Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([I:20])[CH3:19]>>[IH:20].[CH2:18]([NH+:6]1[C:7]2[C:15]([N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:16][C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:19]
Reactant: CCI
Reactant: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Product: CC[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Product: I
Temperature: 135 °C
Yield: 86.9 %

Procedure:
A suspension of quindoline (1 g, 4.6 mmol) from Example 2 and ethyl iodide (3 mL, 37.7 mmol) was heated in a bomb at 135° C. for 15 hours. The excess ethyl iodide was removed and the resulting brown precipitate was collected, washed with ether and dried, yielding 1.5 g (87.7%) of 5-ethylquindolinium hydroiodide. Recrystallization from water afforded bright yellow crystals of 5-ethylquindolinium hydroiodide, mp 256° C. [lit 222-223° C. (Fichter, F.; Boehringer, R. Ber 1906, 3941)]; 1H NMR (DMSO-d6) δ 12.93 (s, 1H, NH), 9.32 (s, 1H, H11), 8.78 (d, J=9.2, 1H, H4), 8.66 (d, J=8.4, 1H, H6), 8.60 (d, J=8.0, 1H, H1), 8.18 (t, J=7.6, 1H, H3), 7.95 (dd, J=8.0, J=7.2, 2H, H2 and H8), 7.87 (d, J=8.4, 1H, H9), 7.55 (t, J=7.6, 1H, H7), 5.55 (q, J=6.8, 2H, NCH2), 1.76 (t, J=7.2, 3H, CH3); 13C NMR (DMSO-d6) δ 145.78, 136.92, 134.34, 133.94, 133.52, 132.71, 130.06, 127.09, 126.42, 125.50, 125.14, 121.81, 117.31, 113.35, 112.80, 47.33, 13.30; MS (EI, m/z) 246 (M+ -1)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[N:2]1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[C:15]([C:14]1[CH:13]=[CH:12][S:11][C:10]=1[NH:9][C:6]([C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:7])(=[O:16])[NH2:17]
Reactant: O=C(Cl)c1cc[nH]n1
Reactant: NC(=O)c1ccsc1N
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 1H-Pyrazole-3-carbonyl chloride (5 mmol) in MeCN (5 mL) is added drop wise to a solution of 2-amino-thiophene-3-carboxylic acid amide (570 mg, 4 mmol), pyridine (0.5 mL, 6 mmol) and DMAP (25 mg, 0.20 mmol) in MeCN (5 mL). The resulting solution is than stirred at 60° C. over 2 days. Next, the mixture is quenched with aqueous NaHCO3. Evaporation of the MeCN gives a suspension that is filtered, the cake is dried, and used as such.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]N(C)C)=[CH:6]1.ClC(OCC)=O.[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][S:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6]1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reaction time: 0.33 h
Yield: 37.9 %

Procedure:
To a stirring solution of methyl 1-(2,4-difluorobenzyl)-3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.906 g, 2.52 mmol) in DCM (20 mL) was added ethyl chloroformate (0.240 mL, 2.52 mmol). The pale yellow homogeneous solution was stirred for 20 minutes. To this stirring solution was added a solution of benzenethiol (0.416 g, 3.78 mmol) and diisopropyl ethylamine (0.814 g, 6.3 mmol) in DMF (10 mL). The reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated in vacuo and purified by flash chromatography yielding a white powder (0.405 g, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 4.01 (s, 3H) 4.27 (s, 2H) 5.32 (s, 2H) 6.74-6.80 (m, 1H) 6.81-6.90 (m, 2H) 7.12 (s, 1H) 7.17-7.24 (m, 3H) 7.26-7.29 (m, 2H) 8.50 (s, 1H) 8.78 (s, 1H). LCMS (APCI, M+H): 425.1.
Reaction SMILES: [CH2:1]([N:17]1[C:21]([CH3:22])=[CH:20][CH:19]([CH3:23])[N:18]1[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[P:25](=[O:29])([OH:28])([OH:27])[OH:26]>>[P:25]([O-:29])([O-:28])([O-:27])=[O:26].[CH2:1]([N+:17]1[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:1]([N+:17]1[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:1]([N+:17]1[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN1C(C)=CC(C)N1C
Reactant: O=P(O)(O)O
Product: CCCCCCCCCCCCCCCC[n+]1c(C)cc(C)n1C
Product: O=P([O-])([O-])[O-]

Procedure:
When 1-hexadecyl-2,3,5-trimethyl-pyrazole methosulfate is treated with a strongly basic ion exchanger (e.g., Amberlite IRA-401), the corresponding quaternary base is released. By adding phosphoric acid, 1-hexadecyl-2,3,5-trimethyl-pyrazolium phosphate is obtained; m.p. 96°-100° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([CH2:20][CH3:21])(O)[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[C:22]1([CH3:29])[C:27]([OH:28])=[CH:26]C=C[CH:23]=1.B(F)(F)F.[CH3:34][CH2:35]OCC>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([CH2:34][CH3:35])([C:20]3[CH:21]=[CH:26][C:27]([OH:28])=[C:22]([CH3:29])[CH:23]=3)[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2cc(C(O)(CC)CC)cc(C)c2o1
Agent: FB(F)F
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)cc(C)c2o1
Yield: 53.6 %

Procedure:
5-(1-Ethyl-1-hydroxy-propyl)-7-methyl-benzofuran-2-carboxylic acid ethyl ester (7.90 g, 27.2 mmol) and o-cresol (5.88 g, 54.4 mmol) and BF3-Et2O (3.86 g, 27.2 mmol) are reacted analogous to Example 1D to give the title compound (5.55 g, 54%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(O)cc2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
267 mg of 5-(4'-t-butyl-dimethylsilyloxy-5,6-dimethoxybiphenyl-3-ylmethyl)-pyrimidine-2,4-diamine (Example 2f)) are dissolved in 6 ml of tetrahydrofuran and treated with 361 mg of tetrabutylammonium fluoride trihydrate. The mixture is stirred at room temperature for 1hr. and subsequently concentrated. The residue is chromatographed on MCl-Gel CHP20P (Mitsubishi Corporation) with water/acetonitrile 4:1. 73 mg (36%) of 5-(4'-hydroxy-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a colourless solid. M.p. 233°.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([S:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].ClC1N2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.C(N(CC)CC)C>CN(C)C=O.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]3[N:15]([C:14]([S:13][C:6]4[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=4)[NH2:3])=[N:18][N:19]=3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: N#CSc1ccc([N+](=O)[O-])c(N)c1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
342 mg of sodium borohydride are added to a mixture of 1.76 g of commercial 3-amino-4-nitrophenyl thiocyanate in 15 cm3 of N,N-dimethylformamide. The reaction is stirred at ambient temperature for 2 h and then 746 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine and 1.25 cm3 of triethylamine are added. The resulting mixture is then heated to 95° C. and then stirred for 1 h at 20° C. After the addition of demineralized water, the mixture obtained is extracted with 3×100 cm3 of ethyl acetate (a small amount of methanol is added due to solubility problems). The organic phases are combined and then dried over magnesium sulphate and concentrated to dryness, so as to give a brown solid which is chromatographed on a 25 g Merck cartridge of silica 15-40 μm (elution with ethyl acetate). 360 mg of 5-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-2-nitroaniline are thus obtained in the form of a green solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(OCc3ccco3)C2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cl
Product: c1coc(COC2CNC2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
1-Chloroethyl chloroformate (534 μL, 4.93 mmol) was added to a solution of 1-benzhydryl-3-(furan-2-ylmethoxy)-azetidine (1.5 g, 4.7 mmol) in dichloromethane (36 mL) at 0° C. The reaction mixture was then heated up to 40° C. and stirred for 2 hours. Ethanol (50 mL) was added and the reaction mixture was stirred for an additional 1 h 30 at 40° C. After concentration to dryness, the crude mixture was triturated in petroleum ether (2×20 mL) to give a yellow oil (558 mg, 74%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(F)c2)sc1C(=O)NCc1ccccc1
Yield: 18 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 18% yield; m.p. 162-165° C.; 1H NMR (CDCl3, 300 MHz) δ 7.64-7.24 (m, 9H), 5.97 (t, J=5.4 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCCCCCCO)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
50.0 g (409 mmol) of 4-hydroxybenzaldehyde and 123.0 g (490 mmol) of 11-bromoundecan-1-ol are dissolved in 400 mL of N,N-dimethylformamide. 113.0 g (819 mmol) of potassium carbonate and 7.0 g (42 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine, concentrated to minimum volume and precipitated in cold heptane. The precipitate is filtered off and washed with cold heptanes. 69.4 g of 4-[(11-hydroxyundecyl)oxy]benzaldehyde are obtained as a white solid (57% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:20][CH:21]([CH3:30])[CH2:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[ClH:45].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:28][C:26]4[CH:25]=[N:24][N:23]([CH2:22][CH:21]([OH:20])[CH3:30])[CH:27]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCCl
Reactant: CC(O)Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(O)Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.160 g, 0.619 mmol) in DCE (5 mL). Add racemic 1-(2-hydroxy-propyl)-1H-pyrazole-4-carbaldehyde (0.175 g, 1.14 mmol) followed by sodium triacetoxyborohydride (0.262 g, 1.24 mmol) and stir at room temperature for 72 hr. Purify via SCX chromatography, followed by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate then 10:90 methanol:ethyl acetate, to give the racemic mixture of the free bases of the title compounds (223 mg, 91%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: ClCC=Cc1ccccc1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CC=Cc1ccccc1
Yield: 63.5 %

Procedure:
In 300 ml of toluene were dissolved 175.4 g of diethylamine and 152.5 g of chloromethylstyrene and the solution was heated to 60°-70° C. for 13 hours. As the reaction progressed, diethylamine hydrochloride precipitated. After filtering off the hydrochloride, the filtrate was washed with water, dried the layer containing toluene with sodium sulfate anhydride, concentrated, and after the addition of 1 g of di-tert-butylcatechol, the mixture was distilled under reduced pressure to provide 120.2 g of diethylaminomethylstyrene as a colorless liquid having a boiling point of 60° C./2 mm Hg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([NH2:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:5][CH:6]([NH:13][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(C)N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCC(C)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise to an ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in THF (100 mL). The resulting mixture was stirred at RT for 1 h, then was diluted with ethyl acetate and washed twice with 10% HCl, twice with sat aq NaHCO3, and then twice with brine. The organic solution was dried (MgSO4), and concentrated to afford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].CS[C:8]([NH2:10])=[NH2+:9].CSC(N)=[NH2+].[CH2:16]([NH2:19])[C:17]#[CH:18]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:16]([NH:19][C:8]([NH2:10])=[NH:9])[C:17]#[CH:18]
Reactant: CSC(N)=[NH2+]
Reactant: C#CCN
Reactant: O=S(=O)([O-])[O-]
Solvent: O
Product: C#CCNC(=N)N
Product: O=S(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a vigorously stirred suspension of 50.11 g. (0.18 moles) of S-methylthiouronium sulfate in 100 ml. of water is added 20 g. (0.36 moles) of propargyl amine under a blanket of nitrogen. The reaction mixture is stirred at room temperature for 4 hours and then warmed slowly to reflux and refluxed for 2 hours. The heat is removed and the reaction mixture allowed to stir at room temperature for 2 days. The mixture is then heated to reflux, filtered and then evaporated to near dryness. The residual oil is triturated in isopropanol and the solid which separates is filtered and dried. This material is then resuspended in 1 l. of boiling methanol and water added dropwise until all of the solid dissolves. The solution is then cooled in an ice bath and the solid which separates is filtered, washed with methanol and dried to give 1-propargylguanidine sulfate (m.p. 200°-201° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:22])[CH:13]=2)[NH:8][C:7]1=[O:23])[CH3:2].[H-].[Na+].[CH2:28]([I:30])[CH3:29]>CN(C)C=O>[IH:30].[CH2:28]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])[C:7]1=[O:23])[CH3:29]
Reactant: CCN(CC)CCN1C(=O)Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)N(CC)c2ccc(Cl)cc2C1c1ccccc1
Product: I
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 1.07 g. of 3-(β-diethylaminoethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 20 ml. of dimethylformamide was added 0.13 g. of 64% sodium hydride, and the resulting mixture was heated with stirring at 60° C (bath temperature) for 1 hour. Thereafter, 0.94 g. of ethyl iodide was added thereto at room temperature, and the mixture was stirred at 100° C (bath temperature) for 4 hours. After cooling, the reaction mixture was poured into 100 ml. of water, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain colorless oily 1-ethyl-3-(β-diethylaminoethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone hydroiodide. This compound was crystallized from ethanol-petroleum benzine to give colorless fine crystals having a melting point of 198°-199° C (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[F:37]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3c(F)c(OC)ccc3c2)cc1
Temperature: -78 °C
Yield: 62.8 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene (1.28 g, 3.72 mmol) in THF (25 mL) at −78° C. was slowly added n-butyl lithium (1.9 mL of 2.5 N in hexanes). The resulting solution was stirred at −78° C. for thirty minutes and a solution of N-fluorobenzenesulfonimide (1.40 g, 4.5 mmol) in THF (10 mL) was added. After 2 additional hr at −78° C., the reaction was warmed to room temperature, poured in water, and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica chromatography (5% THF-hexanes) yielded 0.66 g (63%) of a white solid: Mfp 150–155° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.04 (3H, s), 7.02 (2H, d, J=8.69 Hz), 7.28–7.34 (1H, m), 7.62–7.67 (3H, m), 7.74 (1H, dd, J=1.60 Hz, J=8.79 Hz), 7.93 (1H, s), 8.09 (1H, d, J=8.77 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)cc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 mL was added 3-chloro-5-(trifluoromethyl)benzaldehyde 48 (84.4 mg, 0.404 mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 49, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 49 was eluted at 35% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:12])[C:8]([CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=1[NH:6]2.[CH:27]1([NH:30][C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31]([C:33]2[CH:38]=[C:37]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)=[O:12])[C:8]([CH3:21])=[C:7]4[C:3]=3[C:4]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=3[NH:6]4)[CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:28][CH2:29]1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenylboronic acid using an analogous procedure to that described in the preparation of compound 83. [M+H] calc'd for C30H33N5O2, 496.3; found, 496.5.
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:12](=O)[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]1=2>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:1][NH:2][C:12]1[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[N:3]=1
Reactant: O=C1CCc2ncc3ccccc3c2N1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CNC1=Nc2c(ncc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of anhydrous methylamine (30 ml), 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (5.46 g) and sieve dried tetrahydrofuran (450 ml) was stirred and chilled with ice water, and was treated dropwise over 30 minutes with a preformed complex of titanium tetrachloride (3.0 ml, 5.2 g) and sieve dried tetrahydrofuran (220 ml). The resultant mixture was stirred with cooling for 1 hour, followed by stirring for 3.5 hours at ambient temperature. After standing overnight at ambient temperature the reaction was quenched with water (100 ml) and 10% NaOH solution (30 ml). The suspension was filtered and concentrated to give a biphasic residue (pH 10). The mixture was extracted with dichloromethane (2×200 ml) dried (Na2SO4), filtered and evaporated to dryness (residue wt: 7.66 g). The residue was purified by HPLC (silica gel, eluted with 10% (v/v) methanol in ethyl acetate). The appropriate fractions were concentrated to give 5.1 g of pure product which was recrystallized from toluene (35 ml) to afford 3.56 g of crystals, m.p. 144°-145° C.