Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]=[CH:5]1.Br[CH2:15][C:16]([O:18]CC)=[O:17].O>CN(C=O)C>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: CCOC(=O)CBr
Reactant: Cn1cnc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc2cc(OCC(=O)O)ccc21
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
To a solution of NaH (204 mg, 8.49 mmol) in DMF (5 mL) was added 1-methyl-1H-benzo[d]imidazol-5-ol (420 mg, 2.83 mmol) at 28° C. After being stirred for 5 minutes, ethyl 2-bromoacetate (568 mg, 3.4 mmol) was added and the resulting mixture stirred for a further 16 h under the reaction was complete by TLC. The mixture was treated with water (50 mL) and extracted with ethyl acetate (2×20 mL). The water layer was treated with 2N HCl until pH 3 and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the product (160 mg, 24.1%) as white solid which was used in next step without further purification. LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[CH:34][CH:35]=3)[CH:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccccn2)cc1

Procedure:
In a similar manner to Referential Example 116 except for the use of 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methoxycarbonylmethylpiperazine and 4-(2-pyridyl)benzoic acid hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CCCCCC.[C:33](=[O:35])=[O:34].Cl>C1COCC1>[CH2:1]([O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[C:15]([C:33]([OH:35])=[O:34])=[C:16]([F:19])[C:17]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
36.8 g of the compound (10) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 100 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 26.5 g (76 mmol) of 4-decyloxy-2,3,5,6-tetrafluorobenzoic acid (11).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].CN(C)C=O.[CH2:33](I)[CH3:34].[H-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([CH2:33][CH3:34])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: COC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C(=O)OC)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.8 %

Procedure:
To a mixture of methyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.400 g, 0.00100 mol), N,N-dimethylformamide and ethyl iodide (0.980 g, 0.00628 mol) is added sodium hydride (60%, 0.0900 g, 0.00225 mol) in portions. The mixture is stirred 5 days at room temperature, diluted with methylene chloride, washed sequentially with 8% hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with ether:hexanes:methylene chloride to give the title compound (0.260 g, 60.9%) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].O>C1C=CC=CC=1>[CH2:18]([N:19]([CH2:22][CH2:23][CH:13]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:14]#[N:15])[CH2:20][CH3:21])[CH3:17]
Reactant: N#CCc1cccc2ccccc12
Reactant: CCN(CC)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)CCC(C#N)c1cccc2ccccc12

Procedure:
7 g of sodium amide are added in small quantities to 27.11 g of 1-naphthylacetonitrile in 210 ml of anhydrous benzene. The mixture is heated for 2 hours to reflux and 22 g of 2-chlorodiethylaminoethane are added, the heating being continued to reflux for another two and a half hours. Then, the mixture is cooled and 200 ml of water are added. After decanting, the organic phase is extracted by HCl at 10%. The aqueous phase is washed in ether, neutralized with NaOH at 10%, then extracted with ether. After evaporation of the solvents, a red oil is obtained, which is distilled in vacuo.
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][S:15]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([CH:8]([CH2:14][S:15]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:16])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C1CCCCC1
Agent: Cl
Product: O=C(O)C(Cc1ccccc1)CS(=O)(=O)C1CCCCC1
Yield: 37.5 %

Procedure:
3.2 g of ethyl 2-(R,S)-benzyl-3-cyclohexylsulfonylpropionate are refluxed in 50 ml of 5 N HCl for 8 hours. The mixture is extracted with dichloromethane, and the extract is dried with Na2SO4. The concentration results in 1.1 g of the title compound as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=1)[CH2:7][NH:8]C(=O)OC(C)(C)C)([CH3:3])[CH3:2].CNS(C)(=O)=O>>[NH2:8][CH2:7][C:6]1[CH:16]=[C:17]([CH:18]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)[CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(CNS(C)(=O)=O)c1
Agent: CNS(C)(=O)=O
Product: CC(C)c1cc(CN)cc(CNS(C)(=O)=O)c1

Procedure:
N-(3-(aminomethyl)-5-isopropylbenzyl)methanesulfonamide was synthesized from the tert-butyl 3-isopropyl-5-(methylsulfonamidomethyl)benzylcarbamate following the general procedure as described above for the N-methyl methylsulfonamide.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.O>CN(C)C=O.C(N(CC)C(C)C)(C)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:7][CH2:8][C:9]3[S:1][C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:4]=3[CH2:5]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2c(s1)CCNC2
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)CCN(C(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.237 g, 1.12 mmol), 4-chlorobenzoic acid (0.228 g, 1.46 mmol) in N,N-dimethylformamide (6 mL) was added a solution of fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.444 g, 1.68 mmol) in N,N-diisopropylethylamine (0.6 mL). The reaction solution was then stirred overnight at room temperature. Water was then added and the mixture was extracted into ethyl acetate. The organic layer was washed with brine and evaporated. Purification of the residue obtained on silica gel (0-10% ethyl acetate/DCM) afforded a sticky white solid (208 mg, 53%). LCMS (FA) ES+ 350.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH:2]1([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N+:6]([O-:8])=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCC1
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1OC1CCC1

Procedure:
In a similar manner as in Example 1, bromocyclobutane was reacted with o-nitrophenol to yield 2-cyclobutoxynitrobenzene; which was reduced to the corresponding aniline; reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1Cl
Reactant: CC(=O)C=C=O
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 2-chloro-N1,N1-dihexylbenzene-1,4-diamine (3.11 g, 10 mmol) in toluene (50 mL) was added acetyl ketene (1.68 g, 20 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo to give the title compound as blackish oil (3.94 g, 100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H-].[Na+].CI.[C:36](OCC)(=O)C>C1COCC1>[CH3:36][N:23]([C@@H:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (200 mg, 0.470 mmol) (Preparation description in Example 2, Part D) in THF (4 mL) at 0° C. was added NaH (37.6 mg, 0.940 mmol). The reaction was stirred at 0° C. for 30 min then MeI (0.044 mL, 0.705 mmol) was added. The reaction mixture was then stirred at 0° C. for 16 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers and washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether: ethyl acetate mobile phase to afford (S)-tert-butyl methyl(4-methyl-1-(6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)pentan-2-yl)carbamate (180 mg, 0.409 mmol, 87% yield) as a yellow solid. LC/MS (ESI) m/e 440.4, [(M+H)+, calcd for C25H34N3O4, 440.3]; LC/MS retention time (method I): tR=2.4 min.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCCSCCCBr
Reactant: CCNCC(O)COc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CC)CC(O)COc1ccc(C#N)cc1

Procedure:
4.7 g of 4-[3-(ethylamino)-2-hydroxypropoxy]-benzonitrile, 4.5 g of 1-bromo-3-(propylthio)-propane and 5.8 g potassium carbonate were mixed in 50 ml isopropanol and refluxed over night. The mixture was filtrated and evaporated. The residual oil 8.3 g was separated by column chromatography. Yield 4.9 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:29]2[C:30]3[C:25](=[C:24]([Cl:23])[CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (1.0 g, 3.15 mmol) in acetonitrile (40 ml) were added 5-chloronaphthalenecarboxylic acid (651 mg, 3.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (725 mg, 3.78 mmol) and 1-hydroxybenzotriazole hydrate (482 mg, 3.15 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (200 ml), and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (1.04 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14]C(=O)C.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester (1.02 g in 15 mL methanol) was added 1 mL of conc. sulfuric acid and the mixture heated to reflux on an oil bath. After 1 hour, the mixture was concentrated in vacuo and the resulting solid dissolved in 200 mL ethyl acetate. This was then washed with 10% sodium bicarbonate (2×100 mL) and brine (100 mL) and the organics dried over magnesium sulfate. The concentrate was recrystallized from methanol to give the title compound (0.82 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>O>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[NH:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: Cc1cccc(C)c1N
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Procedure as described for Amidine I using the following amounts: 6.15 mL of 2,6-dimethylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was deep red. Addition of water yielded a yellow solution with suspended solid. Solution was filtered, taken to dryness, resuspended in 100 mL of pentane and stirred vigorously for 1 hour. The resulting white solid was filtered, washed with 10 mL of pentane and dried in vacuo yielding 11.19 g (90%) of white powder. 1H NMR (400 MHz, CDCl3): 7.83 (d, 2H), 7.26 (d, 2H), 7.05 (d, 2H), 6.89 (t, 1H), 4.54 (s, 2H), 2.42 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[I-:11].[Na+]>CC(C)=O>[I:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCCCCCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCCCCCCCI
Yield: 89.5 %

Procedure:
A mixture of 8-chlorooctan-1-ol (25 g, 152 mmol) and sodium iodide (125 g, 834 mmol) in acetone (500 ml) was heated at reflux overnight. The mixture was filtered to remove precipitated sodium chloride, the filtrate was evaporated in vacuo, and the residue partitioned between water (200 ml) and ether (200 ml). The ether layer was separated, washed with 1M sodium thoisulfate solution (200 ml), and dried over anhydrous magnesium sulfate. Filtration, and solvent removal in vacuo, afforded 8-iodooctan-1-ol as a colorless oil (34.85 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:29]1[C:25]2[CH:26]=[CH:27][C:28]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH:33]3[CH2:34][CH2:35][N:36]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:37][CH2:38]3)[C:24]=2[CH:32]=[CH:31][CH:30]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 106.7 %

Procedure:
0.64 gram (4.03 millimoles) of p-fluorobenzoyl chloride, 1.84 grams (18.2 millimoles) of triethylamine, 0.22 gram (1.82 millimoles) of 4-dimethylaminopyridine was added at ambient temperature to a solution of 1.00 gram (3.63 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine in 40 milliliters of dry methylene chloride while protected from atmospheric moisture and the mixture stirred for a total of about 50 minutes. About 10 grams of ice was added to the reaction mixture to quench the reaction and the resulting biphasic mixture stirred and allowed to warm to room temperature. The aqueous and organic phases were separated and the organic phase washed successively with 5 percent hydrochloric acid, aqueous bicarbonate and brine. The washed solution was dried over magnesium sulfate, the drying agent then filtered off and the solvent vaporized in vacuo to obtain 1.54 grams of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(p-fluorobenzoyl)piperidine residue which crystallized in a few hours at ambient temperature. Recrystallization from toluene produced white needles. The product had a melting point of 150°-151° C. Elemental analyses indicated presence of solvent of crystallization; the results calculated for 1 mole of toluene of crystallization were as follows:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[CH:19]=[C:18]([C:20]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:24][CH2:23][CH2:22][O:21]2)[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:35])[CH3:34])=O>COCCOC>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([C:18]3[CH:19]=[C:14]4[C:15](=[CH:16][CH:17]=3)[NH:32][C:33](=[O:35])[CH:34]=[C:12]4[C:11]3[CH:36]=[CH:37][CH:38]=[C:9]([O:8][CH3:7])[CH:10]=3)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cccc(-c2cc(=O)[nH]c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 123 %

Procedure:
Potassium tert-butoxide (33 g) was added portionwise at room temperature to a solution of interm. (7-d) (36.4 g) in 1,2-dimethoxyethane (350 ml) and the mixture was stirred at room temperature overnight. The mixture was hydrolized and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 43 g (100) of 6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2(1H)-quinolinone (interm. 7-e).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10](Br)=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(Br)cc2cc(C(C)=O)oc12
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cccc2cc(C(C)=O)oc12
Yield: 86.3 %

Procedure:
A mixture of 80.1 g of 2-acetyl-5-bromo-7-ethylbenzofuran, 37.5 g of triethylamine and 5 g of 5% palladium-on-carbon in 1300 ml of methanol was hydrogenated at room temperature and atmospheric pressure until 1 molar equivalent of hydrogen had been absorbed. The catalyst was filtered off and the filtrate evaporated to dryness. The residual solid was dissolved in ethyl acetate, the resulting solution washed with water and with brine and dried over anhydrous sodium sulphate. The sodium sulphate was then filtered off and the filtrate evaporated under reduced pressure. The residual solid was crystallized from petroleum ether (boiling range 60°-80°C) to give 48.7 g of 2-acetyl-7-ethylbenzofuran as a white crystalline solid of melting point 59°-60°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[S:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH:39][C:18]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[N:15][S:16][C:17]=3[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[O:20])[CH2:34][O:33]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(Br)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (584 mg, 1.59 mmol) and diisopropylethylamine (0.82 mL, 4.77 mmol) in DMF (6 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (468 mg, 3.18 mmol), EDCI (611 mg, 3.18 mmol) and HOBt (430 mg, 3.18 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 50% to 100%, TBME in cyclohexane) to afford the title compound as a yellow oil (370 mg, 47%). LCMS (method B): RT=3.96 min, [M+H]+=496/498.