Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[O:11][C:10](=[O:23])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:30].[Na+]>CN(C=O)C.O.Cl>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([O:8][CH2:9][C:10]([OH:23])=[O:30])[C@H:12]([OH:11])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1COC(c2ccccc2)(c2ccccc2)[C@@H](C(=O)OCc2ccccc2)O1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)OCc1ccccc1

Procedure:
14 g (36 mmol) of benzyl (S)-5,5-diphenyl-2-oxo-1,4-dioxane-6-carboxylate were dissolved in 50 ml of DMF and, with ice-cooling, 43 ml of 1 N NaOH solution were added. After ten minutes, the mixture was diluted with 300 ml of water and neutralized with 43 ml of 1 N hydrochloric acid and the aqueous phase was extracted with ether. The ether phase was dried, the solvent was distilled off and the residue (8.8 g, 21 mmol of an oil) was directly reacted further.
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BrH:13].O>C1(C)C=CC=CC=1>[Br:13][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][CH:2]=1
Reactant: Br
Reactant: O=C(C#CCO)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1coc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of 4-hydroxy-1-phenylbut-2-yn-1-one (3.2 g, crude) in toluene (60 mL) was added HBr (40%, 15 mL). The resulting solution was stirred for 40 min at 50° C. and then the reaction mixture was poured into water (300 mL), extracted with Et2O (4×100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether) to afford 4-bromo-2-phenylfuran as a yellow solid (1.3 g, 50%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:18]([O:21][NH2:22])[C:19]#[CH:20].Cl.O1CCOCC1>C(O)C>[CH2:18]([O:21]/[N:22]=[C:1](/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)\[CH3:2])[C:19]#[CH:20]
Reactant: C#CCON
Reactant: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: C#CCO/N=C(\C)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (500 mg, 2.281 mmol) in ethanol (6.912 mL) was added O-(prop-2-ynyl)hydroxylamine hydrochloride (368 mg, 3.42 mmol) and HCl 4N in dioxane (1.711 mL, 6.84 mmol). The mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. Saturated sodium bicarbonate was added, extracted with ethyl acetate twice, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (60-100% ethyl acetate/heptane, and then 5% MeOH/ethyl acetate) giving (E)-4-(4-(1-(prop-2-ynyloxyimino)ethyl)phenyl)-1,2,4-triazolidine-3,5-dione (I-6a: 46 mg, 7%) as a white solid. LC-MS (M+1) 273.1, t=0.81 minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H) 3.48 (t, J=2.40 Hz, 1 H) 4.80 (d, J=2.27 Hz, 2 H) 7.53 (d, J=8.59 Hz, 2 H) 7.76 (d, J=8.59 Hz, 2 H) 10.52 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:30]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (250 mg, 1.03 mmol) was dissolved in acetonitrile (0.10 ml), and cooled to 0° C. Triethylamine (244 μl, 1.75 mmol) and cyclobutanecarbonyl chloride (177 μl, 1.55 mmol) were dropwise added to the solution, followed by stirring at room temperature for 1 hour. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under, reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate/hexane (1:4, v/v) gave the entitled compound (283 mg, 85%) as a white solid.
Reaction SMILES: [O:1]([CH3:11])[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].C(N(S(F)(F)[F:18])CC)C>>[F:18][C@H:7]1[CH2:9][O:10][C@@H:2]([O:1][CH3:11])[C@@H:3]([OH:4])[C@H:5]1[OH:6].[O:1]([CH3:11])[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CCN(CC)S(F)(F)F
Agent: CO[C@H]1OC[C@@H](O)[C@H](O)[C@@H]1O
Product: CO[C@@H]1OC[C@H](F)[C@H](O)[C@@H]1O

Procedure:
A known compound, methyl α-D-lyxopyranoside [Compound (1)] of the formula ##STR8## is reacted with diethylaminosulfur trifluoride [(C2H5)2 NSF3 ] to fluorinate selectively only the 4-hydroxyl group of Compound (1), whereby there is produced methyl 4-deoxy-4-fluoro-α-L-ribopyranoside [Compound (2)] of the formula ##STR9## as a 4-deoxy-4-fluoro derivative of Compound (1), with accompanying reversion of the steric configuration of the starting compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[CH:21]=[NH+:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2.[Br-].Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:33][C:34]#[N:35])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[CH:21]=[N:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(O)ccc3c2)c[nH+]n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 4-[(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamoyl]-2-phenyl-3-propyl-2H-pyrazol-1-ium; bromide (0.30 g, 0.646 mmol), prepared in the previous step, bromoacetonitrile (0.054 mL, 0.775 mmol), potassium carbonate (0.446 g, 3.23 mmol) and 10 mL of DMF was stirred under nitrogen at room temperature overnight. The reaction was diluted with ethyl acetate and extracted multiple times with water and with a saturated sodium chloride solution. The organic layer was separated, dried (MgSO4), and the solvent removed under reduced pressure to give a brown oil. The oil was chromatographed on a 90 g KP-SIL 60 Δ Biotage column using 15% ethyl acetate in methylene chloride as the eluent. All fractions containing product were combined and the solvent removed under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.196 g, 60%) as a light yellow solid, mp 175-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([OH:18])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:21]1([CH2:24]O)[CH2:23][CH2:22]1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([O:18][CH2:24][CH:21]3[CH2:23][CH2:22]3)([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: OCC1CC1
Reactant: CC(F)(F)C1(O)c2cc(Cl)ccc2Nc2ncccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)C1(OCC2CC2)c2cc(Cl)ccc2Nc2ncccc21
Yield: 86.1 %

Procedure:
Method KK: To a stirred suspension of 7-chloro-5-hydroxy-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b] [1,8]naphthyridine (37) (173 mg, 0.583 mmol) in cyclopropyl methanol (1.2 mL, 14.58 mmol) was added trifluoroacetic acid (446 μL, 5.83 mmol). The resulting solution was heated at reflux for 3 h 15 min. The reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (40% EtOAc-hexane) afforded 39 (176 mg, 86% yield) as an off-white solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:24]2[CH2:36]I)=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>CN(C)C=O.O>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31])[CH2:25][C@H:24]2[CH2:36][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:22])=[CH:38][CH:39]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl malonate (660 mg) and 180 mg of 50% sodium hydride in 12.5 ml of dry dimethylformamide were stirred at room temperature in a nitrogen stream for 15 minutes, and 1.34 g of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine was added thereto. The resulting mixture was stirred at room temperature for 15 hours, neutralized with 3.75 ml of 1N hydrochloric acid, diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatogrphy to obtain (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11].C([O-])([O-])=O.[K+].[K+].CC(O)C>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.C1(C)C=CC=CC=1>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1)[CH3:11]
Reactant: O=C(O)c1ccsc1Br
Reactant: CCc1ccc(B(O)O)cc1
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: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2sccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-3-thiophenecarboxylic acid (3 g, 14.1 mmol), (4-ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.33 g (71%) of 2-(4-ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH:14]=[CH2:15])[CH:3]=1.[N:16]12[CH2:23][C:20]([CH2:24][NH2:25])([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:25][CH2:24][C:20]23[CH2:23][N:16]([CH2:22][CH2:21]2)[CH2:17][CH2:18][CH2:19]3)=[O:8])=[C:4]([O:12][CH2:13][CH:14]=[CH2:15])[CH:3]=1
Reactant: C=CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC12CCCN(CC1)C2
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2

Procedure:
Following the procedure of Example 1, the title compound is prepared from 4-amino-5-chloro-2-(2-propenyloxy)benzoic acid and 1-azabicyclo[3.2.1]octan-5-methanamine.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:19][C:17]1[CH:18]=[C:13]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[N:14]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[CH:16]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cc1cc(Cl)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(-n2cc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
0.385 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 10 ml of dimethylacetamide and at 0° C. 0.096 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.757 g of 2-chloro-4-methyl-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1) and twice with ethyl acetate and then washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.332 g of 4-methyl-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([C:5](=[O:8])[CH2:6][CH3:7])[CH3:4].[N:10](OCCCC)=[O:11]>C(OCC)C.C1(C)C=CC=CC=1>[OH:11][N:10]=[C:6]([CH3:7])[C:5](=[O:8])[C:3]([CH3:9])([CH3:4])[CH3:2]
Reactant: CCCCON=O
Reactant: CCC(=O)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=NO)C(=O)C(C)(C)C
Temperature: -10 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 40 g of hydrogen chloride in 156 g of diethyl ether is added dropwise at room temperature to 96 g (0.84 mol) of 2,2-dimethyl-3-pentanone in 960 g of toluene. After cooling to −10° C., a solution of 95 g of n-butyl nitrite in 470 g of diethyl ether is added dropwise. The mixture is stirred at from −10° C. to 0° C. for 4 hours and then allowed to come to room temperature. After a total of 16 h, the reaction mixture is washed three times with 1 l of ice-water each time and then extracted twice with 1 l of 1M sodium hydroxide solution each time. The alkaline phase is separated off and neutralized with 20% strength sulfuric acid. The crude product is filtered off with suction and, after drying, recrystallized from n-hexane. 66 g (55%) of the title compound are obtained as a pale yellow powder of melting point 107-110° C.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:28]C(OCC1C=CC=CC=1)=O)=[N:17]C(OCC1C=CC=CC=1)=O)[CH3:2].[ClH:39]>[Pd].CO.C(OCC)(=O)C>[ClH:39].[CH2:1]([S:3][C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH2:28])=[NH:17])[CH3:2]
Reactant: CCS[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 68 %

Procedure:
A methanol/ethyl acetate (1.5 mL/1.5 mL) solution of compound 18 (117 mg, 0.19 mmol) and 1N HCl (0.19 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC. indicated the disappearance of the starting material (about 1 h). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 40 mg (68%) of the title product as a foam.
Reaction SMILES: [CH:1]1[CH:14]=[C:13]2[C:4]([CH:5]3[C:16]([C:17](O)=[O:18])=[C:15]([C:20]([OH:22])=[O:21])[CH:12]2[C:11]2[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[CH:9]1[CH:10]=[C:11]2[C:6]([CH:5]3[C:16]4[C:17]([O:22][C:20](=[O:21])[C:15]=4[CH:12]2[C:13]2[C:4]3=[CH:3][CH:2]=[CH:1][CH:14]=2)=[O:18])=[CH:7][CH:8]=1
Reactant: O=C(O)C1=C(C(=O)O)C2c3ccccc3C1c1ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1OC(=O)C2=C1C1c3ccccc3C2c2ccccc21
Temperature: 0 °C
Yield: 92.5 %

Procedure:
As shown in FIG. 2A, diacid 2 (8.76 g, 29.2 mmol) was suspended in dry dichloromethane (ca. 300 mL) in a dry, septum-capped round-bottom flask, to which was added a few drops of dry dimethylformamide. The mixture was cooled to 0° C. in an ice-water bath and the flask was connected to a oil-bubbler with flexible plastic tubing. Oxalyl chloride (3.9 g, 30.7 mmol) was added dropwise with a syringe as the suspension was stirred. Within few minutes, gas was released through the oil bubbler as the reaction began. The reaction mixture was adequately cooled prior to the addition of oxalyl chloride to avoid a violent release of gas. The reaction mixture was allowed to warm to room temperature as it was stirred overnight (ca. 16 h), during which the reaction mixture became homogeneous. The solvent was evaporated under vacuum and the resulting crude product was recrystallized from toluene to give the title compound as pale beige crystals (7.41 g, 90%). 1H NMR (500 MHz, CDCl3): 7.45 (4H, dd, J=5.2 and 3.2 Hz), 7.09 (4H, dd, J=5.0 and 3.5 Hz), 5.55 (2H, s).
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C@H:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C@H:11]3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:23][CH:24]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCCN2CC[C@@H]3[C@H](C2)c2cccc4c2N3CCC4)cc1
Yield: 31.8 %

Procedure:
The title compound (0.14 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 1-(3-chloropropoxy)-4-fluorobezene (0.37 g, 2.0 mmol), KI (catalytic) and K2CO3(0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.78–2.08 (m, 7H), 2.10–2.30 (m, 1H), 2.32–2.50 (m, 3H), 2.51–2.72 (m, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 1H), 3.12–3.25 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 6.55 (t, J=7.5 Hz, 1H), 6.70–6.92 (m, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].S([O-])([O-])(=O)=O.[C:31](OC=O)(=[O:33])C>N1C=CC=CC=1>[O:24]=[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:25])[N:15]1[CH2:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][CH:31]=[O:33])[CH:4]=2)[NH:8][CH:7]=1
Reactant: NCc1ccc2[nH]cc(CCCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CC(=O)OC=O
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=CNCc1ccc2[nH]cc(CCCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Following the method described in Example 12 (i), a solution of 2-[3-[5-(aminomethyl)-1H-indol-3-yl]propyl]-1H-isoindole-1,3(2H)-dione, sulphate (0.75 g) was reacted with formic acetic anhydride (15 ml) in pyridine (27.5 ml) to give the title compound as a yellow solid (0.49 g) m.p. 150°-152° after crystallisation from ethyl acetate.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC(F)F)COC1
Temperature: 70 °C
Yield: 18.4 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (138 mg, 0.75 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (97.5 mg, 0.5 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=383.0 (M+H)+
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH:20][CH2:21][CH2:22][CH2:23][NH2:24]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][CH2:23][CH2:22][CH2:21][OH:20])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCO
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.300 g, 1.001 mmol), 3-hydroxypropyamine (0.08 ml, 1.001 mmol) and TEA (0.14 ml, 1.001 mmol) in MeCN (5 ml) was stirred at rt. After 18 h the mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) eluting with 33-80% EtOAc (+0.5% TEA) in petroleum ether 40-60° C. to give the title compound (0.145 g, 43%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.50 (m, 2H), 7.46-7.42 (m, 3H), 5.77 (t, 1H), 3.62 (q, 2H), 3.01 (q, 2H), 1.74 (s, 9H), 1.63 (qt, 2H); Mass Spectrum: M−H+ 337.