Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[N+:36](=[C:9]([C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:37]
Reactant: CCOC(=O)CC(=O)c1cccnc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccnc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(2-fluoropyridine-3-yl)-3-oxopropanoate (1.42 g, 6.71 mmol) was dissolved in anhydrous acetonitrile (20 mL), treated with triethylamine (0.781 mL, 1.15 equiv) and cooled to 0° C. To the mixture was added the 4-acetamidobenzenesulfonyl azide (1.77 g, 1.1 equiv) and after stirring 0° C. for 1 hour, the mixture was treated with sodium hydroxide (10 mL, 1 N aqueous). The mixture was poured into sodium carbonate (50 mL, aqueous saturated) and water (200 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed once with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound as a light yellow oil.
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])[O:5]CC)C.[CH3:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22](=O)C)[CH:16]=[CH:15]2.II>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:9]([O:8][C:4](=[O:5])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=2)[CH:13]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc2cc(C)ccc2c1
Agent: [Ag+]
Agent: II
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2cc(C)ccc2c1
Temperature: 80 °C

Procedure:
Triethylorthoformate (1.5 ml) and 1-(6-methylnaphthalen-2-yl)ethanone (1.0 mmol) were dissolved in ethanol (4 ml). To the reaction mixture were added AgNO3 (2.1 mmol) and I2 (1.05 mmol) and the reaction mixture was heated to 80° C. for 20 hours. The reaction mixture was cooled to ambient temperature and concentrated to dryness. The residue was diluted eith EtOAc and filtered through celite. The combined organics were washed with saturated sodium bicarbonate solution and brine. The organic layer was then dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 5% EtOAc in hexanes as the eluant to yield the title compound (50).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][N:47]=1>C(Cl)Cl.CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][N:47]=4)[CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ccc(C(F)(F)F)cn4)CC3)cn2)cc1

Procedure:
The title compound (73 mg, 66%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 150, Step 2, 0.10 g, 0.22 mmol) and TFA (0.18 mL) in CH2Cl2 (6 mL) then K2CO3 (0.62 g) and 2-chloro-5-(trifluoromethyl)pyridine (50 mg, 0.27 mmol) in DMSO (5 mL) in a manner similar to Example 80. The crude material was purified by chromatography on a silica gel column eluted with 1:16 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, 1H, J=2.9 Hz), 8.36 (s, 1H), 8.24 (d, 2H, J=8.3 Hz), 8.02 (d, 1H, J=8.8 Hz), 7.95 (d, 2H, J=8.3 Hz), 7.75-7.70 (m, 1H), 7.51 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 6.94 (d, 1H, J=9.1 Hz), 4.50-4.40 (m, 2H), 3.99 (d, 2H, J=6.4 Hz), 3.21 (s, 3H), 3.00-2.90 (m, 2H), 2.20-2.05 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 492 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[CH3:14][S-:15].[Na+]>C(O)C.C(Cl)Cl.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:14][S:15][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: C[S-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCS
Solvent: ClCCl
Solvent: CCO
Product: CSc1ncc2cc(O)ccc2n1

Procedure:
In the alternate reaction Scheme B, above, the 2-chloro-6-methoxyquinazoline 8 is reacted with sodium thiomethoxide in ethanol, dry methylene chloride, ethane thiol and aluminum chloride to obtain the 2-methylthioquinazolin-6-ol 13. The desired substituent, in this case 4-chloro(2-pyridyl)-N-methylcarboxamide, is added to the alcohol group to obtain the corresponding substituted methylthioquinazoline 14. Treatment with 3-chloroperoxybenzoic acid in acetic acid results in the corresponding sulfonyl 15, which is replaced by a desired substituent, in this case 2-naphthylaniline, to obtain the desired compound of the invention, in this case N-methyl-4-{[2-(naphthalen-2-ylamino)-quinazolin-6-yl]oxy}pyridine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)C(C)C)(C)C.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)C(N)=NO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-(4-fluorophenyl)acetyl chloride (0.518 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.315 g (33%) of ethyl 5-(4-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[I:18]I.[N+]([O-])(O)=O>C(Cl)(Cl)Cl>[C@@H:1]1([N:10]2[CH:17]=[C:16]([I:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: II
Solvent: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)cc1I
Yield: 61.8 %

Procedure:
A mixture of 15 (1.2 g, 4.9 mmol), iodine (1.50 g, 5.9 mmol), CHCl3 (6 mL), and 1 N HNO3 (24 mL) was heated at reflux for 2 hours, and then cooled. The crystalline solid was collected by filtration and washed with ether to give the title compound 16 as a white solid (1.12 g, 62%). 1H NMR (DMSO-d6) δ 11.6 (s, 1H, NH), 8.10 (s, 1H, H-6), 5.95 (d, 1H, H-1′), 5.52 (br, 1H, OH), 5.40-5.10 (br, 1H, OH), 4.15-3.90 (m, 2H, H-2′, H-3′), 3.80-3.60 (m, 3H, H-4′, H-5′), 3.60-3.30 (m, 1H, OH).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CCCCCC.C1COCC1>[CH3:3][NH:4][C:5](=[O:9])[CH:6]([C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:21])=[CH:13][CH:14]=1)[C:7]#[N:8]
Reactant: CNC(=O)CC#N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 62.4 %

Procedure:
Sodium hydride (0.82 g, 20.4 mmoles), washed with Skellysolve B, was suspended in 20 ml of dry THF and treated at 15° C. with N-methylcyanoacetamide (2.0 g, 20.4 mmoles) [prepared in Step A]. The resultant suspension was further cooled to 5° C. and 4-trifluoromethylphenyl isocyanate (3.80 g, 20.4 mmoles) was added over several minutes. After 18 h at ambient temperature the solvent was removed and the residual syrup was poured into a cold mixture of water and 4 ml of 6N HCl. The precipitate was isolated by filtration and recrystallized from ethanol to give 3.63 g of the title compound, mp 184°-186° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][Mg]Cl.[Cu](C#N)C#N.Br[C:14]1[N:32]=[CH:31][CH:30]=[CH:29][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)=[O:17].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:29]=[CH:30][CH:31]=[N:32][C:14]=2[CH2:1][C:2]([CH3:7])([CH3:6])[CH3:3])[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ncccc1C(=O)Nc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2,2-Dimethylpropylmagnesium chloride (1 M-diethylether, 4.8 mL, 4.8 mmol) was added to a suspension of copper cyanide (215 mg, 2.40 mmol) in THF (6 mL) at −78° C. After stirring at the same temperature for 1 hour, 2-bromo-N-(3-tert-butylphenyl)nicotinamide (200 mg, 0.601 mmol) was added all at once as a solid. The reaction mixture was gradually warmed to room temperature and the reaction was allowed to stir overnight. Saturated ammonium chloride solution and ethyl acetate was added, and the reaction mixture was filtered through celite and rinsed with ethyl acetate. The layers were separated and the product was extracted once more with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography using a gradient of 20%-50% ethyl acetate in hexanes to yield N-(3-tert-butylphenyl)-2-(2,2-dimethylpropyl)nicotinamide (168 mg, 0.517 mmol, 86%). Rf=0.45 (toluene: ethyl acetate=2:1).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: O=C1CCCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCCC2
Yield: 66 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 66%; IR (KBr) cm−1: 3379, 3247, 2918, 1577, 1548, 1432, 1416, 1273, 761; 1H NMR (CDCl3):δ 1.63 (m, 2H), 1.79 (m, 2H), 2.24 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.11 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); orange solid, mp: 160–163° C. (petroleum ether).
Reaction SMILES: II.[OH:3][PH2]=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:14][N:15]=2)[N:12]=1>C(O)(=O)C>[C:16]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH:16]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)[C:17]([F:18])([F:19])[F:20])=[CH:14][N:15]=2)[N:12]=1
Reactant: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Reactant: O=[PH2]O
Agent: II
Solvent: CC(=O)O
Product: FC(F)(F)C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Product: O=C(O)C(F)(F)F
Temperature: 150 °C

Procedure:
Iodine (105 mg, 0.412 mmol) and H3PO2 (0.225 mL of a 50% aqueous solution, 2.059 mmol) were added to a solution of (rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-(quinolin-6-yl)ethanol (Stage 274.1, 52 mg, 0.137 mmol) in acetic acid (1.4 mL). The RM was heated at 150° C. for 45 min under microwave irradiations. The solvent was removed. The residue was taken up with EtOAc and extracted with 1N HCl twice. The combined aqueous layers was basified to pH 14 with NaOH pellets. It was then extracted with EtOAc/MeOH (9:1) twice. Combined organic layers was dried over Na2SO4, filtered and concentrated. After purification by preparative HPLC with acetonitrile and water (+0.1% TFA), the fraction containing the product was lyophilized to give a TFA salt of the title compound (tR 1.0 min (conditions 1), MH+=363).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31].C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][O:27][S:39]([CH3:42])(=[O:41])=[O:40])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CO)c3Cl)cccn2c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(glycoloylglycyl)-n-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) and triethylamine (76 mg) in methylene chloride (2 ml) was dropwise added mesyl chloride (52 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-(mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (221 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B>O1CCCC1>[OH:15][CH2:14][C:11]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (40 g, 131 mmol) in tetrahydrofuran (131 mL) at room temperature was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 131 mL, 131 mmol). There was effervescence and the substrate quickly went into solution. The reaction was stirred at room temperature for 3 days. The reaction was cooled to 0° C. and quenched by the cautious addition of 1 M sodium hydroxide. The reaction was diluted with ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Trituration with 10% EtOAc/Hex (300 mL) gave a white powder which was collected by filtration to give 36.9 g (97%). 1H-NMR (CD3OD, 300 MHz) δ 7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H), 3.49 (s, 2H), 2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H), 1.46 (s, 9H). Mass spec.: 292.17 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2ccc(Br)cc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
[I] A solution prepared by dissolving 0.75 g of 4-amino-4'-bromobiphenyl in 10 ml of pyridine, was cooled with ice, and 1.0 g of acetyl chloride was dropwise added thereto. The mixture was stirred over a period of 30 minutes. After the completion of the reaction, the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with dilute hydrochloric acid and further with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.8 g of N-(4'-bromo-4-biphenylyl)acetamide as colorless crystals.
Reaction SMILES: FC1C=CC(C[Mg]Cl)=CC=1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH:16]=[C:17]2[C:24]3[CH:23]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[N:21]([S:29]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:20]=3[CH2:19][CH2:18]2)=[CH:14][CH:13]=1>[Pd]>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[C:24]3[CH:23]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[N:21]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=4)(=[O:30])=[O:31])[C:20]=3[CH2:19][CH2:18]2)=[CH:39][CH:40]=1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CCC2=Cc1ccc(F)cc1
Agent: [Pd]
Agent: Fc1ccc(C[Mg]Cl)cc1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CCC2Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 14 %

Procedure:
The title compound was synthesized from tosyl protected methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (methyl 4-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (0.60 g, 1.8 mmol) and 4-fluorobenzylmagnesium chloride (0.25M in THF, 52 mL, 13 mmol) according to General Procedure 3 to give exo olefin-containing methyl 4-(4-fluorobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (as a mixture of cis/trans isomers), then hydrogenation according to General Procedure 6. In this example, Degussa type, 5% palladium on carbon (˜0.200 g, 0.2 mmol) was used, and the reaction placed under a hydrogen atmosphere in a Parr shaker (˜40 PSI) for 2 hours. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane affording the title compound as white crystals: 0.070 g (14% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.05-2.15 (m, 1H), 2.44 (s, 3H), 2.55-2.65 (m, 1H), 2.70-2.85 (m, 2H), 3.08 (t, 1H), 3.20-3.35 (m, 1H), 3.71 (s, 3H), 6.49 (s, 1H), 6.95-7.00 (m, 2H), 7.10-7.15 (m, 1H), 7.30-7.35 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H).
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][N+](C)(C)C.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(O)C>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:21][C:20]1[N:11]2[CH:12]=[CH:13][C:14]3[C:19]([C:10]2=[N:9][C:8]=1[CH3:7])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: c1c[nH]cn1
Reactant: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cc1nc2c3ccccc3ccn2c1Cc1ncc[nH]1
Reaction time: 7 h
Yield: 71.2 %

Procedure:
A mixture of 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (4.5 g) and imidazole (2.02 g) in ethanol (45 ml) was refluxed with stirring for 7 hours and evaporated in vacuo. To the residue was added water and the resulting precipitates were collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(1-imidazolylmethyl)-2methylimidazo[2,1-a]isoquinoline (2.3 g).
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[OH:19])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccnc1)c1cccc2ccccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 3-bromopyridine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 3-bromopyridine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH 2 with HCl solution. The solution is extracted with diethyl ether. The aqueous solution is made basic with a 5% NaOH solution. The product is extracted with methylene chloride and dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 3-pyridyl-1-naphthylcarbinol.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13](OCC)(OCC)OCC.FC(F)(F)C(O)=O>>[CH3:13][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of ethyl p-aminobenzoate (25.2 g), triethyl orthoformate (80 g) and trifluoroacetic acid (0.2 mL) is refluxed under heating for 3 hours. After cooling, the reaction mixture is concentrated in vacuo and the residue is subjected to azeotropic distillation with ethanol. The residue is suspended in ethanol (400 mL) and thereto is added sodium borohydride (23 g), and the mixture is refluxed under heating for 3 hours. After cooling, to the reaction mixture is added ethyl acetate and water. The mixture is stirred at room temperature for 1 day. The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=4:1) to give ethyl 4-(methylamino)benzoate (12.7 g, yield; 46%) as a pale yellow amorphous powder. MS (APCI) m/z: 180 [M+H]+
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[OH:13].[C:16](O)(=O)[CH3:17].[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:20]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:12][CH:11]=2)[CH:6]([OH:13])[CH2:7][CH2:8]1)[CH2:16][CH3:17]
Reactant: OC1CCNc2ccc(C(F)(F)F)cc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN1CCC(O)c2cc(C(F)(F)F)ccc21
Reaction time: 8 h
Yield: 29 %

Procedure:
6-(Trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-ol (30 mg, 0.14 mmol) obtained in Step 2 was dissolved in methylene chloride (2 ml), propylaldehyde (16 mg, 0.28 mmol), acetic acid (20 μl) and sodium triacetoxyborohydride (59 mg, 0.28 mmol) were added, and the mixture was stirred overnight. The solvent was evaporated, and the residue was subjected to reversed-phase high performance liquid chromatography using ODS as a filler, and eluted with a mixed solution of water and acetonitrile, which contains 0.1% (v/v) trifluoroacetic acid. Aqueous sodium hydrogencarbonate solution was added to the object fraction. Acetonitrile was evaporated under reduced pressure and the remaining aqueous layer was partitioned with ethyl acetate. The solvent was evaporated to dryness to give the title compound (10.4 mg, 0.04 mmol, 29%).