Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>O1CCCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cn[nH]c2c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
A mixture of 6-amino-1H-indazole (2.00 g) and pyridine (2.67 ml) in tetrahydrofuran was stirred at 0° C. and then p-nitrophenyl chloroformate (3.18 g) was added and stirred at the same temperature for 2 hours. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The pale yellow powder was washed with isopropyl ether and diethyl ether, and vacuumed to afford 4-nitrophenyl N-(lH-indazol-6-yl)carbamate (2.67 g).
Reaction SMILES: Br.C([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([O:20]C)[C:12]([F:19])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:22][CH3:23])[CH:8]=1)=[O:6])C.O>CC(O)=O>[CH2:22]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[OH:20])[C:16](=[O:17])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1)[CH3:23]
Reactant: CCOC(=O)c1cn(CC)c2c(OC)c(F)c(F)cc2c1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(O)c21
Temperature: 110 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
48% aq. HBr (35 ml) was added to a solution of 1-ethyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (9.34 g; prepared according to EP 241 206) in AcOH (30 ml). The orange solution was stirred at 110° C. for 24 h. It was poured into water (200 ml) and the grey-white precipitate was filtered. The crystals were collected and dried in vacuo to afford 6.37 g (79% yield) of a beige solid. 1H NMR (DMSOd6; δ ppm): 1.43 (3H, t, J=7); 4.85 (2H, q, J=7); 7.76 (1H, dd, J=8 and J=10); 8.91 (1H, s); 12.02 (1H, broad); 14.90 (1H, broad).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=2)[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:2]1[CH2:5][CH:4]([C:6]3[C:7]([N:12]4[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]4)=[N:8][CH:9]=[CH:10][N:11]=3)[CH2:3]1)[CH:30]=[CH:29]2
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: OCC1CCN(c2nccnc2C2CNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CC(c4nccnc4N4CCC(CO)CC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of [1-(3-azetidin-3-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (284 mg, 1.0 mmol) and 2-chloro-6-methyl-quinoline (purchased from ALDRICH) (177 mg, 1.0 mmol) in DMF (15 mL) was added Cs2CO3 (650 mg, 2.0 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc:Petrol ether=5:1) on silica gel to give (1-{3-[1-(6-methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-methanol (102 mg, 0.26 mmol 26%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C(O[CH:8]=[CH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C.FC(F)(F)C(Cl)=O.C(OCC)=C.Cl>CO>[F:12][C:11]([F:14])([F:13])[C:10]1[NH:4][C:2](=[O:3])[N:1]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: O=c1nccc(C(F)(F)F)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8.74 moles of urea in 2.2 L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel was added dropwise over about 3 hours under N2 atmosphere an equimolar amount of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether. The temperature of the reaction mixture was kept below 15° C. After 15 min, 1.35 L of a concentrated HCl solution (32%) was added to the cooled suspension obtained and a clear solution was obtained. The solution was slowly heated to 60° C. and after 2 hours stirring, a suspension was formed. After overnight stirring at 60° C. and subsequently 1 h stirring at 0 to 5° C., the precipitate was filtered off. The residue was washed with water until neutral pH and subsequently with hexane (ca. 500 ml). After overnight drying on a rotary evaporator under reduced pressure in a 2 L flask, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained as colorless crystals. The yield was 1.2 kg, (85% of the theoretical yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCSc1cc(Cl)ccc1C=O
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 944 mg of 4-chloro-2-ethylsulfanylbenzaldehyde, 765 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 15 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][O:54][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: CC(=O)Cl
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 75.7 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 9f (2.9 g, 3.37 mmol) was dissolved in 20 mL methanol, followed by addition of acetyl chloride (38 μL, 0.5 mmol). The reaction mixture was stirred for 2 hours and was partitioned after 30 mL ethyl acetate and 30 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×2) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 9g (1.9 g, yellow solid), yield: 76.0%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 200 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Combine 4-iodophenol (6.31 g, 28.7 mmol), 6-chloro-nicotinamide (4.51 g, 28.8 mmol), potassium carbonate (10.0 g, 72.4 mmol), and dimethylacetamide (145 mL), stir and heat at 200° C. After 3 h, cool to ambient temperature and dilute with water (600 mL), filter, and dry in vacuo to provide 8.27 g (85%) of the title compound as a white/brown solid: mass spectrum (electrospray): m/z=341.0 (M+1); 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz), 7.82-7.79 (m, 2H). 7.09 (d, 1H, J=8.8 Hz), 7.03-6.99 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Fc1cccc(F)c1CBr
Reactant: O=[N+]([O-])c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F

Procedure:
2-(2,6-difluorophenyl)-4-nitrobenzimidazole (7.7 g, 28 mmol) was reacted with 2,6-difluorobenzylbromide (6.95 g, 33.6 mmol). The crude product was purified by recrystallization from diethylether:hexane (3:1), 9.8 g (24.4 mmol, 87%), yielding white crystals 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole. M.p. 168-170° C. 1H-NMR (300 MHz, CD2Cl2): δ 8.13 (dd, J=8.1, 0.9 Hz, 1H, H5), 7.86 (dd, J=8.1, 0.9 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=8.1 Hz, H6), 7.28 (m, 1H, H4″), 7.12 (m, 2H, H3″,5″), 6.84 (m, 2H, H3″,5″), 5.44 (s, 2H, CH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][C:11](=[O:15])[C:12](=[O:13])[NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(Br)cc(N)c1N
Agent: Cl
Product: Cc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
13.05 g (64.9 mmol) of 5-bromo-2,3-diamino-toluene and 6.42 g (1.1 equiv.) of oxalic acid are stirred at reflux for 16 hours in 2N hydrochloric acid. The mixture is cooled and the solid is filtered off and washed with water. The title compound is obtained in the form of a brown solid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(OCC)(=O)C>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Isonipecotic acid (10.0 g, 0.078 mol) and ethyl acetate (30.0 ml) were charged at room temperature. Acetic anhydride (11.9 g, 1.50 eq) was dropwise added over about 10 min. while retaining not more than 20° C. After stirring at 55±5° C. for 2 hrs., the mixture was allowed to cool to room temperature over 1 hr., ice-cooled and stirred at not higher than 10° C. for 1 hr. The precipitated crystals were collected by filtration and washed with diisopropyl ether (10 ml×2) and dried in vacuo at 50° C. to give the title compound (11.9 g, yield 89.8%) as white crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH2:36]([NH-:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [NH-]Cc1ccccc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 220 μl (2 mmol, 2.14 mg) of benzylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.69) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 8:2 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (135 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][NH:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][N:44]2[C:19]1[S:20][C:16](=[CH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:27][C:3]=2[C:2]([F:32])([F:33])[F:1])[N:7]=[CH:8]3)[C:17](=[O:23])[N:18]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CC2CC1CN2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH:6]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([CH3:32])[CH:21]=1.Cl.C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:20]1[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[C:22]([CH3:32])[CH:21]=1)[CH:7]([CH3:12])[CH:6]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC1c2cc(OC)ccc2NC1C
Reactant: Cc1cc(Cl)nc(-c2ccccc2)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1c2cc(OC)ccc2N(c2cc(C)nc(-c3ccccc3)n2)C1C

Procedure:
A mixture of ethyl 5-methoxy-2-methylindolin-3-ylacetate (2.0g.), 6-chloro-4-methyl-2-phenylpyrimidine (1.76g.) and concentrated hydrochloric acid (0.5ml.) in ethanol (50ml.) was heated under reflux for 5 hours. The solution was cooled, saturated sodium acetate solution (3ml.) was added, and the mixture was concentrated in vacuo. The residue was diluted with water (30ml.) and extracted with ethyl acetate (3 × 30ml.). The combined exracts were washed with water and then dried (Na2SO4), and the solvent was evaporated in vacuo at ca 50° C. to give ethyl 5-methoxy-2-methyl-1-(4-methyl-2-phenylpyrimidin-6-yl)indolin-3-ylacetate as a syrup. This was shown to be pure by TLC (System A) and by NMR spectroscopy (OCH3 at 6.23τ).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr

Procedure:
To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl4 (150 mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl4 was removed under reduced pressure and the residue was diluted dissolved in ether, washed with brine (3×), dried over MgSO4, concentrated. Chromatographed/hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].II.Cl>O1CCOCC1.[Zn]>[OH:8][C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCCC(C)=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCC(C)(O)CC(=O)OCC

Procedure:
To a solution of 2-heptanone (10.1 mL) in 1,4-dioxane (150 mL) were added ethyl bromoacetate (9.6 mL), zinc (8.5 g) and iodine (3.7 g) at room temperature and the solution was sonicated. After 2 hours 1N hydrochloric acid was added dropwise to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue purified by flush column chromatography (n-hexane:ethyl acetate=15:1), to give the title compound (13.9 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1)=[O:5].O1C=CN=C1[Cl:25]>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:25])=[O:12])=[CH:9][N:8]=1)=[O:5]
Reactant: Clc1ncco1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-(2-methylbenzoylamino)nicotinic acid (0.3 g) in dimethylformamide (0.5 ml) and dichloromethane (2.5 ml) is added dropwise oxazolyl chloride (0.2 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[C:13]1([S:19]([N:22]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]2[C:31](OC)=[O:32])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[C:13]1([S:19]([N:22]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[C:23]2[C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[O:32])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 221.2 %

Procedure:
In a three-necked round-bottom flask o-toluidine (0.53 g, 5 mmol) was dissolved in 15 mL of toluene under inert atmosphere. To this solution was added trimethy aluminium (2.5 mL, 5 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution of methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (207 mg, 0.62 mmol) in 15 mL of toluene were added and the reaction mixtures was heated at 80° C. over night. Next, the mixture was allowed to cool to room temperature and 2-3 mL of water were added to hydrolyze unreacted trimethyl aluminium and a 0,5M aqueous solution of disodium tartrate dihydrate were added stirring for a while. Afterwards, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0,5M aqueous solution of disodium tartrate dihydrate (25 mL), water and brine, dried and concentrated in vacuum to afford 560 mg of a residue that was used in the following step without further purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccnc2)cc1
Yield: 88.6 %

Procedure:
To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine (44 g, 0.28 mol), Na2CO3 (200 g) in toluene (500 ml) and water (500 ml) was added Pd(PPh3)4 (16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42 g, 90%).
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:48]([O:50]CC)=[O:49])[C:11](=[O:47])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH2:24][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:48]([OH:50])=[O:49])[C:11](=[O:47])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH2:24][NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4)ccn2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CNC3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
8.3 ml of ethanol, 2.8 ml of THF and 1.5 ml of 1N hydrochloric acid were added to 275.4 mg of ethyl 1-cyclopropyl-9-methyl-8-(2-tritylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (I) and the resulting mixture was stirred at 50° C. for 2 hours. The solvent was distilled off under reduced pressure and water was added to the resulting residue and the resulting residue was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 30 ml of water, 10 ml of ethanol and 5 ml of 1N sodium hydroxide were added to the resulting residue and the resulting mixture was stirred at 50° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 120.0 mg of 1-cyclopropyl-9-methyl-8-(isoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.