Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[NH2:9][CH2:10][CH2:11][SH:12].[ClH:13]>C(O)(=O)C>[ClH:13].[ClH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CN
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN

Procedure:
Sodium amide (0.39 g., 0.01 mole) was dissolved in 40 ml. of liquid ammonia and 4.11 g. (0.01 mole) of [(5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide was added. The suspension was stirred at -40° C. for one hour and then allowed to warm to room temperature as the ammonia evaporated. The triphenyl phosphine was extracted from the residue with benzene and the remaining solids were taken up in water and extracted with chloroform. The chloroform extracts were dried and evaporated to give 4-aminomethyl-5-methylimidazole in 70% yield. This amine was refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH:12](=O)[CH:13]=[CH:14][CH:15]=[CH:16][CH3:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH3:17])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CC=CC=CC=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC=CC=CC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 72.5 %

Procedure:
4 Grams (0.021 mole) of 3-carboxymethylrhodanine was dissolved into 30 ml of acetic acid. To the solution were added 2 g (0.021 mole) of hexa-2,4-dienal and 3.8 g (0.046 mole) of sodium acetate, and the resultant was stirred under mild reflux for 5 hours. The obtained black reaction mixture was concentrated to about one-half its initial volume under reduced pressure. The residual mixture was poured into water to form precipitate. The precipitate was extracted with ethyl acetate and the extract was recrystallized from a mixed solvent of methylene chloride and ethyl acetate to give 4.1 g of 3-carboxymethyl-5-(2,4-hexadienylidene)rhodanine in the form of yellow prism (yield: 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:49])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:22])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and hexylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-hexylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (42.7 mg).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([O:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[O:20][C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:12])(C)(C)C>Cl.O1CCOCC1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:15]3[C:14]([O:13][C@H:11]([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 420 mg (0.81 mmol) (6R)-6-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}heptanoic acid tert.-butyl ester in 5.3 ml 4 N hydrogen chloride in dioxan and stir for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 200 mg (53% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[ClH:10].[Cl:11]N1C(=O)CCC1=O>C(OCC)C>[ClH:11].[Cl:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CCOCC
Product: O=C(CCl)c1cccnc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 12 g (11 mL, 100 mmol) of 3-acetylpyridine in 100 mL of ethyl ether was added 100 mL of 1 M ethereal hydrogen chloride. The resultant precipitate was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1 M hydrogen chloride in acetic acid. After the mixture was stirred until all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved. After 4 h, a white precipitate had formed. The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of ethyl ether to give 15.2 g (83%) of the title compound as a white solid: 1H NMR (200 MHz, d6 -DMSO) δ9.22 (t, H, J=1 Hz), 8.29 (dd, 1H, J=1.6, 5.1 Hz), 8.55 (td, 1H, J=2, 8.1 Hz), 7.82 (ddd, 1H, J=0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH3:21])=[CH:19][C:18](=[O:22])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]2)=[C:7]([CH3:23])[CH:6]=1)(=[O:3])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH:21]=[O:25])=[CH:19][C:18](=[O:22])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]2)=[C:7]([CH3:23])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cn(-c2ccc(OC(C)=O)cc2C)c(C)cc1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(OC(C)=O)cc2C)c(C=O)cc1=O
Yield: 72 %

Procedure:
In 315 ml of dioxane was dissolved 10.5 g of methyl 1-(4-acetoxy-2-methylphenyl)-6-methyl-4-oxo-1,4-dihydronicotinate under heating, and 4.43 g of selenium dioxide was added thereto. They were reacted at 100° C. for 2 hours. After cooling the reaction mixture, to room temperature, selenium was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (25:1 by volume) mixture) to obtain 7.9 g of methyl 1-(4-acetoxy-2-methylphenyl)-6-formyl-4-oxo-1,4-dihydronicotinate having a melting point of 216°-217° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH:19]=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([Mg]Cl)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([CH:19]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)[OH:20])[CH2:23][CH2:22]1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: Cl[Mg]C1CC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C(O)C2CC2)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.25 g, 0.87 mmol) was dissolved in dry THF (9 mL) and chilled to 0° C. Cyclopropylmagnesium chloride (2.6 mL of a 0.5M solution in THF, 1.5 eq.) was then added by syringe to the cold reaction mixture and stirred at 0° C. for 30 minutes. The mixture was then quenched with saturated ammonium chloride solution, extracted with EtOAc, extracts dried over sodium sulfate and concentrated to provide cyclopropyl(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (0.285 g, 98%). m/z (APCI-pos) M+1=329.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Reactant: O=CCCc1ccccc1
Product: O=c1[nH]c2ccc(NCCCc3ccccc3)cc2s1

Procedure:
By reaction of 6-amino-2-benzothiazolone (1.66 g) with 3-phenylpropanal using the procedure of Example 1, the title compound (0.82 g) was prepared.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[C:1]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCCC1
Yield: 102 %

Procedure:
A 50 mL round-bottomed flask containing cyclohexanone (3.82 g, 39 mmol) in anhydrous toluene (20 mL) was fitted with a Dean-Stark trap containing 3 Å molecular sieves, reflux condenser and a heating mantle, pyrrolidine (6.00 mL) was added, and the solution heated to reflux for 18 h. The solvent was evaporated and the crude product 1-cyclohex-1-en-1-ylpyrrolidine was used directly for the next reaction. (6.0 g, 102% yield, 95% purity by HPLC). MS(ESI+): 152.3; MS(ESI−): 150.1.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1OC)[CH2:10]O)=[S:7])(C)(C)C.[ClH:21].[OH2:22]>>[ClH:21].[NH2:5][C:6]1[S:7][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:22])[CH:14]=2)[N:8]=1
Reactant: COc1cnccc1CC(CO)NC(=S)NC(C)(C)C
Reactant: O
Agent: Cl
Product: NC1=NC(Cc2cc[nH]c(=O)c2)CS1
Temperature: 100 °C

Procedure:
A suspension of 0.4 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-methoxy-pyridin-4-yl-methyl)ethyl]-thiourea in 4 mL of aqueous solution of 6N hydrochloric acid is heated at a temperature of about 100° C. for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue obtained is taken up by 25 mL of distilled water and the mixture is washed with 2 times 20 mL of dichloromethane. The aqueous phase is evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue is taken up with 2 times 15 mL of ethanol and concentrated according to the conditions described above, then dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. for 4 hours. About 0.31 g of racemic 4-(2-amino-4,5-dihydro-thiazol-4-ylmethyl)-1H-pyridin-2-one hydrochloride, are obtained in the form of a pale yellow solid melting at 124° C. This product is purified by chromatography on a column of CHIRALCEL OD 20μ in an heptane-ethanol-triethylamine mixture (80/20/0.1 by volume). The fractions containing the expected product are collected and concentrated under reduced pressure (1 kPa) at a temperature of about 40° C. and then the residue is dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. About 0.0131 g of (+)-4-(2-Hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-thiazol-2-ylamine, (αD2°=+12.1+/−0.7 in the 0.5% DMSO) are obtained. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 2.73 (dd, J=13.5 and 7 Hz, 1H); 2.80 (dd, J=13.5 and 7 Hz, 1H); 3.27 (dd, J=11.5 and 5.5 Hz, 1H); 3.62 (dd, J=11.5 and 7.5 Hz, 1H); 4.53 (mt, 1H); 6.13 (dd, J=6.5 and 1.5 Hz, 1H); 6.24 (s large, 1H); 7.34 (d, J=6.5Hz, 1H); from 8.90 to 9.40 (mf very broad, 2H); from 9.60 to 10.40 (mf very broad, 1H)].
Reaction SMILES: [OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@@H:2]([O:1][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8]
Reactant: COC(=O)C[C@H](C)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl (S)-(+)-3-hydroxybutyrate (0.48 g, 4.04 mmol) (Aldrich) was dissolved in dichloromethane (6 mL, dried over molecular sieves). Imidazole (0.39 g, 5.65 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenylsilyl chloride (1.05 mL, 4.04 mmol) was added dropwise and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with additional dichloromethane, washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes) gave (S)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester. (Yield 1.33 g, 92.4%).
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6]1.[CH2:13](O)[CH3:14]>CN(C)C1C=CN=CC=1>[S:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6]1
Reactant: CCO
Reactant: O=C(O)c1ccsc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccsc1
Reaction time: 48 h
Yield: 91 %

Procedure:
13 ml (200 mmol) of thionyl chloride are added dropwise, at 0° C., to a solution of 9 g (70 mmol) of 3-thiophenecarboxylic acid and 86 mg (0.7 mmol) of 4-dimethylaminopyridine in 100 ml of ethanol. The reaction medium is stirred from 0° C. to room temperature over 48 hours and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/dichloromethane mixture. 10 g (91%) of ethyl thiophene-3-carboxylate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:10]1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.O>ClCCl>[CH2:32]([O:33][C:34](=[O:35])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10]2)=[C:2]([F:1])[CH:3]=1)[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1)OCc1ccccc1
Yield: 81.5 %

Procedure:
The above-described product 19a (1 g, 3.9 mmol) was dissolved in dichloromethane (4 mL), and then anhydrous potassium carbonate (0.6 g) was added thereto. Then, Cbz-Cl (1.863 g, 1.537 mL) was slowly dropped, at a rate of 1-2 drops per second, into the mixture maintained in an ice-salt bath. The resultant mixture was reacted for 4 hours at room temperature. After completion of the reaction, water was added into the reaction mixture, followed by extraction with ethyl acetate. The combined ethyl acetate phase was evaporated in vacuum to get a crude product, which was recrystallized with acetone to afford the product 20a (1.235 g) as a white solid, with a yield of 80.8%.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[C:17]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:16]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH3:40][C:8]1[CH:9]=[C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[C:17]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:16]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 546.1 (M+); Rt: 1.85 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1cc(I)ccc1C(=O)O
Product: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-Amino-4-iodo-benzoic acid was sulfonylated with 2,6-difluorobenzenesulfonyl chloride as in EXAMPLE 1, Part A. 1H NMR (500 MHz, CD3OD): 8.05 (d, J=1.6, 1H), 7.72 (d, J=8.4, 1H), 7.68-7.60 (m, 1H), 7.48 (dd, J=8.4, 1.6, 1H), 7.16-7.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(F)c1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-fluoro-2-hydroxy-4-methylbenzoic acid (10.5 g) in methanol (50.0 mL) was added sulfuric acid (5.00 mL) at room temperature, and the mixture was stirred at 60° C. for 24 hr. The solvent was evaporated under reduced pressure, to the residue were added water and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.40 g).
Reaction SMILES: N([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]N2C=NC=N2)=[CH:5][CH:4]=1)N.COC(OC)CC[CH2:20][N:21]1CCC1.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[NH:21]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:9]=[CH:20]1
Reactant: NNc1ccc(Cn2cncn2)cc1
Reactant: COC(CCCN1CCC1)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole (0.92 g, 4.1 mmol) and 4-(1-azetidinyl)butanal dimethylacetal (0.65 g, 3.8 mmol), in 4% H2SO4 (30 ml), was refluxed for 4.5 h. The solution was cooled to room temperature, basified with K2CO3 and extracted with EtOAc (4×100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed on silica-gel eluting with CH2Cl2 /MeOH/NH3 (40:8:1) to give the title-indole. The hydrogen oxalate hemihydrate salt was prepared (30 mg); m.p. 128°-129° C. Found: C, 57.28, H, 5.95; N, 18.05. C16H19N5.C2H2O4.0.45 H2O requires C, 56.97; H, 5.82; N,18.45%). δ (360 MHz, D2O) 2.30-2.54 (2H, m, CH2), 3.07 (2H, t, J=7.0 Hz, CH2), 3.52 (2H, t, J=7.0 Hz, CH2), 3.94-4.13 (4H, m, 2 of CH2), 5.51 (2H, s, CH2), 7.20 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 7.30 (1H, s, Ar--H), 7.51 (1H, d, J=8.4 Hz, Ar--H), 7.62 (1H, s, Ar--H), 8.05 (1H, s, Ar--H), 8.56 (1H, s, Ar--H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([OH:8])[CH3:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>Cl.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:7])[O:8][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][O:15]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(OC1CCCCO1)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 269 parts of p-bromo-α-methylbenzyl alcohol and 225 parts of 2H-3,4-dihydropyran is stirred and cooled to 0° C. Then there are added dropwise 10 drops of concentrated hydrochloric acid solution and the whole is stirred in an ice-bath (room temperature is reached). After stirring for 24 hours, the reaction mixture is poured onto 1200 parts of ether. The organic phase is washed twice with a sodium hydrogen carbonate solution and twice with water, dried, filtered and evaporated. The residue is distilled, yielding 2-(p-bromo-α-methylbenzyloxy)tetrahydropyran; bp. 165°-177° C. at 20 mm. pressure.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C=C(N2CCOCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.60 g, 1.59 mmol) and morpholine (3 ml) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=4)([CH3:31])[C:19](=[O:30])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>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.C1COCC1>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@:18]2([CH3:31])[N:17]3[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])=[CH:14][N:15]=[C:16]3[N:20]([C:21]3[CH:22]=[C:23]([Cl:29])[C:24]([F:28])=[C:25]([Cl:27])[CH:26]=3)[C:19]2=[O:30])=[CH:34][CH:35]=1)#[N:40]
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ester obtained (12.6 g, 22 mmol) was combined with THF (100 mL). Morpholine (18.6 mL, 210 mmol) and Pd(PPh3)4 (500 mg, 0.40 mmol) were added and the reaction was allowed to stir at room temperature for 16 h. The solution was filtered through diatomaceous earth and then concentrated. The residue was diluted with ethyl acetate (150 mL) washed with water (2×50 mL), 1M HCl (2×50 mL), brine (1×50 mL) and then dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica-gel) using 10-100% ethyl acetate in hexanes to provide 10.4 g of the title compound.