N,N-dimethylformamide (30 ml). The reaction was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane:methanol (9:1) to give the sub-title compound as an oil. (3.55 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:10][C:2]1=2.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][NH:43][CH3:44])=[CH:34]1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([N:43]([CH3:44])[CH2:42][C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH3:32])[CH:34]=3)=[O:15])=[CH:10][C:2]1=2
Reactant: CNCc1cn(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCCN2
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)OCCN2
Yield: 83.3 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (0.11 g, 0.53 mmole), from Preparation 7, for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 1-methyl-3-(methylaminomethyl) indole (0.10 g, 0.59 mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the title compound (0.16 g, 82%) was prepared as a light yellow solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:6]([CH2:5][C:4]1[CH:21]=[CH:22][C:23]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:2]([CH3:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:47])=[O:48]
Reactant: Cc1cc(CNc2ccc(OCCN3CCCC3)cc2)ccc1OC1CCCCO1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)c(C)c2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To a solution of [3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.062 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to give the title compound of Step A (0.089 g). MS 593.3 (M+1)+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:13]([CH2:24][CH3:25])[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1)=[O:15])[CH3:12].C(N(CC)CC)C>ClCCl.O>[CH2:24]([N:13]([CH2:11][CH3:12])[C:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=1)=[O:15])[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
Oxalyl chloride (10.8 ml) was dissolved in dichloromethane (260 ml), added with dimethyl sulfoxide (17.5 ml) at −78° C. under an argon gas flow and stirred at the same temperature for 5 minutes. The reaction mixture was added with a solution of 4-diethylcarbamoylbenzyl alcohol (12.80 g) dissolved in dichloromethane (260 ml) at −78° C. and further stirred at the same temperature for 30 minutes. The reaction mixture was added with triethylamine (43.1 ml) at −78° C. and further stirred at room temperature for 30 minutes. After the reaction mixture was added with water (500 ml) and the layers were separated, the aqueous layer was extracted with dichloromethane (500 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 12.075 g of the title compound. Yield: 95%.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[C:12]([C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1N)#[N:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:15]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[C:12]#[N:13])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: C=CCBr
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-cyano-4-nitroaniline (489 mg, 3.0 mmol) was added during 40 minutes, while maintaining the temperature of the reaction mixture at 23-27° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 26° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) gave 367 mg (65%) of allyl-2-cyano-4-nitrobenzene as an orange oil. 1H NMR (CDCl3, 400 MHz) δ 8.51, (d, 1H, J=2.4 Hz), 8.39, (dd, 1H, J=8.6, 2.4 Hz), 7.58, (dd, 1H, J=8.6, 0.5 Hz), 6.00-5.90, (m, 1H), 5.29-5.17, (m, 2H), 3.74, (d, 2H, J=6.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 151.3, 146.8, 133.5, 131.4, 128.4,127.9, 119.6, 116.2, 114.4, 38.9; Anal HRMS Calcd. for C10H8N2O2 (M): 188.0585.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2]2
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1
Yield: 92.7 %

Procedure:
A solution of 52.9 g of ethyl 4-chloro-6,7-difluoroquinoline-3-carboxylate in 750 cm3 of ethanol, in the presence of 19.7 g of triethylamine, was hydrogenated at atmospheric pressure, at a temperature in the region of 20° C., for 1 hour in the presence of 3 g of 5% palladium on carbon (type D). After removing the catalyst by filtration at high temperature, being concentrated to dryness under reduced pressure (5.2 kPa) at about 50° C., the residue was taken up, with stirring, in 1.2 liters of water, dewatered, and washed 3 times with 200 cm3 of water. It was dissolved in 1 liter of diethyl ether; the ethereal extracts were washed twice with 100 cm3 of water and were dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was recrystallized from 600 cm3 of diisopropyl ether. 42.8 g of ethyl 6,7-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 135° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:26][CH2:27][C@H:28]([OH:38])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:38][C@H:28]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH2:27][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 230) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85(t, J=7.0 Hz, 3 H), 1.15–1.45 (m, 12 H), 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (brt, J=6.7 Hz, 2 H), 3.54 (brd, J=12.3 Hz, 2 H), 3.70–3.90 (m, 3 H), 6.66 (d, J=6.7 Hz, 2 H), 6.75 (d, J=8.3 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2 H), 8.89 (brs, 1 H), 9.28 (brs, 1 H); MS (ES) m/z: 534.1 (MH+); HRMS Calcd. for C28H44N3O5S (MH+): 534.3002. Found: 534.3017.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][C:21]3([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[C:26]1([C:21]2([CH2:20][NH:19][C:17]([N:14]3[CH2:13][CH2:12][CH:11]([S:10][C:7]4[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]5[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=5)=[CH:9][CH:8]=4)[CH2:16][CH2:15]3)=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NCCc1ccc(SC2CCN(C(=O)NCC3(c4ccccc4)CCCC3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(NCC1(c2ccccc2)CCCC1)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 64.3 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-N-[(1-phenylcyclopentyl)methyl]-1-piperidinecarboxamide (0.785 g, 1.793 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.62 g, 1.533 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.830 g, 0.986 mmol).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=[O:18])[NH:6][C:7]3[CH:8]=[C:9]4[C:16](=O)[CH2:15][CH2:14][C:10]4=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C1COCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH:16]1[C:9]2[C:10](=[CH:11][C:12]3[CH:13]4[CH2:1][CH2:2][CH2:3][CH:4]4[C:5](=[O:18])[NH:6][C:7]=3[CH:8]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCc2cc3c(cc21)NC(=O)C1CCCC31
Reactant: NCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2cc3c(cc2C2CCCC12)CCC3NCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A solution of 400 mg (1.66 mmol) of 1,2,3,3a,7,8,9,10b-octahydro-dicyclo-penta[c,g]quinoline-4,7-dione in 50 ml of 1,2-dichloroethane and 50 ml of THF is mixed with 0.22 ml (1.82 mmol) of 3-chlorobenzylamine, 526 mg (2.49 mmol) of sodium (triacetoxy)borohydride and 0.01 ml (0.17 mmol) of acetic acid. After 24 hours at room temperature, 0.44 ml (3.6 mmol) of 3-chlorobenzylamine, 1.05 g (5.0 mmol) of sodium(triacetoxy)-borohydride and 0.02 ml (0.34 mmol) of acetic acid are added to it and stirred for another 24 hours at room temperature. The reaction solution is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 360 mg of 7-(3-chlorobenzylamino)-1,2,3,3a,7,8,9,10b-octahydro-dicyclopenta[c,g]quinolin-4-one.