Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:22]1([CH:28]([CH3:31])[CH:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H][H]>>[C:22]1([CH:28]([CH3:31])[CH2:29][OH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C=O)c1ccccc1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(CO)c1ccccc1
Yield: 58.3 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an ethanolic solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol) and 2-phenylpropionaldehyde (1.21 mL, 9 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (95%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 715 mg of 2-phenyl-1-propanol was obtained (yield: 58%).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:19]([C:17]3[S:18][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:20])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-chlorothiophene-2-carboxylic acid (Aldrich) according to methods A and C; yield 56 mg, 0.17 mmol (53%): 1H NMR (300 MHz, methanol-d4) δ 1.95 (d, J=14 Hz, 2H), 2.17 (s, 1H), 2.29 (d, J=14 Hz, 2H), 2.43 (s, 2H), 3.55 (s, 2H), 3.64 (d, J=2 Hz, 4H), 4.34 (s, 1H), 7.04 (d, J=4 Hz, 1H), 7.69 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 297, 299 (M+H)+; Anal. C14H17ClN2OS.HCl 0.1H2O: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Br:26]Br>C(Cl)Cl.C(OCC)C>[Br:26][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (1 g, 2.4 mmol) in methylene chloride (30 ml) at room temperature was added bromine (4.9 ml, prepared 1.0 M solution in methylenechlordie, 4.9 mmol) dropwisely. The reaction mixture was stirred at room temperature for 1 hour and the resulting solution was diluted with ethyl ether (50 ml). The reaction mixture was quenched with saturated sodium bicarbonate solution (30 ml) and extracted with ethyl ether (50 ml twice). The organic solution was evaporated under reduced pressure, and crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (401 mg, 40%) and produce the title compound (520 mg, 45% yield) as white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N([C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[N+]=[N-]>C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.O>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([NH:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:15]([O:17][CH2:18][CH:19]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:16])=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a stirred solution of D-lysine hydrochloride (4.5 g) in 175 ml of a sodium carbonate solution (10% in water):acetone (6:1) solution is added dropwise a solution of 9-fluorenylmethyl azidoformate in acetone (150 ml). After 16 hours the mixture is diluted with water and washed three times with hexane. The mixture is then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate solution is washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, then concentrated in vacuo to about 20 ml. The solution is added to hexane (1 l.) and the precipitate is collected and dried to afford the title compound: NMR (dimethylsulfoxide) δ1.0-1.9 (m, 6H), 2.7-3.2 (m,2H), 3.8-4.7 (m,7H), 6.8-8.3 (m,19H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:20]N1C(=O)CCC1=O.O>C1COCC1>[Br:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(Br)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.0 g (38.419 mmol) of methyl tetrahydrofuran-3-carboxylate (prepared analogously to: J. Org. Chem. 1996, 2690) were dissolved in 200 ml of THF and cooled to −78° C., and then 76.83 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added. After 30 min at −78° C., 10.26 g (57.63 mmol) of N-bromosuccinimide suspended in 50 ml of THF were added gradually. Thereafter, the mixture was left to warm up to RT overnight. The mixture was then admixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel (eluent: dichloromethane). This gave 491 mg (6% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:30]([O:29][C:27]([NH:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(NC(=O)OCc3ccccc3)c2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the product from Step A (133 mg) in dichloromethane (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.21 mL) followed by benzyl chloroformate (0.1 mL). The reaction mixture was stirred at 0° C. for 90 min, then diluted with dichloromethane (10 mL) and poured into saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 80% ethyl acetate/hexanes gradient) to give the title compound. LC/MS 359.3 (M+1).
Reaction SMILES: [ClH:1].[N:2]1([C:11](=[O:36])/[CH:12]=[CH:13]/[C@@H:14]([NH:19][C:20]([C:22]2([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C)C>[ClH:1].[NH2:28][C:22]1([C:20]([NH:19][C@@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])/[CH:13]=[CH:12]/[C:11]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:36])=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N)CCOCC1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
A solution of concentrated aq. HCl (0.22 mL, 2.64 mmol) was added to a solution of 1,1-dimethylethyl [4-({[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.517 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65° C. (bath temp). After 1 h 45 min, the solvent was evaporated under reduced pressure at 60° C. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65° C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 130.6 mg (60%) of the title compound. LC-MS m/z 386 (M+H)+, 0.79 (ret time). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.15 (d, J=7.03 Hz, 1H); 7.25 (d, J=7.03 Hz, 1H); 7.18 (t, J=7.65 Hz, 1H); 7.06 (t, J=7.91 Hz, 1H); 6.81 (dd, J=15.18, 6.40 Hz, 1H); 6.49 (br. s., 1H); 4.73-4.85 (m, 2H); 4.21 (t, J=8.28 Hz, 2H); 3.91-3.97 (m, 2H); 3.70-3.77 (m, 2H); 3.25-3.21 (m, 2H); 2.35-2.48 (m, 2H); 1.82 (d, J=14.31 Hz, 2H); 1.63-1.71 (m, 2H); 1.50-1.57 (m, 1H); 0.98 (dd, J=11.92, 6.40 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>C1C=CC=CC=1>[C:19]([CH2:23][CH2:24][C:25]([NH:12][C:4]1[C:5](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:26])([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)CCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1cc(Cl)ccc1C(=O)OC

Procedure:
To the solution of 444 g of methyl 4-chloro-anthranilate in 1.3 lt of benzene and 199 ml of pyridine, that of 406 g of 3-carbomethoxy-propionyl chloride in 200 ml of benzene is added dropwise while stirring and cooling with ice. The mixture is stirred for 19 hours at room temperature, filtered and the filtrate evaporated. The combined residues are taken up in 3 lt of chloroform, the solution washed with water, 1 lt of N hydrochloric acid, 1 lt of 10% aqueous sodium bicarbonate and again with water, dried, filtered, evaporated and the residue recrystallized from acetonitrile, to yield the methyl N-(3-carbomethoxypropionyl)-4-chloroanthranilate melting at 80°-84°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH:21]=[O:22])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:43])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH:21]=[O:22])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:34])([F:33])[C:26]([F:31])([F:32])[C:27]([F:30])([F:29])[F:28])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2NC=O)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2NC=O)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
0.7 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-formylamino-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole was dissolved in 20 mL of chloroform, and 360 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.72 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-formylamino-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CC(=O)CC(c2cc([N+](=O)[O-])ccc2F)C1
Temperature: 0 °C
Yield: 83 %

Procedure:
60 g of 5-(2-fluorophenyl)-cyclohexane-1,3-dione were dissolved in 500 ml of concentrated sulfuric acid at -20° C. and nitrated with 18.3 g of 98% strength nitric acid at -20° C. in the course of 60 minutes. The reaction mixture was stirred into 5 l of ice water, and the precipitated crystals were filtered off under suction and dried. 60.5 g (83% yield) of 5-(2-fluoro-5-nitrophenyl)-cyclohexane-1,3-dione of melting point 171°-173° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:15]1[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: OC1CCNC1
Product: OC1CCN(c2ccccc2C(F)(F)F)C1
Yield: 67 %

Procedure:
The title compound (3.72 g, yield 67%) was obtained from 2-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)[CH:21]=3)[CH2:17][C:16](=[O:34])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M107) (0.23 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (133 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)[Mg]Cl
Product: COC(=O)c1ccc(C(O)C(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and isopropylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.[C:19]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:21][C:19]([NH:26][CH:27]([CH:28]([CH3:30])[CH3:29])[C:31]([O:18][CH2:17][CH2:16][CH2:15][C:4]1[N:3]=[N+:2]([O-:1])[C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][CH2:11][CH2:10]3)=[CH:14][C:6]=2[N:5]=1)=[O:32])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixture of alcohol 70 (50 mg, 0.20 mmol), N-Boc Valine (44 mg, 0.20 mmol), DCC (46 mg, 0.22 mmol) and DMAP (2.5 mg, 0.02 mmol) in DCM (10 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give the crude ester, which was suspended in DCM (2 mL) and filtered to remove urea by-products. The filtrate was concentrated to give crude ester 310 (84 mg, 93%) as a pale-brown gum: 1H NMR δ 8.27 (s, 1H, H-9); 7.76 (s, 1H, H-5), 4.96-5.03 (m, 1H, CH), 4.28 (t, J=6.5 Hz, 2H, CH2O), 3.08-3.16 (m, 6H, H-6, H-8, CH2), 2.21-2.31 (m, 4H, H-7, CH2), 2.08-2.17 (br m, 1H, CH), 1.46 [s, 9H, C(CH3)3], 0.97 (d, J=6.9 Hz, 3H, CH3), 0.91 (d, J=6.9 Hz, 3H, CH3), NH not observed; HRMS calcd for C23H32N4O5 (M+) m/z 444.2373, found 444.2382.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 4 °C
Yield: 55.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-chloro-1,8-naphthyridine (3.6 g). The product produced by precipitation in water (4.3 g; m.p. 208° C.) is dissolved in boiling acetonitrile (660 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-methoxybenzamide (3.5 g) is produced, m.p. 208° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=1)C.[OH-].[Na+].Cl>C1COCC1.O>[NH2:15][C:13]1[N:12]=[C:11]([NH2:16])[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])[N:14]=1
Reactant: CCOC(=O)CCCCc1cc(N)nc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(CCCCC(=O)O)nc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ethyl ester 2-2 (190 mg, 0.8 mmol) in THF (10 mL) and water (10 mL) was treated with 1 N NaOH (1.6 mL, 1.6 mmol). After stirring at room temperature for 16 hours, the solution was neutralized with 1N HCl and then the solvents removed in vacuo. The residue, 2-3 was used as such in the next step.
Reaction SMILES: [Na].[OH:2][CH:3]=[C:4]1[CH2:9][CH2:8][O:7][C:5]1=O.S(O)(O)(=O)=O.[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[NH:17])[NH2:16]>C(O)C>[CH2:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:17]=[C:3]([OH:2])[C:4]([CH2:9][CH2:8][OH:7])=[CH:5][N:16]=2)[CH2:23][CH2:22]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1OCCC1=CO
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: OCCc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 28.9 %

Procedure:
10.0 g (73.5 mmoles) of 2-hydroxymethylenebutyrolactone sodium salt [synthesized by the method described in J. O. Fissekis et al., J. Org., Chem. 29, 2670 (1964)] and 19.6 g (73.3 mmoles) of 1-amidino-4-benzylpiperazine sulfate were added to 360 ml of ethanol, and the solution was refluxed for 5 hours. Ethanol was evaporated, and the residue was mixed with water and extracted with chloroform. The chloroform layer was dried, concentrated, and purified by silica gel column chromatography to give 6.66 g (yield 29%) of 2-(4-benzylpiperazino)-4-hydroxy-5-(2-hydroxyethyl)pyrimidine as crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc2c(c1)NCC2)N1CC(CC)C=N1
Solvent: Cc1ccccc1
Product: CCNC(=NS(=O)(=O)c1ccc2cc[nH]c2c1)N1CC(CC)C=N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
0.14 g 2,3-Dihydro-1H-indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide was dissolved in 25 mL toluene, the mixture was degassed, and 10 mol % of palladium on carbon was added. The mixture was stirred overnight at 50° C. The mixture was cooled to room temperature and filtered over Hyflo, and the Hyflo was washed with toluene. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (DCM→DCM/EA 95:5→DCM/EA 8:2) to give 70 mg of 1H-Indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.52 Hz, 3H), 1.06 (t, J=7.22 Hz, 3H), 1.32-1.57 (m, 2H), 2.89-3.00 (m, 1H), 3.35-3.54 (m, 3H), 3.89 (t, J=11.44 Hz, 1H), 6.54 (br.s., 1H), 6.84 (d, J=1.50 Hz, 1H), 6.96 (br.s., 1H), 7.36 (t, J=2.86 Hz, 1H), 7.59-7.70 (m, 2H), 8.26 (d, J=1.20 Hz, 1H), 9.55 (br.s., 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cn(-c2ccnc3ccccc23)c1C
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)Cl)cn(-c2ccnc3ccccc23)c1C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added at a temperature in the region of 20° C. under an argon atmosphere to 1.1 g (4.1 mmol) of 3-carboxy-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform. After stirring at the reflux point of the solvent for 1.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and is then brought back to dryness to give 1.17 g (4.1 mmol) of 3-chlorocarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole in the form of a brown-yellow solid which is used directly in the following step.
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.S(=O)(=O)(O)O>>[NH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
Ten grams of 4-acetamido-3-nitrobenzophenone were added portionwise to 40 ml. of sulfuric acid. The reaction temperature was moderated with a water bath. After stirring about 45 minutes the reaction mixture was carefully poured over ice. The precipitated product was filtered to yield 4-amino-3-nitrobenzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:17]/[N:18]([CH3:20])[CH3:19]
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)/C=C/c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A reaction mixture of 8.49 g (48 mmol) of 2-chloro-4-nitrotoluene and 15.03 mL (72.8 mmol) of tert-butoxybis(dimethylamino)methane in 200 mL of THF is refluxed for 8 hours. The reaction solution is evaporated down and the residue is combined with petroleum ether. The precipitate is filtered off, rinsed with petroleum ether and dried at ambient temperature under a high vacuum. The product is used in other reactions without further purification. Yield: 11 g, C10H11ClN2O2 (M=226.66); calc.: molecular ion peak (M+H)+: 227/229; found: molecular ion peak (M+H)+: 227/229; Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate (3:1)).