Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:5][N:4]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(Cl)(Cl)(Cl)[Cl:55]>O1CCCC1>[Cl:55][C:16]1[N:11]2[N:10]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSc1nccc(-c2nn3ccccc3c2-c2ccnc(SC)n2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CSc1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(SC)n2)n1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a −78° C. solution of 2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.72 g, 2.0 mmol) in tetrahydrofuran (50 mL) was added a 2 M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (2.9 mL, 5.9 mmol) dropwise. The reaction mixture was stirred for 15 minutes, then carbon tetrachloride (5 mL) was added. The reaction mixture was stirred for 1 hour and quenched with brine and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:9 acetone:dichloromethane) to give 260 mg (32%) of 7-chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine. 7-Chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.098 g, 0.24 mmol) was dissolved in dichlormethane (3 mL) and cooled to 0° C. To the solution was added 3-chloroperoxybenzoic acid (0.13 g, 0.73 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, and concentrated under reduced pressure. To 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.027 g, 0.062 mmol) was added 2-methoxyethylamine (2 mL) and the reaction was heated to 100° C. in a sealed tube overnight. The reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 acetone:dichloromethane to give 15 mg (49%) of N-(2-methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine. 1H NMR (CDCl3): δ 8.41 (d, 1H), 8.16 (d, 1H), 7.69 (d, 1H), 7.36 (d, 1H), 7.05 (m, 1H), 6.65 (d, 1H), 6.33 (t, 1H), 6.09 (d, 1H), 5.57 (m, 1H), 5.42 (t, 1H), 3.37–3.80 (m, 21H); MS m/z 494 (M+1).
Reaction SMILES: [CH2:1]([C:6]1([CH:23](Cl)[C:24]#[C:25][C:26]#[C:27][CH:28]([C:30]2([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:35][CH2:34][CH:33]([CH:36]3[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)Cl)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2-].[Na+].N.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:6]1([C:23]#[C:24][C:25]#[C:26][C:27]#[C:28][C:30]2([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:31][CH2:32][CH:33]([CH:36]3[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:38][CH2:37]3)[CH2:34][CH2:35]2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(C2CCC(CCCCC)(C(Cl)C#CC#CC(Cl)C3(CCCCC)CCC(C4CCC(CCCCC)CC4)CC3)CC2)CC1
Agent: N
Agent: [Cl-]
Agent: [NH2-]
Solvent: CCOCC
Product: CCCCCC1CCC(C2CCC(C#CC#CC#CC3(CCCCC)CCC(C4CCC(CCCCC)CC4)CC3)(CCCCC)CC2)CC1
Reaction time: 0.5 h

Procedure:
8.32 g of 1,6-bis(4,4′-dipentylbicyclohexyl-4-yl)-1,6-dichlorohexa-2,4-diyne are dissolved in 30 ml of diethyl ether and added dropwise to a solution of sodium amide in liquid ammonia (prepared from 1 g of sodium). After 30 minutes, the excess amide is decomposed using ammonium chloride, the ammonia is evaporated, and the residue is subjected to conventional work-up, giving 1,6-bis(4,4′-dipentylbicyclohexyl-4-yl) hexa-1,3,5-triyne (C 90 N (63) I, Δε=−1.56, Δn=−0.028).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:11]4)[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=N
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 19 Step 2, 1.41 g, 4.57 mmol) and 2-oxopropanethioamide (Intermediate 2, 1.42 g, 13.7 mmol) were dissolved in dry MeOH (30 mL) and the resulting solution was heated at 60° C. under an atmosphere of nitrogen. After 15 h the reaction was allowed to cool to r.t. A precipitate had formed which was filtered off and dried in vacuo, yielding the title compound (1.16 g, 64% yield) as a mixture of isomers. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.18 (m, 4 H), 1.47 (m, 2 H), 1.87 (m, 2 H), 2.27 (m, 3 H), 3.03 (m, 3 H), 3.20 (s, 3 H), 6.98 (d, 1 H), 7.34 (d, 1 H), 7.51 (dd, 1 H); MS (APCI+) m/z 394 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N#N.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1(C)C=CC=CC=1.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>[CH:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:15]
Reactant: Clc1ccc2ccccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccccc2n1
Temperature: 125 °C
Yield: 73.9 %

Procedure:
2-chloroquinoline (1-1) (1.00 g, 6.1 mmol) in toluene (25 mL) was sparged with N2 gas for 5 min, and tributyl(vinyl)stannane (2.52 g, 2.33 mL, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.353 g, 0.31 mmol) were added. The mixture was heated at 125° C. for 1 h, then cooled and concentrated in vacuo. The residue was suspended in CH2Cl2 (20 mL) and purified by silica gel flash column chromatography (80 g cartridge), eluting with 0-30% EtOAc/hexanes over 20 min. The fractions containing the desired product (1-2) were pooled, and after solvent removal in vacuo, 700 mg (74%) of a clear oil were obtained. LC/MS: m/z (M+H)=156.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1.[NH3:13].Cl>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1nc(Br)cnc1O
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(Br)cnc1O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In 3 mL of methanol is suspended 0.6 g of methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 1969, 12(2), 285-287]. Then, 6 mL of 25% aqueous ammonia is added thereto and the resulting solution is stirred at ambient temperature for 17 hours. The reaction mixture is adjusted to pH 3 by adding 6 mol/L hydrochloric acid. The solvent is distilled off under reduced pressure. Isopropyl ether and water are added to the residue and filtered to obtain 0.33 g of 6-bromo-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(O)C[C@H]1C(=O)NC1(C#N)CC1
Reaction time: 4 h

Procedure:
To a solution of (1R,2R)-2-(1-cyano-cyclopropylcarbamoyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester (0.38 mmol) in THF (2.0 ml) was added at −15° C. sodium borohydride (0.38 mmol) and stirring was continued for 4 h. The mixture was partitioned between 1N aqueous HCl and ethyl acetate, the organic layer was dried, evaporated and the residue chromatographed on silica using ethyl acetate to give (1R,2R)-2-(1-cyano-cyclopropylcarbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester as a 2:1 mixture of epimers as a colorless solid. MS: 267.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.CO[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=1.N12CCCCC1C=CCCN2>CO>[C:7]([C:6](=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]1)[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:8]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COC1=NCCCCC1
Agent: C1=CC2CCCCN2NCC1
Solvent: CO
Product: N#CC(=C1CCCCCN1)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
Agitate a mixture of 5.0 g of 4-chlorobenzyl cyanide, 5.5 g of caprolactim methyl ether and 0.5 g of diazabicyclo [5.4.0]undec-5-ene under nitrogen for 18 hours at 125°. Cool the thus-obtained reaction mixture to ambient temperature and then rub down the crystallizing residue with 20 ml of methyl alcohol before filtering to obtain 5.5 g of the title compound. Recrystallize this compound from methyl alcohol to obtain a product with a MP of 114° to 117°.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:44](=[C:45]([NH:47][S:48]([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)(=[O:50])=[O:49])[CH:46]=1)[NH:43][C:42]([C:56]([NH:58][CH2:59][CH2:60][S:61]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:41]2.C(=O)([O-])O.[Na+]>ClCCl>[S:61]1[CH2:60][CH2:59][N:58]=[C:56]1[C:42]1[NH:43][C:44]2[C:40]([CH:41]=1)=[CH:39][C:38]([O:37][CH3:36])=[CH:46][C:45]=2[NH:47][S:48]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)(=[O:49])=[O:50]
Reactant: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C3=NCCS3)cc2c1
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
A mixture of triphenylphosphine oxide (1.15 g), trifluoromethanesulfonic anhydride (0.35 mL) and dichloromethane (12 mL) was stirred for 15 min under ice-cooling. 5-Methoxy-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.45 g) was added, and the mixture was stirred for 2 hr under ice-cooling. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in ethyl acetate-hexane, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-40:60), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (114 mg, yield 42%) as pale-yellow prism crystals. melting point 188-189° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:23][N:24]=O)CCC.[Na].[Cl-].[Na+]>O1CCCC1.C(OCC)C.Cl>[OH:23][N:24]=[C:12]1[C:11](=[O:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=C1CCC(c2ccccc2)Oc2ccccc21
Reactant: CCCCON=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C(=NO)CC(c2ccccc2)Oc2ccccc21
Temperature: -20 °C
Reaction time: 48 h
Yield: 90.8 %

Procedure:
5.36 g (22.5 m moles) of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one (compound R1 of Reference Example 1) was dissolved in a mixture of 130 ml of tetrahydrofuran and 230 ml of ethyl ether, and 13.4 ml of hydrogen chloride-saturated ethyl ether was added to the solution, which was then cooled to -20° C. 5.79 ml (49.5 m moles) of sodium butylnitrite was added dropwise to the solution, and the reaction mixture was allowed to stand at -15° C. to -20° C. for two days. A saturated sodium chloride aqueous solution was added to the reaction mixture to separate the phases. An organic phase was obtained, washed with water, and dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated, and the concentrate was washed with hexane and dried to obtain 5.46 g (yield 90.8%) of the desired compound.
Reaction SMILES: C([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7](O)=[O:8])C(C)C.C(OC(=O)C)(=O)C.[NH4+:21].[OH-]>>[C:7]([NH2:21])(=[O:8])[CH2:6][CH2:5][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: NC(=O)CCCC(=O)O

Procedure:
Accordingly, 3-isobutylglutaric acid, compound 1, is converted into the corresponding anhydride, compound 2, by treatment with acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 3, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 3-salt. Combining the salt with an acid liberates the R enantiomer, compound 4. Finally, Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([CH3:12])=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[S:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[C:4]([F:13])[C:5]=3[CH3:12])[NH:9][C:8]=2[CH3:11])=[N:16]1
Reactant: Clc1nsc2ccccc12
Reactant: Cc1cc2c(C)c(F)cc(Cl)c2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1[nH]c2c(Cl)cc(F)c(C)c2c1-c1nsc2ccccc12
Reaction time: 1 h

Procedure:
A solution of the product from step b) (200 mg) and 3-chloro-1,2-benzisothiazole (171 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 hour, and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated. The residue was purified by silica chromatography using 20% acetone in isohexane as eluent to give the title compound (219 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[NH2:20][C:19]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]#[N:17])[CH:18]=1
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 2 h

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)succinonitrile (1.0 g) and sodium bicarbonate (40 ml of a saturated aqueous solution) and dichloromethane (915 ml) was stirred at 20° C. for 3 hours at pH 9. Sodium carbonate solution was then added until the pH was 11 and the stirring continued overnight. A small amount of sodium hydroxide solution was added to give a pH of 12, followed three hours later by a small quantity of Aliquat 336 (trademark, tricaprylylmethylammonium chloride), and after 2 hours the reaction was complete. A dichloromethane extract was washed (water and brine), dried (sodium sulfate) and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[OH:29][CH:27]1[CH2:28][N:25]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: OC1CNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CC(O)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) and azetidin-3-ol hydrochloride (70.7 mg, 0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropy)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (215 mg, 91%) as a colourless oil. MS: m/e=366.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:26]1[CH:25]=[C:24]([S:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=3)[CH2:16][CH2:17]2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(Cl)c3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
To a stirred solution of {4-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 0.19 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (57 mg, 65%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (br. s., 1H), 7.95 (dd, J=9.0, 6.1 Hz, 1H), 7.84-7.92 (m, 2H), 7.71-7.83 (m, 3H), 7.69 (s, 1H), 7.34-7.42 (m, 2H), 3.83 (d, J=11.2 Hz, 2H), 3.27-3.34 (m, 7H), 2.63 (t, J=11.2 Hz, 2H), 1.88-1.96 (m, 2H), 1.69-1.83 (m, 2H); MS cald. for C23H22ClFNO4S [(M−H)+]: 462, obsd. 462.2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:23])[CH:20]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)[CH3:21])[CH3:17]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Cc2ccc(Cl)cc2)cc1
Yield: 72.6 %

Procedure:
A solution of 22 g of 4-(4-chlorobenzyl)-phenol and 18.5 g of α-bromopropionic acid ethyl ester in 100 ml of dimethyl formamide was stirred for 2 hours at 100° C together with 16 g of potassium carbonate. After cooling, the reaction mixture was poured into 1 liter of water. An oil precipitated which was separated and dried over sodium sulfate. By means of vacuum distillation, 23.3 g of 2-[p-(4-chlorobenzyl)-phenoxi]-propionic acid ethyl ester were obtained. b.p.: 146° - 151° C/0.1 mm Hg/nD22 : 1.5527 ##STR4##
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].N1C=CC=CC=1.Cl.[CH2:16]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:16]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])=[O:38])=[CH:40][CH:41]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)C(F)(F)F)cc1

Procedure:
A solution of 1.25 g. of trifluoromethanesulfonamide in 35 ml. of pyridine was treated with 3.5 g of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride at 10°-15° C. and then stirred under reflux for 3 hours. Evaporation afforded a gum which was stirred with 150 ml. of H2O and extracted with three 50 ml. portions of CHCl3. The extracts were combined, dried (MgsO4), and evaporated to yield a white solid. Crystallization from ether-acetone gave 2.0 g. of product, melting point 172°-174° C.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.ClCCl.CCOCC>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: OCC1CCCC1
Reactant: Clc1cncc(Cl)n1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Clc1cncc(OCC2CCCC2)n1
Reaction time: 2.5 h
Yield: 61 %

Procedure:
K-t-BuO (1.65 g, 14.7 mmol) was added portionwise to a stirred mixture of cyclopentanemethanol (2.99 g, 29.9 mmol) and 2,6-dichloropyrazine (1.90 g, 12.8 mmol) in dioxane (6 mL) at 0° C. (ice-bath). The reaction mixture was then stirred for 2.5 h, while the temperature was allowed to reach room temperature. The reaction mixture was diluted with dichloromethane/ether (1:1), filtered, and concentated in vacuo. The beige liquid was purified by column chromatography on silica gel (18×4 cm) using n-hexane/ethyl acetate (94:6) as eluent. Two chromatographic runs afforded 1.66 g (61%) of the title compound as a colorless oil. HRMS m/z calcd for C10H13ClN2O (M)+212.0716, found 212.0723. Anal. (C10H13ClN2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@H:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@H:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: C[C@@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (R)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C22H23ClN4O2 (410.90); mass spectrum: (M+H)+=411/413 (chlorine isotope) and (M−H)-=409/411 (chlorine isotope).