Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:15])=[N:3]1.C[N+]1([O-])CCOCC1.CC(O)C>C(#N)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH:14]=[O:15])=[N:3]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CO)cccc2n1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)O
Solvent: CC#N
Product: Cn1cc2c([C@@H]3C[C@H]3C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Trans-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (500 mg, 2.47 mmol), 4 Å molecular sieves (200 mg), 4-methylmorpholine N-oxide (724 mg, 6.18 mmol) and tetra-n-propylammonium perruthenate(VII) (43.6 mg, 0.124 mmol) were dissolved in acetonitrile (25 mL), and the mixture was stirred at room temperature for 2 hr. 2-Propanol was added, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (382 mg, yield 77%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=2[N:14]=1)[CH3:12]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH3:12])[C:13]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[O:19])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:18]
Reactant: CC(=O)Nc1nccs1
Reactant: CC(Cl)c1nc2c(F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Cl)C(=O)Nc1c(F)cccc1C(=O)CC(=O)Nc1nccs1
Yield: 39.2 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 17 g of N-(2-thiazolyl)-acetamide in 340 ml of tetrahydrofuran, 160 ml of butyllithium-hexane solution and 0.06 moles of the product of Step D in 130 ml of tetrahydrofuran were reacted to obtain 8.7 g of 2-[(2-chloro-1-oxo-propyl)amino]-β-oxo-N-(2-thiazolyl)-3-fluoro-benzene propanamide melting towards 170° C.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].S(Cl)([Cl:19])=O.C(Cl)(Cl)Cl>CCCCCC>[Cl:19][CH2:14][CH2:13][N:12]1[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2ccccc2c(=O)n1CCO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1nc2ccccc2c(=O)n1CCCl
Temperature: 25 °C
Yield: 32.8 %

Procedure:
2-ethyl-3-(2-hydroxyethyl)quinazoline-4 (3H)-one (5.00 g; 22.91 mmol) and thionyl chloride (1.672 mL, 22.91 mmol) were added to a 150 mL reactor, together with 60 mL of chloroform. The reaction medium was heated to reflux and for completing the reaction, which was accompanied through CG/MS. After the end of the reaction, 100 mL of hexane were added and the solution was agitated at room temperature in order to precipitate the product. The resulting suspension was vacuum filtered, washed with two portions of hexane and dried, yielding 3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one as a white solid (1.78 g; 7.52 mmol; yield: 32.8%).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:29]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C@@H:30]([OH:40])[CH:31]([OH:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)CC)C>CN(C=O)C>[NH2:2][CH:32]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH:31]([OH:39])[CH:30]([OH:40])[CH2:29][CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or-R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chlorofrom/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12]1=[O:44]>C(Cl)Cl>[O:18]=[C:17]1[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12](=[O:44])[CH:11]1[NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Yield: 35.2 %

Procedure:
A solution of phenyl isocyanate (25.6 mg) in methylene chloride (1 ml) was added to a solution of 2-(3-Amino-2,4-dioxo-5-pyrdin-2-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (100 mg) in methylene chloride (1 ml) and the resultant mixture was stirred at rt for 4 h. The solvents were removed in vacuo and the residue was recrystalised from ethyl acetate to afford the title product (44 mg) as an off-white solid. 1H NMR (300 MHz, CDCl3); 1.03 (2×d, J=7 Hz, 6H), 3.81 (s, 3H), 4.17 (d J=16 Hz, 1H), 4.37 (d, J=16 Hz, 1H), 5.0 (sept, J=7.1 Hz, 1H), 5.40 (d, J=6.3 Hz, 1H), 6.40 (d, J=5.3 Hz, 1H), 6.8-7.3 (m, 17H), 7.80 (br, 1H), 8.42 (d, J=3.9 Hz, 1H).Tlc (10% MeOH, CH2Cl2) Rf=0.53. m/z [MH]+ =593.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][C@@H:13]1[CH3:22].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][C@@H:13]2[CH3:22])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 27, 2.5 g, 15.82 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.72 g, 15.82 mmol) in dichloromethane (200 mL) were added HOBt (2.42 g, 15.82 mmol) and N-methyl morpholine (5.2 mL, 47.46 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.43 g, 28.47 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in petroleum ether) afforded methyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 2.2 g (46%) as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].N12CCCN=C1CCCCC2>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH:18]=[CH2:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CCO1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A warm (35° C.) solution of 2-(1-trifluoromethanesulfonyloxy-ethyl)-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.384 g, 3.284 mmol) in dichloromethane (40 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16.422 mmol). After stirring at 35° C. for 2 h, the reaction was cooled to 0° C. and quenched with hydrochloric acid (1 M, 50 mL). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound as an orange oil which was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 3.13-3.29 (m, 2H), 3.60-3.73 (m, 1H), 3.79 (s, 3H), 3.83-3.92 (m, 2H), 4.24 (d, J=13.1 Hz, 1H), 5.37 (d, J=10.9 Hz, 1H), 5.55 (d, J=17.4 Hz, 1H), 5.84 (dd, J=17.4, 10.9 Hz, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[CH3:9][O:10][C:11](=[O:23])[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=1)[CH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:33][CH:34]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a 2M solution of LDA in THF (5.4 mL, 10.8 mmol) in 300 mL THF cooled to −78° C. was slowly added 4-tertbutylphenyl acetic acid methyl ester (2 g, 9.8 mmol). After stirring for 1 hr at −78° C. a solution of 2.7 g of 1-benzyloxy-4-bromomethylbenzene (Chow and Mak, J. Org. Chem 1997, 62(15), 5116) in THF (10 mL) was added. The mixture was allowed to warm to room temperature overnight. Saturated ammonium chloride was added and the solution extracted with ethyl acetate. The solution was washed with brine, dried over sodium sulfate and concentrated to afford 3-(4-Benzyloxyphenyl)-2-(4-tert-butylphenyl)-propionic acid methyl ester as a yellow oil. TLC: Rf=0.42 hexane/ethyl acetate (8:1). The crude was carried on as is for the next step.
Reaction SMILES: [CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:11])[F:12]
Reactant: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCNC1

Procedure:
A solution of (R)-tert-butyl 3-(N-methyl-2-(trifluoromethyl)benzamido)pyrrolidine-1-carboxylate (1 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 2 hours, concentrated and diluted with water. It was then basified with aqueous NaHCO3 solution till pH=˜9, and extracted with EtOAc. The combined extracts were dried, filtered, and concentrated to give (R)—N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].C(Cl)Cl.Cl>C1COCC1.CCO>[C:30]([N:27]([CH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:16]=1[C:10]1[C:11]([O:14][CH3:15])=[CH:12][CH:13]=[C:8]([C:5]([CH3:6])([CH3:7])[C:4]([OH:33])=[O:3])[CH:9]=1)[CH2:28][CH3:29])(=[O:32])[CH3:31]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)O)ccc1OC)C(C)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 2-{2′-[(acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-2-methyl-propionic acid ethyl ester (0.290 g, 0.63 mmol) in THF (2.6 mL) and EtOH (2 mL) was added 1N aqueous NaOH (1.9 mL), and the reaction was stirred at 50° C. overnight. Analytical LCMS indicated that starting material was still present, so additional 1N aqueous NaOH (1 mL) was added, and the reaction was stirred at 70° C. for 2 hours. Additional 1N aqueous NaOH (1 mL) was added, and the reaction was stirred for another 6 hours. The mixture was worked-up with CH2Cl2 and 1N aqueous HCl, and the organic layer was dried over Na2SO4, decanted, and concentrated. The residue was purified by preparative HPLC to give the title compound. M+H is 438.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Br:17])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([Cl:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
(4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester (1.6 gm, 6.45 mmol) was taken in carbon tetrachloride (13 ml). N-Bromosuccinimide (1.26 gm, 7.09 mmol) was added in one lot followed by benzoyl peroxide (171 mg, 0.7 mmol). The reaction mixture was refluxed for 2 days. The reaction mixture was cooled to room temperature and filtered; filtrate was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide bromo-(4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (2.08 gm) as a gummy mass. The crude material was used as such for further reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][O:10][CH3:11])[CH:7]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(NC(C)C)(C)C.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][O:10][CH3:11])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: COCCn1cc(Br)cc([N+](=O)[O-])c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COCCn1cc(-c2cccc(F)c2F)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Palladium acetate (41.0 mg, 0.18 mmol) was added to a solution of 5-bromo-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one (500 mg, 1.81 mmol), 2,3-difluorophenyl boronic acid (570 mg, 3.61 mmol), diisopropylamine (0.759 mL, 5.41 mmol) and 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt (310 mg, 0.541 mmol), in N,N-dimethylformamide (15 mL) and water (5 mL) and heated to 80° C. After 2 h, the mixture was allowed to cool to ambient temperature and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (335 mg). MS 311 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=2.7 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.23-7.18 (m, 2H), 7.15-7.12 (m, 1H), 4.33 (t, J=4.8 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 3.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](I)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[C-:31]#[N:32].[K+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:31]([C:22]1[CH:21]=[N:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:7]3[C:8]4[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=4)[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6]3)=[CH:14][CH:15]=2)[CH:23]=1)#[N:32]
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cc(I)cn3)cc2)c2cccc(F)c2c1=O
Reactant: [C-]#N
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(-n3cc(C#N)cn3)cc2)c2cccc(F)c2c1=O
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 5-fluoro-1-[4-(4-iodo-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.100 g, 0.193 mmol), potassium cyanide (0.038 g, 0.52 mmol), and tributyltin chloride (0.68 mg, 1.9 μmol) in 2 mL of acetonitrile under nitrogen was added bis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reaction mixture was stirred at 120° C. for 48 hours, cooled to room temperature, and purified via reverse phase HPLC to provide the title compound which gave a proton NMR spectrum consistent with theory. This compound could be further hydrolyzed to the corresponding carboxylic acid, as described in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2ccc(Cl)cc2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 45 %

Procedure:
4-Methoxy-6-(4-chloro-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307e was synthesized from compound 305 (1 g, 3.59 mmol) and (4-chloro-phenyl)-boronic acid 306e (842 mg, 5.39 mmol), according to the procedure as described for compound 307b, was a beige solid in 45% yield. MS (ESI, EI+): m/z=355 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21]CC)=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[O:35])=[CH:5]1)[N:16]=[C:15]([C:19]([OH:21])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Product: O=C(NCc1ccn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)c1)Nc1ccc(Cl)cc1
Yield: 18.2 %

Procedure:
Using the compound (200 mg, 519 μmol) of Example 5 and 4-chlorophenyl isocyanate (80.6 μl, 622 μmol) and through the process similar to Example 38, 44.6 mg of title compound were obtained as yellowish brown powder. Yield 18%.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1SC.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:21][CH2:20]1>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:21][CH2:20]1
Reactant: CSc1nc2c(c(=O)n1C)CCCC2
Reactant: NCCCN1CCN(c2ccc3ccccc3n2)CC1
Product: Cn1c(NCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Temperature: 140 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
A mixture of 420 mg of 3-methyl-2-methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one as synthesized in Step 7-29-A and 540 mg of 2-[4-(3-aminopropyl)piperazin-1-yl]quinoline as synthesized in above Step 7-29-B was heated under stirring at 140° C. for 6 hours. The residue was purified on silica gel column chromatography (chloroform:methanol=10:1) to provide 420 mg (48%) of 3-methyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylamino]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].CC([O-])=O.[Na+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([F:21])[CH:14]=1>O.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:2]/[NH:3][C:4]([NH2:6])=[O:5])=[C:15]([F:21])[CH:14]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)N/N=C/c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of aminourea hydrochloride (2.8 g, 25 mmol) and NaOAc (4.1 g, 49 mmol) in water (50 mL) was added dropwise a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol) in methanol (50 mL). The resulting solution was stirred at rt for 3 h. The solids formed were collected by filtration to obtain compound 59a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H7BrFN3O: 260.0 (M+H). Found: 260.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1>CC(O)=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC[C@H]2COC(C)(C)O2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OCC[C@H](O)CO)cc1

Procedure:
A solution of (4S)-4-[2-(4-methoxyphenoxy)ethyl]-2,2-dimethyl-1,3-dioxolane (8.2 g, 30.8 mmol) in AcOH/water was stirred at rt for 5 h and concentrated in vacuo. The residue was co-evaporated with toluene (3×) and then pumped under high vacuum to give the desired product. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.91 (2 H, d), 4.43 (2 H, s), 3.80 (3 H, s), 3.77 (1H, m), 3.66-3.42 (5 H, m), 1.86-1.76 (1H, m), 1.68-1.60 (1H, m).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:40][C:27]([F:39])([F:26])[S:28]([C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(S(=O)(=O)C(F)(F)F)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-trifluoromethanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=531.1 (M+H)+