Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=[O:16].[K+].[K+].[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]2[CH2:27][NH:28][CH2:29][C@H:22]12>CC#N.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9]([N:28]3[CH2:27][C@@H:23]4[C@@H:22]([NH:21][CH2:26][CH2:25][CH2:24]4)[CH2:29]3)=[O:16])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C1CN[C@H]2CNC[C@H]2C1
Reactant: Clc1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(c1nc2cc(Cl)ccc2[nH]1)N1C[C@H]2CCCN[C@H]2C1
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a suspension of 5-chloro-2-trichloromethyl-1H-benzoimidazole (30 mg, 0.11 mmol) and K2CO3 (46 mg, 0.33 mmol) in CH3CN/H2O (10:1, 3 mL) was added cis-octahydro-pyrrolo[3,4-b]pyridine (28 mg, 0.22 mmol). After 1 h at 100° C., the mixture was filtered and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated to give a yellow oil, which was purified by FCC to give a brown solid (14 mg, 40%). MS (ESI): mass calcd. for C15H17ClN4O, 304.11; m/z found, 305.4 [M+H]+. 1H NMR (mixture of rotamers; MeOD): 7.70-7.58 (m, 2H), 7.35-7.25 (m, 1H), 4.43-4.28 (m, 0.6H), 4.19-4.09 (m, 0.6H), 3.77-3.69 (m, 1H), 3.46-3.40 (m, 0.3H), 3.38-3.33 (m, 0.3H), 3.33-3.28 (m, 2H), 3.04-2.82 (m, 1.5H), 2.71-2.53 (m, 1H), 2.50-2.31 (m, 1.5H), 1.95-1.43 (m, 4H).
Reaction SMILES: C(=O)([O-])O.[Na+].[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C:11]1=[O:17].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CC(C)=O.O>[CH2:22]([O:21][C:19]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][OH:6])[C:11](=[O:17])[C@@H:12]1[CH3:16])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCCN(CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1C(=O)N(CCCO)CCN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
Sodium hydrogencarbonate (976 mg, 11.6 mmol) was added to a solution of (S)-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (example 20D; 1.00 g, 5.81 mmol) in acetone (5 mL) and water (5 mL), then a solution of benzyl chloroformate (1.04 g, 5.81 mmol) in acetone (1 mL) was added at 0° C. The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (1.79 g), which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:35](Cl)=[O:36])[N:27]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:35]([C:28]2[N:27]=[C:26]([CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=23)=[O:36])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 4-chlorobenzylamine (0.080 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (85 mg, 47%). 1H NMR (DMSO-d6) δ 8.52 (1H), 8.35 (1H), 8.05 (1H), 7.35 (4H), 7.08 (1H), 6.85 (1H), 4.45 (2H), 3.58 (4H), 3.20 (2H), 2.78 (2H), 2.45 (4H); m/z (M+H)=399.16.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH:19]=O)=[CH:17][N:18]=2)[CH:15]=1.[CH3:21][NH:22][NH2:23].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16](/[CH:19]=[N:23]/[N:22]([CH3:21])[S:32]([C:26]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:33])=[O:34])=[CH:17][N:18]=2)[CH:15]=1
Reactant: CNN
Reactant: O=Cc1cnc2ccc(-c3cc4ccccc4[nH]3)cn12
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCO
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)/N=C/c1cnc2ccc(-c3cc4ccccc4[nH]3)cn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(1H-indol-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (Intermediate 6, 115 mg, 0.3691 mmol) in ethanol (10 mL) was added methyl hydrazine (0.04 mL, 0.7395 mmol) at RT. The reaction mixture was heated at 80° C. for 4 h. Ethanol was evaporated. Pyridine (5 mL) was added to this residue, followed by addition of 2-methyl-5-fluoro benzene sulfonylchloride (0.07 mL, 0.5535 mmol). The reaction mixture was stirred at RT overnight. Pyridine was evaporated. Water was added to this residue and extracted with dichloromethane. Organic layer was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (Silica gel, 1.5% methanol in chloroform) to obtain the title compound. Yield: 28 mg (17%); 1H NMR (DMSO-d6; 500 MHz): δ 11.83 (s, 1H), 9.09 (s, 1H), 9.81 (s, 1H), 8.34 (s, 1H), 8.27 (d, 1H, J=9.5 Hz), 8.08 (d, 1H, J=9.5 Hz), 7.74 (d, 1H, J=6.5 Hz), 7.61 (d, 1H, J=8 Hz), 7.43 (m, 3H), 7.18 (t, 1H, J=8), 7.07 (t, 1H, J=7.5 Hz), 6.91 (s, 1H), 3.48 (s, 3H); MS: m/z 460 (M−1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10](=O)[CH:11]=[CH:12][CH3:13].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([CH3:13])[CH:11]=[C:10]2[CH3:9]
Reactant: Nc1ccccc1Cl
Reactant: CC=CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c2cccc(Cl)c2n1
Yield: 42 %

Procedure:
To 4.0 g (0.03 mol) of o-chloroaniline in 50 ml of hydrochloric acid at 100° C. was added dropwise 3.4 g (0.04 mol) of 3-penten-2-one. The mixture was refluxed for 12 hours, then neutralised with 5N sodium hydroxide and extracted with dichloromethane. The organic extract was dried and concentrated to an oil. This was purified on a silica gel column to give 2.54 g (42% of the title product; m.p. 66°-68° C. Anal. Calcd. for C11H10NCl: C, 68.94; H, 5.26; N, 7.31; Cl, 18.50. Found C, 68.87; H, 5.27; N, 7.29; Cl, 18.48.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cnc(-c2ccc(Br)cc2)cn1
Temperature: 50 °C

Procedure:
5-Bromopyrazin-2-amine (173 mg, 0.99 mmol) and (4-bromophenyl)boronic acid (100 mg, 0.490 mmol) were placed in a sealable vial followed by toluene (1.5 mL), ethanol (1.5 mL), and K2CO3 (0.7 mL, 2 M). The resultant mixture was then sparged with argon for 10 minutes before adding tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.15 mmol), and heating at 50° Celsius. Reaction progress was monitored by LCMS. Once the reaction was complete, the reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and the resultant filtrate concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.52-8.31 (d, J=1.5, 1H), 8.08-7.95 (d, J=1.6, 1H), 7.86-7.71 (d, J=8.4, 2H), 7.63-7.49 (d, J=8.6, 2H), 4.81-4.61 (s, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>C(#N)C.CN(C=O)C>[N:19]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(I)cn21
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(I)cn21
Yield: 76.9 %

Procedure:
2-(7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)ethyl methanesulfonate (0.150 g, 0.39 mmol) was reacted with sodium azide (0.076 g, 1.17 mmol) in ACN/DMF (4 ml, 1:1 ratio) for 4 hours at 80° C. under N2. The solvents were removed under vacuum, the residue was partitioned between water and DCM. The organic phase was dried (Na2SO4), filtered and evaporated, yielding the title compound as a white solid (0.097 g, 0.30 mmol, 75%).
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:11].Cl[S:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O>[CH3:4][C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[S:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:11]
Reactant: ClSN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2snnc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(N(SN2CCOCC2)C(=O)c2snnc2C)cc1
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To 10 ml of methylene chloride were added 0.50 g (2.1 mmol) of 4-methyl-N-(4-methylphenyl)-1,2,3-thiadiazole-5-carboxamide and 0.50 g (3.3 mmol) of N-(chlorosulfenyl)morpholine. Then, 0.33 g (3.3 mmol) of triethylamine was slowly added thereto, and the resulting mixture was reacted with stirring for 5 hours. After the reaction was completed, the reaction mixture containing the objective product was poured into water, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude crystal thus obtained was washed with ether. As a result, 0.38 g of the objective compound was obtained (Property: m.p. 60° C. (decomposed); Yield: 52%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][N:50]=1)[NH2:48]>C(Cl)Cl>[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][N:50]=1)[NH:48][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:15]
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1cnc(-c2ccccc2)nc1)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, 0.57 mmol) and DIPEA (0.57 mmol) in DCM (5 mL) is added N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine (109 mg, 0.57 mmol). The reaction mixture is stirred at rt for 18 hours and then concentrated. The residue is purified by silica gel chromatography eluting with 10-75% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid N′-methyl-N′-[5-trifluoromethyl-pyridin-2-yl]-hydrazide as a solid (189 mg). MS: 374 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.54 (s, 3H), 6.82 (d, 1H), 7.53-7.59 (m, 3H), 7.74 (d, 1H), 8.45 (d, 2H), 8.53 (d, 2H), 9.25 (s, 2H). IC50=100 nM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[F:11][C:12]([F:51])([F:50])[C:13]1[CH:14]=[C:15]([C@H:23]2[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=3B3OC(C)(C)C(C)(C)O3)[C@H:24]2[CH3:49])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[F:51][C:12]([F:11])([F:50])[C:13]1[CH:14]=[C:15]([C@H:23]2[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=3[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=3)[C@H:24]2[CH3:49])[CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: C=C(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C=C(C)c1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 100 °C

Procedure:
In a tube were placed 2-bromo-6-isopropenylpyridine (17.5 mg, 0.0878 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (26.2 mg, 0.0439 mmol), DME (190 μL), EtOH (62 μL), and 1M aqueous Na2CO3 (100 μL, 0.1 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (9 mg, 7.8×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.15 (15% EtOAc/hexanes). LCMS=589.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.81-7.85 (m, 2H), 7.74 (s, 1H), 7.69-7.69 (m, 3H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 5.94 (s, 1H), 5.48 (d, J=7.7 Hz, 1H), 5.36 (s, 1H), 5.06 (d, J=16.0 Hz, 1H), 4.47 (d, J=16.1 Hz, 1H), 3.91 (m, 1H), 2.23 (s, 3H), 0.50 (d, J=6.6 Hz, 3H).
Reaction SMILES: [H][H].Cl.[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.CC[C:32]([C:34](Cl)=[O:35])=[O:33]>C(O)C.O1CCCC1.[Ni]>[Br:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]3[NH:4][C:34](=[O:35])[C:32](=[O:33])[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:6]=3[CH:7]=[CH:8][C:9]=2[CH:10]=1
Reactant: [H][H]
Reactant: CCC(=O)C(=O)Cl
Reactant: Nc1c(NC2CCCCC2)ccc2cc(Br)ccc12
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c3ccc(Br)cc3ccc2n(C2CCCCC2)c1=O
Temperature: 0 °C

Procedure:
A solution of 6-bromo-2-methoxy-1-nitronaphthalene (10.0 g, 35.6 mmol) and 8 ml of cyclohexylamine in 50 ml of dry N,N-dimethylformamide was heated with stirring at 120° C. for 17 h. The mixture was evaporated to dryness and the residue was triturated with 50 ml of ethanol at 0° C.. The solid was isolated by filtration and washed with light petroleum to give 10.4 g (84%) of 6-bromo-2-cyclohexylamino-1-nitronaphthalene. The crude product was suspended in 150 ml of 96% ethanol and hydrogenated at room temperature and 40 psi over Ni/Raney After the hydrogen uptake was completed, the reaction mixture was filtered into 50 ml of 4M hydrochloric acid and concentrated to dryness. Crude 1-amino-6-bromo-2-cyclohexylaminonaphthalene hydrochloride (9.8 g, 27.6 mmol) was taken up in 80 ml of dry tetrahydrofuran. Dry triethylamine (7.7 ml, 55.3 mmol) was added, followed by the dropwise addition of ethyloxalyl chloride (3.1 ml, 27.7 mmol) with stirring at 0° C.. The mixture was stirred over night at room temperature and finally at reflux for 4 h. The cooled mixture was filtered and the solid was washed with water and ethanol affording 5.2 g (51%) of the title compound M.p. 347.0° C. (N,N-dimethylformamide, DSC); IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): 1.13-2.93 (m, 10H, 5CH2), 4.33-4.90 (m, 1H, NCH), 7.47-8.67 (m, 5H, ArH), 12.1 (broad s, 1H, NH); MS (m/z): 372 (M+, 17%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[N:15][OH:16])[NH2:14])(=[O:3])[CH3:2].[C:17](Cl)(=O)[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:14]=[C:17]([CH2:18][CH2:19][CH3:20])[O:16][N:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(N)=NO
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of intermediate (14) (0.00898 mole) and butanoyl chloride (0.0094 mole) in pyridine (140 ml) was stirred at room temperature for 40 hours and then heated to reflux. After 21 hours the reaction was cooled and concentrated in vacuo. The residue was extracted between DCM and saturated aqueous NaHCO3 and the organic fraction was dried over Na2SO4, filtered, and concentrated.The residue was subjected to silica gel flash column chromatography (eluent 100% CH2Cl2 to 95/5 CH2Cl2/ether), yielding 1-acetyl-2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole (compound 89, mp. 93–94° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)C=O.N1CCCCC1.[C:31](O)(=O)[CH2:32][C:33]([OH:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 66.7 %

Procedure:
270 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde and 6 g of piperidine were added, at 25° C., to 89.5 g of malonic acid in 570 ml of pyridine. The reaction mixture was stirred for 5 hours at 85° to 90° C. and was then heated for 90 minutes under reflux, after which it was poured onto water, the mixture was acidified with hydrochloric acid and the product was filtered off. The crystalline product was recrystalized from n-butanol. 200 g (66% of theory) of 3-(5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitrophenyl)propenoic acid, of melting point 192° C., were obtained in the form of yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1.N1C(C)=CC(C)=CC=1C>CC1C=CC=C(C)C=1C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: Cc1cccc(C)c1C
Solvent: Cc1cc(C)nc(C)c1
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCCc2ccccc21
Temperature: 25 °C
Yield: 18 %

Procedure:
A stirred mixture, under nitrogen, of 2,5-dibromonitrobenzene (140.5 g, 0.50 mole), 1,2,3,4-tetrahydroquinoline (133.2 g, 1.00 mole) and symmetrical collidine (121.2 g, 1.00 mole) in 1,2,3-trimethylbenzene (500 ml) as solvent was heated at 160°-165° C. for 7 days. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo (100° C.). The residue was taken up in dichloromethane (1.5 l) and the solution was extracted three times with dilute hydrochloric acid, once with dilute sodium hydroxide solution, three times with water, dried over anhydrous sodium sulfate and concentrated. This residue was dissolved in 1:1 hexane:toluene (250 ml) and adsorbed on a chromatography column containing 3 kg of silica gel. Elution with 1:1 hexane:toluene gave 30 g (18%) of product, as an oil. A portion of the oil was Kugelrohr distilled at an oven-temperature of 163°-165° C. (0.1 mm Hg) to provide the analytical sample.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].CN(C=O)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
To 70 mg (0.25 mmol) Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine in 1.4 ml DMF 87 μl (0.5 mmol) Huenig's base and 54 μl (0.38 mmol) benzyl chloroformate were added. The solution was stirred at RT over night, was concentrated and the residue was dissolved in ether and 0.1M NaOH. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2MeOH 5:1 yielded 40 mg (38%) 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester as light yellow oil, MS: 411 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3][CH2:4][CH2:5][Mg]Br.BrCCC=C(C)CCC1C(C)(C)CCCC=1C.[Mg].BrCCBr.[CH3:41][Si:42]([CH3:51])([CH3:50])[C:43]1[O:47][CH:46]=[C:45]([CH:48]=[O:49])[CH:44]=1.Cl>C(OCC)C>[OH:49][CH:48]([C:45]1[CH:44]=[C:43]([Si:42]([CH3:51])([CH3:50])[CH3:41])[O:47][CH:46]=1)[CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(=CCC[Mg]Br)CCC1=C(C)CCCC1(C)C
Agent: CC(=CCCBr)CCC1=C(C)CCCC1(C)C
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(=CCCC(O)c1coc([Si](C)(C)C)c1)CCC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)-3-hexenylmagnesium bromide (0.70 mmol, prepared from 0.21 g., 0.70 mmol 1-bromo-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)-3-hexene and 2.1 mmol magnesium, with a catalytic amount of 1,2-dibromoethane as initiator), in one ml ethyl ether at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.13 g., 0.77 mmol) in one ml ether. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then poured over crushed ice containing several drops of hydrochloric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 20% ethyl ether/hexane) to give the desired alcohol.