Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][CH2:6][C:7]([OH:9])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:6][C:7]([O:3][CH2:2][CH2:1][O:4][C:7](=[O:9])[CH2:6][Cl:5])=[O:9]
Reactant: OCCO
Reactant: O=C(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCl)OCCOC(=O)CCl
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In a 2 liter, 4 necked round bottom flask equipped with a mechanical stirrer, a solution of ethylene glycol (100 grams, 1.611 moles), chloroacetic acid (385 grams, 4.031 moles) and para toluenesulphonic acid (1 gram) in toluene (750 ml), was refluxed for 8 hours using a Dean-Stark apparatus. It was then cooled to room temperature. The toluene layer was washed with water (2×300 ml), 5% sodium bicarbonate solution (3×500 ml) and again with water (2×300 ml), dried over sodium sulfate, and distilled to provide crude 1, which was purified by high vacuum distillation to provide pure 1 (242 grams, 69.8%), which slowly crystallized to white crystals. m.p: 44° C., IH NMR (CDCl3) δ4.16 (s, 2H, CH2), 4.85 (s, 2H, CH2)
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.C(N)C.Br[C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[OH-].[K+].S(=O)(=O)(O)O>[Cu](Cl)Cl.C(OCC)C.O.CO.CN1CCCC1=O>[C:1]1([C:7]#[C:8][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCC#CBr
Reactant: C#Cc1ccccc1
Agent: Cl[Cu]Cl
Agent: CCN
Agent: Cl
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CCCCCCCCC#CC#Cc1ccccc1
Reaction time: 6 h
Yield: 48 %

Procedure:
A four neck flask was charged with 10 ml of N-methylpyrrolidone, and 1.02 g (10 mM) of phenylacetylene was dissolved therein. Separately one dropping funnel was charged with 150 mg of hydroxylamine hydrochloride, 100 mg of copper chloride and 5 g of a 70% aqueous solution of ethylamine, and another dropping funnel was charge with 2.61 g (10 mM) of 11-bromo-10-undecynoic acid in 10 ml of a 10 % methanol solution of potassium hydroxide. After attaching the funnels to the flask, the flask was filled with nitrogen gas and then the mixture was kept at 15° C. First the ethylamine solution of copper chloride was added dropwise while vigorously agitaging the mixture in the flask. Then the methanol solution of potassium hydroxide which dissolved 11-bromo-10-undecynoic acid was added dropwise for 1 hour at 20° C. while agitating the mixture. The agitation was continued for another 6 hours at 20° C. While keeping the inner temperature of the vessel at a temperature of not more than 22° C., 2N-aqueous sulfuric acid solution was added dropwise to change the reaction mixture from alkaline state to acid state. After adding 100 ml of water, the mixture was extructed with 500 ml of diethyl ether. The obtained ether layer was dried on anhydrous sodium sulfate, followd by removing the ether. The residue was recrystallized from petroleum ether to give a crystal of 13-phenyl-10,12-tridecadiynoic acid (yield: 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])(C(O)=O)[C:21]([OH:23])=[O:22])=[C:8]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:7]=[CH:6]2.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:21]([OH:23])=[O:22])=[C:8]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Temperature: 120 °C
Yield: 88.2 %

Procedure:
Next, the resulting 2-[7-[6-methoxy-2-(4-methoxyphenyl) napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)-malonic acid (1.0 g) was dissolved in dimethyl sulfoxide (10 ml) and the mixture was heated for 4 hours at 120° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (820 mg, Yield 94%).
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to −20° C., then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-fluoropropionate H-4.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH:42]4[O:46][CH2:45][CH2:44][O:43]4)=[CH:37][CH:36]=3)[N:31]=2)[CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C>CO>[CH3:45][O:46][CH:42]([O:43][CH3:44])[CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[N:31]=[C:30]([CH2:29][O:28][C:24]3[CH:23]=[C:22]([CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH2:14])[CH:27]=[CH:26][CH:25]=3)[O:34][N:33]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(CC4OCCO4)cc3)no2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(Cc1ccc(-c2noc(COc3cccc(C(N)c4ccccc4)c3)n2)cc1)OC
Yield: 96.6 %

Procedure:
Hydrogen chloride in dioxan (4.0 M, 5 mL, 24 mmol) was added to a solution of tert-butyl((3-((3-(4-((1,3-dioxolan-2-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate (1.01 g, 1.85 mmol) in methanol (5 mL), and the resultant solution was stirred at ambient temperature for 2 hours. The solvent was evaporated at reduced pressure, and the residue was loaded onto an SCX-2 cartridge. The cartridge was eluted with methanol (eight column volumes) followed by ammonia/methanol. Fractions containing the product were combined and evaporated at reduced pressure to afford the title compound (0.796 g, 96%).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([S:19][C@@H:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[S:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6].O.Cl>CO.[Cl-].[Na+].O>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([S:19][C@@H:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[S:25][CH2:26][C:27]([OH:29])=[O:28])[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]=1[OH:14])([CH3:4])[CH3:6]
Reactant: COC(=O)CS[C@@H]1CCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
Lithium hydroxide hydrate (1.0 g, 0.025 mole) was added to a solution of the compound of Example 8 (4.13 g, 0.010 mole) in methanol (40 ml). Water (20 ml) was added over 10 minutes to the reaction mixture. 1.0N hydrochloric acid (25 ml) was added slowly to the reaction mixture followed by water (50 ml) and brine (50 ml). The mixture was extracted twice with 75 ml of diethyl ether. The combined diethyl ether extracts were washed with brine (25 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil by a gentle flow of nitrogen gas. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>>[C:1]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)CCO
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)OCCN(C)C

Procedure:
The procedure of Example II is repeated employing lauroyl chloride and 2-dimethylaminoethanol to form 2-dimethylaminoethyl laurate. When the intermediate is quarternized with 1-bromodecane, the softening compound produced is N-(2-dodecanoyloxyethyl)-N,N-dimethyldodecanaminium bromide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2.N1CCCCC1>CO>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:20]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])/[C:33](=[O:39])[NH:34]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 57 %

Procedure:
3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (40 mg, 0.134 mmol) and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 were dissolved in 0.3 ml of methanol under stirring, and added with piperidine (0.03 ml, 0.3 mmol) to the solution. Upon the completion of the addition, the mixture was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 28 (40 mg, yield 57%) as a yellow solid.
Reaction SMILES: C(OO)(=[O:3])C.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1.CCCCCC>C(Cl)(Cl)Cl>[NH2:6][C:7]1[N+:12]([O-:3])=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([Cl:18])[N:8]=1
Reactant: COC(=O)Nc1cc(Cl)nc(N)n1
Reactant: CC(=O)OO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C

Procedure:
32 ml (0.20 mol) of 40% peracetic acid are added slowly to a solution of 20.2 g (0.10 mol) of methyl 2-amino-6-chloro-4-pyrimidinecarbamate in 500 ml of chloroform. The suspension obtained is warmed to 50° for 4 hours, whereby a clear solution gradually results. After cooling to room temperature, there is obtained by the slow addition of hexane a crystalline precipitate which is recrystallized from chloroform/methanol. There is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide of melting point 220°-221°.
Reaction SMILES: [C:1]([O:4][CH:5](I)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O:44][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(=O)OC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a mixture of the above 1-iodoethyl acetate (311 mg, 1.457 mmol) and chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 201.7 mg, 0.327 mmol) in dimethylformamide (6 mL) was added cesium carbonate (659 mg, 2.00 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was taken up in ethyl acetate, washed with water and then brine. The organic layer was dried over sodium sulfate and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 20/80) to give 1-acetoxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (149.4 mg, 65% yield). MS (ES+) m/z calcd. for C35H36Cl2F2N3O6: [(M+H)+]: 702.19, found: 702.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][N:44]1[CH:48]=[N:47][C:46]([CH2:49]O)=[N:45]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([O:23][CH2:49][C:46]3[N:47]=[CH:48][N:44]([CH3:43])[N:45]=3)=[N:13][C:12]=12
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Reactant: Cn1cnc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2nc3c(-c4ccccc4F)nnn3cc2-c2ccccc2)n1
Yield: 48.8 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (77 mg, 0.25 mmol), triphenylphosphine (165 mg, 0.63 mmol) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (80 mg, 0.63 mmol) were suspended in dry tetrahydrofuran (1.5 ml). Diethyl azodicarboxylate (100 μl, 0.63 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 48 hours before purification by preparative tlc (40% EtOAc/hexanes) to give a white solid which was recrystallised from ethyl acetate/hexanes to afford 3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (49 mg, 49%) as white needles, m.p. 170-171° C.; δH (400 MHz, d6-DMSO) 3.84 (3H, s, NCH3), 5.57 (2H, s, OCH2), 7.35-7.41 (2H, m, ArH), 7.43-7.51 (4H, m, ArH), 7.73 (2H, dd, J=8.1 and 1.8 Hz, ArH), 8.14 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.45 (1H, s, triazole CH), 9.51 (1H, s, pyrimidine CH); m/z (ES+) 402 (M+H+).
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23](F)[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1>C(O)(=O)C.C(O)C>[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23]([NH:1][CH3:2])[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1
Reactant: c1ccncc1
Reactant: Cc1c(F)c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: CN
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 30 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-5-hydroxy-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 30° C. for 2 days. Acetic acid (1 drop) and ethanol (1 ml) were added to the reaction mixture, and the solvent was distilled off. Methanol was added to the residue, and solids were collected by filtration to obtain the title compound (33 mg) as a brown powder.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: CC(=O)c1ccc(F)cc1N(C)C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1cc(F)ccc1C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of sulphuryl chloride (20.6 ml) in dichloromethane (30 ml) was added dropwise over a period of 45 minutes to the solution of 2'-acetyl-5'-fluoro-N-methylformanilide whilst maintaining the temperature below 2° with ice/water cooling under a nitrogen atmosphere. The mixture was stirred for 3 hours maintaining the temperature below 2°. Water (80 ml) was added dropwise over 15 minutes maintaining the temperature below 10°. The dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-5'-fluoro-N-methylformanilide.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N isopropyl chloroformate in toluene (0.3 mL, 0.3 mmol) dropwise and stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (49 mg, 48%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.31-1.49 (m, 6H), 1.52-1.64 (m, 1H), 1.65-1.88 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.10-2.20 (m, 2H), 2.26 (d, J=7.81 Hz, 1H), 2.89-3.15 (m, 4H), 3.31-3.44 (m, 2H), 3.42-3.51 (m, 2H), 3.53-3.64 (m, 1H), 4.78-4.90 (m, 1H). MS (M+1): 407.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:4]=2[NH:3]1.[Li+].[OH-].Cl>O1CCOCC1>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of 18 (1.0 mmol) in dioxane (4 mL) was added aqueous LiOH (1 M, 4 mL, 4.0 mmol). The solution was stirred at 23° C. for 1 h and then quenched with aqueous HCl (4 M, 2 mL, 8 mmol). The resulting solid was isolated by filtration, washed with water and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=12.81 (s, 1H), 10.88 (s, 1H), 7.48-7.54 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 4.67 ppm (s, 2H). ESI-MS: m/z 194.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Agent: [Yb]
Solvent: ClCCl
Product: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=O)=[C:15]([O:24][CH3:25])[CH:14]=1.[NH2:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:32]([N:30]1[CH:31]=[C:27]([NH:26][C:20](=[O:22])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[O:24][CH3:25])[CH3:23])[CH:28]=[N:29]1)[CH3:33]
Reactant: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)O
Reactant: CCn1cc(N)cn1
Product: CCn1cc(NC(=O)C(C)c2ccc(Oc3ccnc4ccc(F)cc34)cc2OC)cn1
Yield: 39 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-[4-(6-fluoroquinolin-4-yloxy)-2-methoxyphenyl]propionic acid was reacted with 4-amino-1-ethylpyrazole. The resultant mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid in 39% yield; 1H NMR: (DMSOd6) 1.32 (t, 3H), 1.38 (d, 3H), 3.81 (s, 3H), 4.02-4.11 (m, 3H), 6.7 (d, 1H), 6.85 (m, 1H), 7.0 (d, 1H), 7.38-7.44 (m, 2H), 7.75 (m, 1H), 7.90 (s, 1H), 7.96 (m, 1H), 8.12 (m, 1H), 8.69 (d, 1H), 9.97 (s, 1H); Mass Spectrum: M+H+ 435.