Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]([CH3:22])[CH3:21]
Reactant: CC[K]
Reactant: CC(C)CNCC(C)C
Reactant: O=C(O)C1OC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)N(CC(C)C)CC(C)C
Yield: 59.8 %

Procedure:
Following the procedure of Example 34, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and diisobutylamine (1.3 g) to give 0.81 g of ethyl N,N-diisobutyl-2,3-epoxysuccinamate (Compound No. 56) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[NH2:5])[CH3:2].[Cl:7][C:8]1[C:12]([Cl:13])=[N:11][C:10](=[C:14](Cl)Cl)[N:9]=1.[O:17]1CCOCC1>>[CH2:1]([O:3][C:4](=[O:6])[NH:5][C:14]([C:10]1[NH:11][C:12]([Cl:13])=[C:8]([Cl:7])[N:9]=1)=[O:17])[CH3:2]
Reactant: C1COCCO1
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: CCOC(N)=O
Product: CCOC(=O)NC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 60 %

Procedure:
A solution of 20 g (0.225 mol) of carbamic acid ethyl ester and 21.8 g (0.1 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in 50 ml of dioxane was heated briefly to the boil (about 115° C.) After cooling, the product was precipitated with water, filtered off, washed with water and dried. 15 g (60% of theory) of N-(4,5-dichloroimidazol-2-oyl)-carbamic acid ethyl ester with a melting point of 208° C. (from acetonitrile) were obtained.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]#[N:42])=[C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][N:29]([CH:34]([CH2:38][CH3:39])[C:35](O)=[O:36])[C:28](=[O:40])[CH:27]=2)[CH:25]=1.[NH2:43][C:44]1[CH:53]=[C:52]([F:54])[C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([F:55])[CH:45]=1.O>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]#[N:42])=[C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][N:29]([CH:34]([CH2:38][CH3:39])[C:35]([NH:43][C:44]3[CH:45]=[C:46]([F:55])[C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:52]([F:54])[CH:53]=3)=[O:36])[C:28](=[O:40])[CH:27]=2)[CH:25]=1
Reactant: COC(=O)c1c(F)cc(N)cc1F
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCC(C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
At 60-70° C., 110 μl (0.46 mmol, 4 eq.) of T3P (50% in ethyl acetate) were added dropwise to a solution of 46 mg (0.13 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.27 mmol, 2 eq.) of methyl 4-amino-2,6-difluorobenzoate in 1 ml of pyridine. The reaction mixture was heated to 90° C., stirred at 90° C. for 30 min and cooled to RT, and water and ethyl acetate were added. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 10-50% mixtures). Yield: 54 mg (79% of theory)
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].O.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18].[CH2:21](O)[CH3:22]>>[CH3:14][S:13][C:3]1[N:2]([NH:1][CH:17]([O:18][CH2:21][CH3:22])[C:16]([OH:20])=[O:19])[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=1
Reactant: O=CC(=O)O
Reactant: CCO
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Solvent: O
Product: CCOC(Nn1c(SC)nnc(C(C)(C)C)c1=O)C(=O)O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
214 g (1 mol) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5-one, 101 g (1.1 mols) of glyoxylic acid monohydrate and 2 liters of ethanol were stirred for 12 hours at room temperature. The product which had precipitated was filtered off and the filtrate was concentrated, whereupon further material crystallized out. The combined filtrate residues were stirred in about 500 ml of cold water for 1/2 hour and the product was filtered off and dried at 40° C in vacuo. 304 g (96% of theory) of N-(3-methylthio-6-tert.-butyl-1,2,4-triazin-5-on-4-yl)- α-ethoxy-glycine of melting point 154°-55° C (decomposition) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1O
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=1[NH2:8].[CH3:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19].N#C[Br:24]>C(Cl)Cl>[CH3:14][O:13][C:9]1[C:7]2[N:8]=[C:16]([NH2:17])[N:3]3[CH2:4][CH2:5][N:1]=[C:2]3[C:6]=2[CH:12]=[CH:11][CH:10]=1.[N:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:15].[BrH:24]
Reactant: N#CBr
Reactant: COc1cccc(C2=NCCN2)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Br
Product: COc1cccc2c1N=C(N)N1CCN=C21
Temperature: 10 °C
Reaction time: 8 h

Procedure:
2-(4,5-Dihydro-1H-imidazol-2-yl)-6-methoxyaniline (Step 3, 22.0 g, 115 mmol) and Et3N (48.1 mL, 345 mmol) were dissolved in CH2Cl2 (200 mL), cooled to 10° C. in an ice bath and cyanogen bromide (24.4 g, 230 mmol) was added portionwise. A slight exotherm was noted, and the reaction was stirred overnight. The reaction was concentrated under reduced pressure, then treated with EtOAc (150 mL) and concentrated under reduced pressure again. Finally, the residue was treated with Heptane and concentrated under reduced pressure to give the title compound as a mixture with Et3N.HBr (62 g, 99%): HPLC MS RT=1.08 min, MH+=217.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.85 (3H, s), 4.09-4.16 (2H, m), 4.31-4.38 (2H, m), 7.23 (1H, t), 7.31 (1H, d), 7.57 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-nitro-4-(trifluoromethyl)phenylamine (2 g, 8.3 mmol, Oakwood) in EtOAc (26 mL) and EtOH (13 mL) was added tin (II) chloride dihydrate (13.1 g, 45 mmol, Aldrich). The reaction mixture was stirred at 70° C. for 1 h. The light-yellow reaction solution was poured to crushed ice (50 mL) and carefully neutralized using saturated aqueous solution of NaHCO3. The resulting suspension was extracted with EtOAc (3×60 mL). The combined organic extracts were dried over MgSO4, filtered and the filtrate evaporatedcon in vacuo to give the title compound as white solid, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 211.4 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:27](O)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([NH2:58])([CH3:57])([CH3:56])[CH3:55].CCOCC>CN(C=O)C.CCN(C(C)C)C(C)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:27](=[O:28])[NH:58][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A solution of BOC-O-(2,6-dichlorobenzyl)-L-tyrosine (Bachem, 2.00 g, 4.54 mmol) in 20 mL of DMF and iPr2NEt (1.6 mL) was cooled to 0° C. and treated with HBTU (1.72 g, 4.54 mmol). The resulting solution was stirred at 0° C. for 30 minutes and treated with tert-butyl amine (0.48 mL, 4.54 mmol). The resulting solution was stirred overnight. The reaction mixture was poured into ether (100 mL) and washed sequentially with saturated aqueous NaHCO3 solution (20 mL) and brine (4×20 mL). The organic phase was collected and dried (MgSO4) and concentrated. The crude reaction product was purified by chromatography (silica gel, 2:1 heptane/EtOAc). The solid obtained was crystallized from hot heptane, collected by suction filtration and dried to give the title compound as a white solid (1.56 g, 69%), mp=82-86° C.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[NH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[NH2:27]>>[NH2:11][C:10]1[C:9]([N:8]=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([NH2:13])[N:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)[N:27]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccc(C(=O)O)cc2)c(N)c1N=Nc1ccccc1
Reaction time: 4 h

Procedure:
4-(3,5-diamino-4-phenylazopyrazol-1-yl)benzoic acid was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-hydrazinobenzoic acid (76 mg, 0.5° mmol). After reacting for 4 hrs, the reaction remained as a slurry; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 22 mg (14%) of the compound as a brown solid.
Reaction SMILES: C[Mg]Cl.C[C:5](C)([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)[CH:6]=[O:7].Cl.O1C[CH2:21][CH2:20][CH2:19]1>>[CH3:19][CH:20]([CH3:21])[CH:6]([OH:7])[CH2:5][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1cccc(CC(C)(C)C=O)c1
Agent: C[Mg]Cl
Agent: Cl
Product: Cc1cccc(CCC(O)C(C)C)c1
Reaction time: 5 h

Procedure:
A solution of 10 g of methylmagnesium chloride in 100 ml of tetrahydrofuran was added at a temperature of from 25° C. to 30° C., and with the exclusion of air, to 17 g of 2,2-dimethyl-3-(3-methylphenyl)-propionaldehyde (according to Example 3). After 5 hours at 30° C., the reaction mixture was poured onto ice and acidified with hydrochloric acid. The phases were then separated and the organic phase was washed with 100 ml of water and 100 ml of sodium bicarbonate solution. Finally, drying was carried out with solid potassium carbonate. Fractional distillation yielded 15 g of end product at 0.12 mbar in a temperature range of from 79° C. to 82° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[C:22]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)(=[O:20])=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) from 7-benzenesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and L-alanine. MS-(−)-ion: M−1=399.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=O)[O:28]C(C)(C)C)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH:46]1[CH2:48][CH:47]1C(Cl)=O.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27]([C@H:47]1[CH2:48][C@@H:46]1[C:42]1[S:41][CH:45]=[CH:44][CH:43]=1)=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CC1c1cccs1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C

Procedure:
A precooled (0° C.) solution of tert-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (250 mg, 0.55 mmol) and dichloromethane (10 mL) was treated dropwise with trifluoroacetic acid (2 mL). The resulting solution was maintained at room temperature for 16 h, then concentrated to afford a yellow oil that was dissolved in dichloromethane (5 mL) and added to a room temperature solution of 2-thiophen-2-yl-cyclopropane carbonylchloride (100 mg, 0.60 mmol), triethylamine (0.20 mL, 1.4 mmol) and dichloromethane (4 mL). The resulting reaction was maintained overnight, then transferred to a separatory funnel and partitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (10%-50% ethyl acetate in hexanes) to afford (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J=5.6, 3.0 Hz, 2H), 7.76 (dd, J=5.6, 3.0 Hz, 2 H), 7.29-7.34 (m, 2H), 7.07 (dd, J=5.2, 1.1 Hz, 1H), 6.87-6.92 (m, 3H), 6.77 (d, J=3.0 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 5.29-5.37 (m, 1H), 4.03 (dd, J=14.1, 10.1 Hz, 1H), 3.97 (dd, J=14.1, 4.0 Hz, 1H), 3.81 (dd, J=8.8, 5.8 Hz, 1H), 3.73 (dd, J=9.1, 6.8 Hz, 1H), 2.57 (ddd, J=9.5, 5.9, 4.0 Hz, 1H), 1.86 (dq, J=13.1, 6.5 Hz, 1H), 1.66 (ddd, J=8.4, 5.1, 4.2 Hz, 1H), 1.52-1.63 (m, 2H), 1.23-1.36 (m, 2H), 1.14 (ddd, J=8.3, 6.3, 4.3 Hz, 1H), 1.02 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>C(O)CC(C)C>[ClH:1].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=3)[N:3]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1Cl
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1Cl
Product: Cl
Yield: 79 %

Procedure:
The title compound was prepared similarly by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and 1-(2-furoyl)piperazine in isoamyl alcohol, M.P. 229°-31° C., 79% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([SiH2:15][O:16][C:17]([CH3:32])([CH3:31])[C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH2:29][OH:30])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([SiH2:15][O:16][C:17]([CH3:31])([CH3:32])[C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C=O)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
0.64 ml of oxalyl chloride was added at −60° C. to a solution of 0.76 ml of dimethyl sulphoxide in 10 ml of CH2Cl2. After 5 minutes 2 g of ethyl 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-hydroxymethyl-benzoate (Example 31.1) in 20 ml of CH2Cl2 were addded over 5 minutes in a manner such that the temperature did not exceed −60° C. After 15 minutes 4.295 m triethylamine were added. The reaction mixture was left too warm to room temperature and was worked up by extraction and yielded 2.0 g of ethyl 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-formyl-benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.N1([C:16]([N:18]2[CH:22]=[CH:21]N=C2)=[O:17])C=CN=C1.Br.NCC([C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)=O>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:28]4[CH:37]=[CH:36][C:31]5[O:32][CH2:33][CH2:34][O:35][C:30]=5[CH:29]=4)[CH2:22][NH:18][C:16]3=[O:17])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: NCC(=O)c1ccc2c(c1)OCCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: Br
Product: O=C1NCC(c2ccc3c(c2)OCCO3)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.37 g, 2.78 mmol), di(1H-imidazol-1-yl)methanone (0.496 g, 3.06 mmol), TEA (1.16 mL, 8.34 mmol), aminomethyl-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ketone hydrobromide (0.761 g, 2.78 mmol), TEA (0.775 mL, 5.56 mmol), PdC (10%, 0.02 g) as described in method 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (252 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[C:16]([N+:24]([O-:26])=[O:25])[CH:17]=2)=[CH:4][C:3]=1[F:23]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2nc(Cl)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To 10 ml of conc. sulfuric acid was added 1.5 g of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Potassium nitrate (1.4 g) was added in portions to the solution, which was heated and stirred at 80° C. for 2 hours. The reaction solution was allowed to cool down, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration and successively washed with water, ethanol, and diethyl ether to give 1.1 grams of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19](Cl)[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19]([O:29][C:26](=[O:28])[CH3:27])[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12
Reactant: CC(Cl)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21

Procedure:
The product from Step 2 (4 g) and sodium acetate (6 g) were refluxed together in glacial acetic acid (60 ml) for 1 hour. The mixture was cooled, diluted with ethyl acetate (300 ml) and washed with water (3×100 ml), then with aqueous sodium bicarbonate and again with water, dried and evaporated down. The residue was chromatographed on a column of silica gel eluting with a 1:9 mixture of ethyl acetate-hexane to afford, after trituration in ether and filtration, the pure title compound (1.2 g), m.p. 195°-196° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[C:28]([Cl:46])[CH:27]=1>C(O)(C)C>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:25][C:26]3[CH:45]=[CH:44][C:29]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[C:28]([Cl:46])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2Cl)CC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (3.27 g) and isopropyl alcohol (50 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (4.70 g) as a white powder.