Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[OH-].[K+]>O.NN>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ncccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Cc1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of oxo-(1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid methyl ester (0.300 g, 1.47 mmol) is refluxed in hydrazine monohydrate (10 mL) for 1 hour to give a solution. KOH pellets (0.300 g, 5.35 mmol) are added and reflux is continued for 1 hour. The reaction mixture is evaporated to dryness in vacuo. To the residue is added dry MeOH (10 mL) and the solution is cooled in an ice bath. Concentrated H2SO4 (0.5 mL) is carefully added and the reaction mixture is refluxed at 80° C. for 1 hour. The reaction mixture is evaporated to dryness in vacuo, then partitioned between saturated NaHCO3 aqueous and EtOAc. The EtOAc layer is separated and the aqueous phase is extracted with a further portion of EtOAc. The organics are combined, dried (Na2SO4) and evaporated in vacuo. The crude product is purified by flash chromatography with a pre-packed Isolute™ silica column, eluting with 1:8 EtOAc/iso-hexane-neat EtOAc gradient to afford (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid methyl ester; MH+=191.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[CH3:20])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(Cl)ccc2c1N
Reactant: Cc1ccc(C)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3C)c(Cl)ccc2c1N
Yield: 44.7 %

Procedure:
Using method A, 4-amino-7-chloro-8-iodo-N-propyl-cinnoline-3-carboxamide (78 mg, 0.20 mmol) and (2,5-dimethylphenyl)boronic acid (63 mg, 0.417 mmol) were reacted to afford the title compound (33 mg, 45% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 7.85 (bm, 1H), 7.75 (m, 1H), 7.15-7.24 (m, 2H), 6.98 (s, 1H), 3.43 (apparent q, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.95 (s, 3H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=369 (M+H) HPLC 2.15 min.
Reaction SMILES: Cl.NO.C1([NH:10][C:11]([CH3:21])=[CH:12][C:13]([CH:15]2[N:19]([CH3:20])[CH2:18][CH2:17][CH2:16]2)=[O:14])CCCCC1>CO>[CH3:21][C:11]1[CH:12]=[C:13]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]2[CH3:20])[O:14][N:10]=1
Reactant: CC(=CC(=O)C1CCCN1C)NC1CCCCC1
Agent: Cl
Agent: NO
Solvent: CO
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Hydroxylamine HCl (70 mg, 1.0 mmol) was added to a solution of 3-(cyclohexylamino)-1-(1-methyl-5-pyrrolidinyl)-2-butene-1-one (160 mg, 0.64 mmol, from step 12a above) in 5 mL of methanol, and the mixture was stirred at 20°±5° C. for 4 hr. The solvent was removed under vacuum at 25° C., and the residue suspended in 3 mL of water and 1 mL of H2SO4. The mixture was heated to 70° C. for 90 min, then cooled to room temperature and adjusted to pH 10 with 50% NaOH (4 g). The mixture was extracted with ethyl acetate, and the extracts were dried ,over Na2SO4 and concentrated. The residue was confirmed as title product by chromatographic analysis. The analytical data correspond to that given in Example 1.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.C(#N)C.[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][CH3:29])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CCN1CCCC1CN
Solvent: CCOCC
Solvent: CC#N
Product: CCN1CCCC1CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 17 h
Yield: 43.1 %

Procedure:
3-(1.6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (250 mg. 1.06 mol) (AIT-0027) was placed into a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then 3 ml acetonitrile and 280 mg (2.18 mmol) 2-(aminomethyl)-1-ethyl-pyrrolidine were added and the solution was heated to reflux. Not all of the ester dissolved at reflux, but as the reaction proceeded, the solution became homogeneous. Reflux was continued for 17 hours, at which time the solvent had completely evaporated. The residue was treated with acetonitrile and allowed to cool. A white precipitate had formed. Ether was added and the solution was stirred to wash the precipitate. The solution was filtered by Buchner vacuum filtration and the precipitate was washed with ether. Upon drying, 300 mg (0.94 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]propanamide (AIT-0029) was obtained as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O.C(O)C>O>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[CH3:25])[CH:11]=[CH:10]2
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Solvent: CCO
Solvent: O
Product: CN(c1ccc(O)cc1)c1ccc2cc(Cl)ccc2n1

Procedure:
A mixture of 2,6-dichloroquinoline (1.1 g; prepared according to the method of O Fischer, Chem. Ber., 35, 3683 (1902), 4-(N-methylamino)phenol sulfate (1.5 g), ethanol (5 ml) and water (20 ml) was heated under reflux for a period of 24 hours. Water (50 ml) was added to the mixture and the aqueous mixture was extracted with chloroform (2×100 ml). The chloroform extracts were dried (anhydrous MgSO4) and the solvent was evaporated to give 4-[N-(6-chloro-2-quinolinyl)-N-methylamino]phenol (1.1 g) as a dark oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.0-6.6 and 7.2 (10H, m and d of d, quinoline, hydroxy and phenyl protons); 3.6 (3H, s, N--CH3).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([C:21]3[CH:20]=[C:19]([Br:22])[S:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[N:10]=[C:9]1SCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[NH4+:32]>N.CO>[NH2:32][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[C:11]2([C:21]3[CH:20]=[C:19]([Br:22])[S:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[N:10]=1
Reactant: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CCCc1sc(Br)cc12
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CO
Product: NC1=NC2(CCCc3sc(Br)cc32)C(=O)N1Cc1ccccc1
Temperature: 90 °C
Yield: 41 %

Procedure:
1′-Benzyl-2′-(benzylthio)-2-bromo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one (0.25 g, 0.5 mmol) and ammonium iodide (0.43 g, 3 mmol) were suspended in 7 N NH3/methanol solution (10 mL). The mixture was heated at 90° C. for 18 hr. The solution was concentrated in vacuo and the crude residue partitioned between water and dichloromethane. The product was extracted into dichloromethane (×3), the organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The crude residue was purified on silica gel using 7 N NH3/methanol in dichloromethane (1:9) to afford the title compound as a foam (80 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:11][C:12]3([O:24][N:25]=2)[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]3)[CH:5]=[CH:6][CH:7]=1.Cl[C:27]1C=C(C#CC2CC3(CCN(C(OC(C)(C)C)=O)C3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:11][C:12]3([CH2:27][CH2:13][N:14]([C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[O:18])[CH2:15][CH2:16]3)[O:24][N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC1)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: O=C(N1CCCC1)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 106 but replacing Compound 22d for Compound 27c. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 7:3 to 3:7) giving 52 mg of the title compound giving pale yellow solid. Yield: 72.6%.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=2[O:28][CH2:27]1>>[Cl:25][C:22]1[S:21][C:20]([C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C@H:7]3[CH2:8][CH2:9][C@H:4]([NH:3][C:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:26][CH2:27][O:28][C:29]=5[CH:34]=4)=[O:36])[CH2:5][CH2:6]3)[CH2:13][CH2:14]2)=[O:19])=[CH:24][CH:23]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(5-chloro-thiophen-2-yl)-methanone dihydrochloride (100 mg) and benzo[1,3]dioxole-5-carboxylic acid (45 mg) by procedure C. Yield: 62 mg (52%). Off-white solid. MS (m/z): 503.2 ([M+H]+).
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].CCCCCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (53 mL) under nitrogen atmosphere was added 2-chloro-5-iodobenzotrifluoride (7.1 g), followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (0.65 g). The mixture was stirred under reflux for 2.5 hours and then cooled to room temperature. To the resulting mixture was added hexane (100 mL) and filtered, and the filtrate was washed with water (50 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as colorless oil (4.8 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:55]2[C:50](=[N:51][CH:52]=[CH:53][CH:54]=2)[O:49][N:48]=1>CN(C=O)C.C1COCC1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:46][C:47]2[C:55]3[C:50](=[N:51][CH:52]=[CH:53][CH:54]=3)[O:49][N:48]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1noc2ncccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3noc4ncccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 8 mL of DMF at 0° C. is added 0.78 mL (0.78 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 154 mg (0.972 mmol, 1.1 equiv.) of 3-bromomethyl isoxazolo[5,4-b]pyridine (Abignente, A.; De Capraris, P.; Stein, M. L. Farmaco Ed. Sci. 1975, 30, 992) in 2 mL of DMF is added. The resulting solution is stirred for 2.5 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC using an Si60 column and hexane/EtOAc 1/1 as eluent afforded 280 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 400 MHz) δ8.57 (dd, 1H, J=1.5, 4.6), 8.23 (dd, 1H, J=1.5, 7.8), 7.39-7.10 (m, 12H), 6.94 (m, 2H), 4.99 (m, 1H), 4.23 (m, 3H), 3.84 (s, 3H), 3.79 (d 1H, J=8.4), 3.57 (dd, 1H, J=5.3, 16.4), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 590 (MH+), 589 (M+), 425; Anal. (C34H31N5O5) Calcd. C, 69.26; H, 5.30; N, 11.88 Found C, 69.13; H, 5.32; N, 11.84.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:23](=[O:24])[O:12][N:11]=[C:10]2[C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A mixture of N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (76.5 g, 0.204 mol), 1,1′-carbonyldiimidazole (49.7 g, 0.307 mol), and ethyl acetate (720 mL) was heated to 60° C. and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N HCl (2×750 mL), dried over sodium sulfate, and concentrated to give the desired product (80.4 g, 98%) as a crude brown solid. LCMS for C13H12BrFN5O4 (M+H)+: m/z=400.0, 402.0. 1H NMR (400 MHz, DMSO-d6): δ 7.94 (t, J=8.2 Hz, 1H), 7.72 (dd, J=9.1, 2.3 Hz, 1H), 7.42 (m, 1H), 6.42 (t, J=5.7 Hz, 1H), 3.46 (t, J=5.4 Hz, 2H), 3.36 (t, J=5.8 Hz, 2H), 3.26 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=C1CCC(c2ccc(OCCCCl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1CC[C@H](c2ccc(OCCCCl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[4-(3-chloropropoxy)phenyl]cyclohexanone (800 mg) in methanol (10 mL) is cooled to a temperature close to 0° C. Sodium borohydride (57 mg) is added and the mixture stirred for one hour at room temperature, then concentrated under reduced pressure. Water (15 mL) is added and the insoluble separated by filtration, rinsed with diethyl ether and dried under reduced pressure to give 550 mg of trans-4-[4-(3-chloropropoxy)phenyl]cyclohexanol as a white solid used without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[NH:18][C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[Br:25][C:26]1[C:27]([CH2:33]Br)=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1>C1COCC1>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[N:18]([CH2:33][C:27]3[C:26]([Br:25])=[CH:31][CH:30]=[C:29]([Cl:32])[N:28]=3)[C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Reactant: Clc1ccc(Br)c(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil; 105 mg, 2.53 mmol) in THF (10 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 20; 68 mg, 0.21 mmol) in THF (2 mL) dropwise. The resultant mixture was stirred at 0° C. for 20 min prior to the addition of 3-bromo-2-bromomethyl-6-chloropyridine (59 mg, 0.21 mmol) as a solution in THF (1 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and was partitioned between H2O (25 mL) and EtOAC (35 mL). The aqueous layer was re-extracted with EtOAc (3×35 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.94-7.90 (brs, 2H), 7.83 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 5.64 (m, 1H), 5.36 (d, J=17.6 Hz, 1H), 4.46 (d, J=17.6 Hz, 1H), 3.84 (m, 1H), 2.44 (m, 1H), 2.14 (m, 1H), 1.34 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[Cl:1])=[CH:16][CH:17]=1)[CH3:31]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3nc4ccccc4nc3OC)CC2)c1
Yield: 64.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1OC
Yield: 66.3 %

Procedure:
Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K2CO3 (1.3 gr, 9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at 100° C. in DMSO (5 mL) for 20 hours. Reaction mixture was diluted with DCM and washed with water. Organic phase was dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g (yield 66%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH:17][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrotoluene (4.32 grams; 0.02 mole), N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole), triethylamine (2.02 grams; 0.02 mole) and toluene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-p-toluidine.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Product: Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-methyl-3-nitrophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (68% yield). ESI/MS 365 (M+H); RT=2.65 min; NMR (CDCl3) 10.35 (1H, s); 8.31 (1H, d, J=9 Hz); 8.11 (1H, s); 7.61 (2H); 7.31 (2H); 7.01 (1H, d, J=9 Hz); 3.31 (4H, m); 2.88 (4H, m); 2.74 (3H, s).