Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Te:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].[K+].O.[OH-].[Na+]>CO.ClCCl.CCOCC>[Te:15]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([Te]c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Oc1ccc([Te]c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Silyl ether 4b (54.2 g, 0.1 mol) was taken up in methanol (200 mL) in a 500 mL round bottom flask. Potassium fluoride (11.6 g, 0.2 mol) was added, and the reaction mixture was heated to reflux for 1.5 h under argon. After the reaction mixture was cooled to room temperature, it was poured into rapidly stirring water (1.2 L), using additional methanol (20 mL) to facilitate the transfer. The pH was adjusted to 14 with 10% NaOH (approx. 40 mL), and the reaction mixture was filtered through Celite diatomaceous earth. The filtrate was transferred to a separatory funnel and washed twice with dichloromethane. The aqueous layer was transferred to a 2 L Erlenmeyer flask in an ice bath, and 25% aq. acetic acid was added to pH 6, resulting in formation of a cream-colored precipitate. The product was isolated by filtration, washed with water, and air dried, to give the crude product (29 g). It was adsorbed onto flash silica gel (150 mL) using ether. Vacuum chromatography on 1 L flash silica gel, eluting with dichloromethane then 1:4 ethyl acetate:dichloromethane gave the pure product. Trituration with dichloromethane gave, in two crops, pure 4c as a yellow solid (24 g, 76%). 1H NMR (CDCl3, 5 drops DMSO) d 8.77 (2H, s), 7.29 (4H, d, J=8.4), 6.47 (4H, d, J=8.4).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:11])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCCCC(=O)O
Product: CC(=O)c1ccc(OCCCC(=O)O)c(C(=O)NCCN(C)C)c1
Yield: 14.9 %

Procedure:
A sample of 0.140 g (0.50 mmol) of 5-acetyl-2-(3-carboxypropoxy)-benzoic acid, methyl ester (Example 19) is heated on a steam bath, under dry conditions with 5.49 mL (50.0 mmol) of N,N-dimethylethylenediamine for 5 hours. The mixture is allowed to cool for 20 hours to ambient temperature and evaporated under vacuum at 55° C. The brown gum produced is triturated with ether, and the remaining residue taken up in water and acidified with hydrochloric acid. This is then extracted with ethyl acetate, and the aqueous solution is evaporated under vacuum, leaving a gum. It is next triturated with hot chloroform and this solution is evaporated to give a brown glass. This is chromatographed on a preparatory silica gel plate which is eluted with a 9/1 mixture of chloroform to methanol. The product band is cut from the plate, triturated with the above solvent mixture, filtered, and evaporated leaving 0.025 g (15%) of 5-acetyl-2-(3-carboxypropoxy)-N-(2-dimethylaminoethyl)-benzamide as a light brown gum: MS (FAB) m/e 337.1753 Δ=+0.9 mmμ (M+ +H), 359 (M+ +Na). 1HNMR (CDCl3) is consistent with the desired product.
Reaction SMILES: C([NH:4][CH:5]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)[C:6]1[S:10][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[N:8][C:7]=1[CH3:15])(=O)C.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[NH2:4][CH:5]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)[C:6]1[S:10][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[N:8][C:7]=1[CH3:15]
Reactant: CC(=O)NC(c1cc(C)ccn1)c1sc(NC(=N)N)nc1C
Agent: Cl
Solvent: CO
Product: Cc1ccnc(C(N)c2sc(NC(=N)N)nc2C)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(5-(acetylamino-(4-methylpyridin-2-yl)-methyl)-4-methylthiazol-2-yl)guanidine (176 mg) in methanol (8.8 ml) was added hydrochloric acid (6 N, 4.6 ml), and the mixture was stirred at 90° C. for 4 hours. The mixture was evaporated under reduced pressure. The residue was recrystallized from ethanol to give N-(5-(amino-(4-methylpyridin-2-yl)methyl)-4-methylthiazol-2-yl)-guanidine trihydrochloride (141 mg).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[F:34][C:35]([F:40])([F:39])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
2,2,2-Trifluoro-1-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-ethanone was prepared according to General Procedure J by the reaction of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59) with trifluoroacetic acid, followed by reaction of the resulting amine with trifluoroacetic anhydride (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.10-2.16 (m, 4H), 3.55-3.65 (m, 1H), 4.00-4.04 (m, 1H), 4.41-4.44 (m, 1H), 5.18-5.24 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=470.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:28])([C@@H:14]([C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[CH3:29][Mg]Br.[Cl-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:28])([C@@H:14]([C@@:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)([OH:22])[CH3:29])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C(=O)c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2[C@](C)(O)c1cccs1
Yield: 49 %

Procedure:
To a stirred solution of the above ((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(thiophen-2-yl)methanone was added methylmagnesium bromide solution (3 M in diethyl ether, 2 mL, 6 mmol) dropwise at −78° C. under argon. The reaction mixture was then stirred at RT for 2.5 hr before saturated aqueous ammonium chloride solution (6 mL) was added slowly with water bath cooling. The mixture was extracted with ethyl acetate (3×5 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (10-100% ethyl acetate in hexanes) gave (S)-1-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-(thiophen-2-yl)ethanol (58 mg, 0.14 mmol, 49% yield for steps (h)+(i)+(j)) as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24].C(N(CC)CC)C.Cl>ClCCl>[O:11]=[C:12]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24]
Reactant: CCCCCCCCCCC(O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(=O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.41 mmol) in dichloromethane (3 ml) -78° C. was added dimethylsulfoxide (0.063 ml, 0.82 mmol), and over 5 minutes, 1-(10-hydroxyeicosyl)-3,7-dimethylxanthine (0.135 g, 0.28 mmol) in dichloromethane (2 ml). The reaction was stirred at -78° C. for 30 minutes and after the addition of triethylamine (0.23 ml, 1.64 mmol) allowed to warm to 25° C. over 30 minutes. Hydrochloric acid (1.0M, 10 ml) and dichloromethane (5 ml) were added, the organic phase separated and the aqueous phase washed with dichloromethane (10 ml). The organic portions were combine and dried over magnesium sulfate. Evaporating the solvent left a slightly yellow solid, which upon purification by chromatography (silica, ethyl acetate) produced 0.110 g of 1-(10-oxoeicosyl)-3,7-dimethylxanthine as a white solid (85% yield).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][N:21]2[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1ccc(NCc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: Cc1ccc(N2Cc3ccccc3P2(=O)c2ccccc2)cc1
Temperature: 26 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.9 g, 0.061 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzyl-4-toluidine (5.9 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. The suspension containing the dilithio compound was stirred for 4 hours at 26° C. and then cooled to 0° C. A solution of phenylphosphonic dichloride (6.25 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension and the resulting mixture was stirred for 1.5 hours at 26° C. The reaction was quenched with the rapid addition of 6 ml. of acetic acid. The mixture was concentrated in vacuo and the resulting residue partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried over sodium sulfate and concentrated in vacuo to yield a brown-green glass. The brown-green glass was crystallized from ethyl acetate to yield light green plates which were recrystallized from toluene to yield 1-phenyl-2-(4-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.9 g, 20% yield) as white crystals having a melting point of 197°-199° C. and the following analysis:
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20](C(=O)C(F)(F)F)=[CH:19][CH:18]=2)[N:7]=1)=[O:4].[C:31](OC(=O)CC)(=O)[CH2:32]C>CN(C)C1C=CN=CC=1.O>[C:17]1([N:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:31][CH3:32])=[N:7]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Reactant: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(c2ccccc2)C1

Procedure:
A mixture of 10.0 g. of 3-amino-1,5-diphenyl-2-pyrazoline (prepared in Example 4), 30.0 ml. of propionic anhydride and 500 mg. of 4-dimethylaminopyridine is heated on a steam bath for 3 hours. The mixture is poured into water to separate an oil. The oil crystallizes and the solid is collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate then is columnized and recrystallized twice as for Example 26 (A) to give 6.0 g. of the product of the Example as colorless plates, m.p. 148.0°-148.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1.O.O.Cl[Sn]Cl.Cl.C([O-])(O)=O.[Na+]>CO.ClCCl.O>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[C:4]([CH:3]=1)=[N:8][S:7][N:6]=2
Reactant: O=[N+]([O-])c1cc2nsnc2cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1cc2nsnc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A solution is prepared by dissolving a compound (2) (16.8 g, 0.0779 mol) in methanol (800 mL), and SnCl2.2H2O (87 g, 0.389 mol, 5.0 eq), water (80 mL) and 1N HCl (30 mL) are sequentially put into the solution. The reactant is agitated and reflowed overnight, cooled down to room temperature (24° C.), and condensed under a reduced pressure. The condensate is dissolved in dichloromethane, neutralized with a saturated NaHCO3 aqueous solution, and then passed through Celite. An organic layer is dried and condensed under a reduced pressure so as to obtain a yellow solid-phase compound (3) (13.8 g, yield: 95%). 1H NMR (400 MHz, CDCl3): δ ppm 7.99 (s, 1H), 7.14 (s, 1H), 4.54 (br s, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]=[CH:37][N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:4]=4)[CH:37]=[N:38][CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1
Reactant: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(3-phenyl-propoxy)-benzonitrile from step 3 (35 mg, 0.13 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (70 mg, 0.13 mmol) in CH2Cl2 (650 μl) was added DIEA (50 μl, 0.27 mmol) followed immediately by the addition of Tf2O (33 μl, 0.19 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (650 μl) and heated to 60° C. for 14 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:32]([O:35][CH3:36])[O:33][CH3:34])=[N:9][C:10]2[N:11]([C:17](=[O:31])[NH:18][C:19]3[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:37][NH2:38]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:29]([C:22]1[C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:38][CH3:37])=[C:8]([CH:32]([O:33][CH3:34])[O:35][CH3:36])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:31])=[N:20][CH:21]=1)#[N:30]
Reactant: CN
Reactant: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 167, 2.59 g, 4.98 mmol) in THF (83 ml) was added methylamine 2 M in THF (37.4 ml, 74.70 mmol) at ambient temperature and the reaction mixture was stirred at room temperature for approximately 4 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated to yield the title compound as a light yellow solid. (UPLC-MS 3) tR 0.88 min, ESI-MS 455.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 14.00 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 5.51 (s, 1H), 4.88-4.79 (m, 1H), 4.06-4.01 (m, 2H), 3.86 (s, 2H), 3.50 (s, 6H), 2.88-2.80 (m, 2H), 2.49 (s, 3H), 2.03-1.96 (m, 2H), 1.43 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.COC1C=CC(C[NH2:20])=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:20])[CH:6]=[CH:5]2
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: Nc1ccc2cc(Br)ccc2n1
Temperature: 140 °C

Procedure:
6-Bromo-2-chloro-quinoline (3.34 g, 13.8 mmol) was dissolved in p-methoxybenzylamine (5 mL) and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography, and the isolated material was refluxed in TFA (6 mL) for 1 hour. The mixture was concentrated and purified by silica gel chromatography to give the desired product, 8a.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10](N)[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.CO>[CH2:10]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCNCC1
Reactant: CCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCN1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a suspension of 4-piperidone hydrochloride monohydrate (20.6 g) and n-butylamine (25.0 g) in methylene chloride (300 ml) was added triethylamine (63 ml), and the mixture was stirred at room temperature for 12 hours. Methanol was further added to the reaction solution, and the solution was made uniform. To the solution were added water (7 ml) and anhydrous potassium carbonate (21.1 g), and the mixture was stirred for 30 minutes. The reaction solution was filtered off with Celite, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (13.0 g) as a yellow oily substance. Yield=62%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(N(CC)CC)C>[Cl:38][C:34]1[CH:33]=[C:32]([C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
0.25 g of p-methoxybenzoyl chloride were added to 10 ml of a methylene chloride solution containing 0.529 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) and 0.41 ml of triethylamine, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was then worked up and purified as described in Example 68 to give 0.682 g of the title compound as a powder.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(=O)([O-])O.[Na+].C1COCC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([C:17]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CNC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.1 %

Procedure:
To a mixture of azetidin-3-ol hydrochloride (200 mg), saturated aqueous sodium hydrogen carbonate solution (2 mL) and THF (2 mL) was added benzoylchloride (132 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]=1)[C:15]([OH:17])=O.[CH3:35][NH:36][CH:37]([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([N:36]([CH3:35])[C:15](=[O:17])[CH:14]([CH3:13])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]=1)([CH3:39])[CH3:38]
Reactant: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reactant: CNC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)N(C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (1.65 g) is added to a stirred solution of dextrorotatory α-methyl-2-phenyl-4-quinazolinepropanoic acid (2 g) in tetrahydrofuran (20 cc). The mixture is stirred for one hour at room temperature (until the evolution of gas has ceased) and N-methylisopropylamine (1.03 cc) is then added. The mixture is stirred for three days at room temperature (approximately 20° C.), then heated under reflux for 6 hours, N-methylisopropylamine (1.03 cc) is added and the mixture is heated under reflux for a further 12 hours. The treatment is then similar to that described in Example 85. After two recrystallizations in acetonitrile, laevorotatory N-isopropyl-N-methyl-α-methyl-2-phenyl-4-quinazolinepropanamide (19 g), m.p. 171.2° C., is isolated; αD at 0.5% in EtOH at 23° C.=-12.1°±2°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=2[O:35][CH3:36])=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2ccc(C(=O)NCCCCCC(=O)Nc3ccccc3N)cc2C)c(OC)c1
Yield: 66 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 2,4-dimethoxyphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (38 mg, 66%).