Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC1(C([O-])=O)C(COC(=O)C2C=CC=CC=2)=CC=C(C2C=CC=CC=2)C1OCC1C=CC=CC=1)(=O)C1C=CC=CC=1>>[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cccc(-c2cccc(O)c2)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C(OCC1=CC=C(c2ccccc2)C(OCc2ccccc2)C1(COC(=O)c1ccccc1)C(=O)[O-])c1ccccc1
Product: CCOC(=O)c1cccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 1 g (4.1 mmol) of ethyl 3′-hydroxybiphenyl-3-carboxylate with 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, 2.1 g (85%) of ethyl 3′-[3,4-bis(benzoyloxymethyl)benzyloxylbiphenyl-3-carboxylate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Cl)c1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of 6.30 g (19.4 mmol) 4-[(3-chlorophenyl)amino]-6-nitro-3-quinolinecarbonitrile, 300 ml ethanol, and 21.9 g (97 mmol) SnCl2 dihydrate were heated to reflux under N2. Removed heat at 2.5 hours, added ice water and made basic with sodium bicarbonate. Stirred for 2 hours and extracted with chloroform. Dried organic layer with sodium sulfate, filtered, stripped solvent and dried residue in vacuo, giving 5.74 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=295.1, 297.1.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].CC(C)(OC([N:47]1[C:51]2[CH:52]=[CH:53][C:54]([CH:56]=O)=[CH:55][C:50]=2[N:49]=[N:48]1)=O)C>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:56]/[C:54]1[CH:53]=[CH:52][C:51]2[NH:47][N:48]=[N:49][C:50]=2[CH:55]=1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(C=O)ccc21
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2[nH]nnc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.5 mL, 3.97 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 1.00 g, 1.89 mmol) in tetraliydrofuran (3 mL) at −20° C. After 10 min, a solution of 1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazole-5-carboxaldehyde (Example 40; 467 mg, 1.89 mmol) in tetrahydrofuran (3 mL) was added. The solution was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1:1; 4 mL). After the solution was stirred at room temperature for 2 h, the solvent was evaporated and the residue co-evaporated with toluene (2×5 mL) to remove residual trifluoroacetic acid. Ethyl acetate (20 mL) was added and the solution was washed with 5% sodium bicarbonate solution (20 mL). After the aqueous layer was back extracted with ethyl acetate, the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The residual material was chromatographed over silica gel (5-10% methanol/dichloromethane) to give (Z)-3-(1H-benzotriazol-5-yl)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (690 mg, 66% yield) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[O:20][C:16]([CH:17]([CH3:19])[CH3:18])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)C(C)C
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C(C)C
Yield: 60.7 %

Procedure:
7.0 g of ethyl 3-(4-fluorobenzoylamino)-3-isobutyrylpropionate, 35 ml of dimethylformamide and 5.7 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.0 g of ethyl 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetate are thereby obtained. Yield: 60.6%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=1)[C:5]([NH:7][C:8]1[S:12][N:11]=[C:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31](Cl)=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=3)[C:5]([NH:7][C:8]3[S:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[O:6])=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: Cc1nsc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Reaction time: 10 h
Yield: 17.7 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (237 mg, 0.77 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (151 mg, 0.77 mmol) and potassium carbonate (213 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and at 160° C. for 10 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (64 mg).
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])(O)=O.[Na+].O>O1CCOCC1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cn(C2CCCCO2)nc1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (1 g, 0.00326 mol) in 1,4-dioxane (30 ml) were added 4-nitrophenylboronic acid (0.654 g, 0.00392 mol) and sat. NaHCO3 solution (8 ml). The reaction mixture was degassed using argon for 0.5 h. Tetrakis(triphenylphosphine) palladium (0.188 g, 0.000163 mol) was added under an argon atm. and the resultant suspension was heated for 8 h at 90° C. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (100 mL×3). The combined extracts was washed with brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by SGC using hexane:EtOAc (0%-40%) as eluent to obtain 3-(4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (550 mg, Yield 56%). LCMS (ESI): RT=2.32 min, m/z=302.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]1([C:12]2[N:17]=[C:16]([C:18]([NH:20][C:21]3[CH:29]=[N:28][CH:27]=[CH:26][C:22]=3[C:23](O)=[O:24])=[O:19])[C:15]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[N:17]=[C:16]([C:18](=[N:20][C:21]3[CH:29]=[N:28][CH:27]=[CH:26][C:22]=3[C:23]([N:5]3[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[O:24])[OH:19])[C:15]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(C(=O)c2ccncc2N=C(O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 13 %

Procedure:
According to the general method described above (step 3), reaction of 3-dimethylamino-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (13%) as sticky yellow solid
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Cl-].[NH4+].O.C(O)C>[Fe].COCCO>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=3)[CH2:13][CH2:12]2)=[O:24])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: COCCO
Product: Nc1ccc(C(=O)N2CCC(C(=O)c3ccc(F)cc3)CC2)cc1
Yield: 82.8 %

Procedure:
4-(4-Fluorobenzoyl)-1-(4-nitrobenzoyl)piperidine (4.75 g) was added slowly to a stirred mixture of iron powder (4.75 g), ammonium chloride (0.57 g), water (28.5 ml), ethanol (38 ml) and methyl cellosolve (76 ml) under reflux. The resulting mixture was stirred under reflux for 30 minutes and filtered. The filtrate was concentrated in vacuo. The residue was diluted with saturated sodium bicarbonate solution and extracted twice with methylene chloride. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was recrystallized from ethanol to give 1-(4-aminobenzoyl)-4-(4-fluorobenzoyl)piperidine (3.6 g) as pale yellow crystals.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]1[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18])=[O:15])=O)(C)(C)C>C(O)C>[ClH:1].[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]1[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Agent: Cl
Solvent: CCO
Product: NCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
Hydrogen chloride gas was introduced to the solution of 1-[N-[3-(t-butoxycarbonylamino)propyl]carbamoyl]-5-fluorouracil (5.1 g.) which was prepared in Example 20 in ethanol (30 ml.) until precipitates were appeared for 1 hour with stirring under cooling with ice. The reaction mixture was further stirred for 1 hour at ambient temperature, and diethyl ether (100 ml.) was added therein. The resultant crystalline precipitates were collected by filtration and were dried over phosphoric anhydride to give 1-[N-(3-aminopropyl)carbamoyl]-5-fluorouracil hydrochloride (1.5 g.).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C(O)C>[N:12]1([CH2:2][C:3]2[NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CCO
Product: c1ccc2[nH]c(Cn3ccnc3)nc2c1
Yield: 13.2 %

Procedure:
A solution of 2-chloromethyl-1H-benzimidazole (4.85 g) and imidazole (9.9 g) in ethanol (37 ml) was stirred at 70° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g) with a mixture of methanol and dichloromethane (5:95) as an eluent to afford an oil, which was crystallized from ethyl acetate. Recrystallization from a mixture of methanol and diethyl ether to give 2-(imidazol-1-yl)methyl-1H-benzimidazole (0.76 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[F:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[F:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(F)c1

Procedure:
2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 10 mL trifluoroacetic acid and stirred at ambient temperature for 1 hour. Concentrated solution, redissolved in 100 mL CHCl3, repeated CHCl3 co-concentration 3 times to yield title compound as an oil. (quant. yield) APCI (AP−): 361.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([OH:13])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:13]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C)c1cc(F)ccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc(F)ccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.64 g) is added to a solution of (2-dimethylamino-4-fluorophenyl)acetic acid (2 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.3 g) and triethylamine (2.8 g) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.1 g) is obtained in the form of white crystals melting at 164° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[N:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2ccnnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccnnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridazin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.065 mmol), β-alanine (576 mg, 6.5 mmol) and NaOMe solution (10 mL, 5.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 522.35 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=3)[CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]=[C:8]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=1)[CH:9]=[C:10]2[N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CNc1nccc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c3cc(OC)ccc3c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nccc(-c2cc(N3CCNCC3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Tert-butyl 4-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)piperazine-1-carboxylate was dissolved in dichloromethane (25 ml) and 4.0 M HCl in dioxane (10 ml) was added to the reaction. The reaction was allowed to stir at room temperature for 15 hours and 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-methylpyrimidin-2-amine hydrochloride 112 was isolated by filtration as a yellow solid (1.27 g). LC/MS (m/z): 350 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH:4]=[C:5]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=[O:20])=[CH:15][C:16]=3[C:17](=[O:18])[N:8]2[CH2:7][CH2:6]1.[CH2:26](I)[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH:4]=[C:5]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([O:21][CH2:26][CH3:27])=[O:20])=[CH:15][C:16]=3[C:17](=[O:18])[N:8]2[CH2:7][CH2:6]1
Reactant: CCI
Reactant: Cc1ccccc1C=C1CCn2c1nc1ccc(C(=O)O)cc1c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc3n(c(=O)c2c1)CCC3=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid (1 g) was reacted with ethyl iodide (0.93 g) and anhydrous K2CO3 (0.83 g) in dimethylformamide (10 ml) under stirring at room temperature for 16 hours. After dilution with ice water the precipitate was filtered and washed with water until neutral: crystallization from chloroform-ethanol gave 0.9 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid, ethyl ester, m.p. 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+].ClOC(C)(C)C.[C:34]1([C:40]#[CH:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH+:9]1[CH:41]=[C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:11]([C:12]2[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])[NH:10]1
Reactant: C#Cc1ccccc1
Reactant: Fc1cccc(F)c1N=NNc1c(F)cccc1F
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Product: Fc1cccc(F)c1N1N[NH+](c2c(F)cccc2F)C=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of triazene 8d (808 mg, 3 mmol) and anhydrous potassium hexafluorophosphate (750 mg, 4 mmol) in dry dichloromethafne (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. Stirring is pursued at −78° C. for 30 min, and phenylacetylene 9a (660 μL, 6 mmol) is added. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10da as an off-white solid (0.79 g, 51%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an chloroform solution of 10da. 1H-NMR (CD3CN, 300 MHz): δ=9.23 (s, 1H), 7.94-7.83 (m, 2H), 7.70-7.66 (m, 1H), 7.63-7.53 (m, 4H), 7.47 (t, J=7.9 Hz, 2H), 7.37 (td, J=8.0, 3.3 Hz, 2H). 13C-NMR (CD3CN, 75 MHz): δ=157.7 (d, J=258 Hz), 157.0 (d, J=257 Hz), 147.3, 137.6 (t, J=10 Hz), 136.9 (t, J=10 Hz), 133.9, 133.1, 130.9, 130.0, 122.1, 114.9 (d, J=21 Hz), 114.7 (d, J=22 Hz), 113.7 (t, J=8 Hz), 111.9 (t, J=8 Hz). 19F-NMR (CD3CN, 282 MHz): δ=−72.0 (d, J=705 Hz, 6F), −117.4 (2F), −119.2 (2F). HR-MS (ESI): Calcd. for C20H12F4N3 [M+]: 370.0962. found 370.0967.
Reaction SMILES: CCCCCCC=CCCC.[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CN(C=O)C.CCCCC>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[S:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH3:32]
Reactant: SCc1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
]undec-7-ene (DBU) is added dropwise at 20° C., under argon, to a solution of benzenemethanethiol (11.72 ml; 100.0 mmol) in anhydrous DMF (20.0 ml). After 0.5 hour at 20° C., the reaction mixture is cooled to 0° C. and tributyltin chloride is added dropwise. The mixture is allowed to warm to room temperature and stirring is continued for 5 hours. The reaction mixture is taken up in pentane (400 ml), washed with water (3×300 ml) and brine (100 ml), washed with sodium sulphate, filtered and then concentrated under reduced pressure. 39.0 g of tributyl[(phenylmethyl)thio]stannane are obtained in the form of a colourless oil, which is used without further purification in the following step.