Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:24]([C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[N:16]=1)[CH3:25]
Reactant: CCc1nc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2cc(F)ccc2n1C1CCNCC1

Procedure:
1-(1-Benzyl-piperidin-4-yl)-2-ethyl-5-fluoro-1H-benzimidazole (6.4 g) in methanol (100 ml) was hydrogenated with Pd/C (10%, 1.5 g) at room temperature for 8 h. The catalyst was removed and the filtrate was evaporated and dissolved in ethanol. The solution was acidified with conc. HCl(aq) and recrystallised by the addition of acetone. This yielded 5.3 g of the title compound as colourless crystals.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17](/[CH:20]=[CH:21]/[CH2:22][CH2:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[NH2:32][OH:33].O>C1COCC1>[OH:33][NH:32][CH:21]([CH2:20][S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:30])([F:1])[F:31])=[CH:10][N:9]=2)[CH2:16][CH2:15]1)(=[O:19])=[O:18])[CH2:22][CH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Reactant: NO
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine (10.9 g, 23.7 mmol) in THF (200 mL) was added 50% aqueous solution of hydroxylamine (11 mL) and the reaction stirred at room temperature for 2 hours. Water (100 mL) was then added and then this was extracted with EtOAc (3×100 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo to give 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine as a pale yellow solid (11.1 g, 22.6 mmol, 96%).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)[CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:31][CH:30]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)O)cc2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure G using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2, c-Hex/EtOAc 9:1) as a colorless oil (77%). M+ (ESI): 546.1. HPLC, Rt: 6.4 min (purity: 100%). 1H NMR (CDCl3) δ: 7.40 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.16-7.05 (m, 4H), 6.91 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.66 (s, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 4.51 (s, 1H), 4.40 (s, 1H). 4.36 (s, 1H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 2.41 (m, 4H), 1.74-1.08 (m, 23H), 0.90 (t, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[S:13][C:12]2[N:11]3[C:14]([CH3:17])=[N:15][N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].S([O-])(O)=[O:29].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[CH:5]=[C:4]([C:1]([OH:29])=[O:3])[S:13][C:12]=2[N:11]2[C:14]([CH3:17])=[N:15][N:16]=[C:10]2[CH2:9][N:8]=1
Reactant: CC(=O)c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reactant: O=S([O-])O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [O-]Cl
Product: Cc1nnc2n1-c1sc(C(=O)O)cc1C(c1ccccc1Cl)=NC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
2-Acetyl-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.0 g) synthesized by the method described in Artneim.-Forsch./Drug Res. 28 (II), Heft 7, 1153-1158 (1978) was added to a 10% aqueous sodium hypochlorite solution (21 ml), and the mixture was stirred at 60° C. for 1.5 hours. Sodium hydrogensulfite (2.9 g) was added to the reaction mixture. Then, an aqueous citric acid solution was added to adjust the reaction mixture to pH 3. The obtained crystals were collected by filtration, and washed with water to give 0.5 g of (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH2:21]([O:28][C:29]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (3R)-3-(tert-butyloxycarbonylamino)pyrrolidine (10.0 g) and triethylamine (5.43 g) in methylene chloride (100 mL) was added dropwise a solution of benzyloxycarbonyl chloride (7.7 mL) in methylene chloride (20 mL) over a period of 15 minutes under nitrogen gas atmosphere and ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water (70 mL) and the mixture was extracted with chloroform. The extract was washed successively with water (70 mL), 5% citric acid solution (70 mL) and a saturated brine (70 mL) and the organic layer was dried over anhydrous magnesium sulfate. After concentration in vacuo, the resultant product was triturated in diisopropylether to give (3R)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)pyrrolidine (11.8 g, yield: 70%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20].[OH:21]P([O-])([O-])=O.[K+].[K+].OP([O-])(O)=O.[K+]>CS(C)=O.O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20])=[O:21]
Reactant: O=P([O-])([O-])O
Reactant: CCOC(=O)CCN1C(=O)c2ccc(CBr)cc2C1=O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCN1C(=O)c2ccc(C=O)cc2C1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The crude material from step 2 was dissolved in DMSO (70 mL). Powdered K2HPO4 (18 g, 0.10 mol) and KH2PO4 (7 g, 0.05 mol) were added. The mixture was stirred at 80° C. for 5 hours, diluted with water (500 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), and concentrated. After column chromatography (hexane, ethyl acetate 3:1) 4.8 g of the title compound was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]1[C:40]([C:41]([C:43]([F:46])([F:45])[F:44])=O)=[CH:39][CH:38]=[C:37]([C:47]([F:50])([F:49])[F:48])[CH:36]=1.CCCCCC>C1COCC1>[CH3:13][O:14][CH:15]=[C:41]([C:40]1[CH:39]=[CH:38][C:37]([C:47]([F:50])([F:49])[F:48])=[CH:36][CH:35]=1)[C:43]([F:46])([F:45])[F:44]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 25.0 ml of n-butyllithium/hexane solution (1.2M solution) was added to a solution of 12.7 g of methoxymethyltriphenylphosphonium chloride in 100 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 30 minutes and at -20° C. for 30 minutes. A solution of 6.0 of 4-trifluoromethyl-α,α,α-trifluoroacetophenone in 10 ml of dry THF was slowly added to the reaction solution at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at room temperature for 14 hours. Thereafter, 150 ml of n-hexane was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with dilute HCl-ice water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and 6.1 g of the crude product (E/Z=ca. 1/1) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8].C(O)C.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)=[CH:3][C:2]=1[C:35]1[CH:36]=[N:31][CH:32]=[N:33][CH:34]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)c(Br)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(NC1=N[C@@]2(c3ccc(F)c(-c4cncnc4)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Temperature: 97 °C
Yield: 79 %

Procedure:
A solution of N-((4aR,6R,7aS)-7a-(3-bromo-4-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.588 g, 1.31 mmol) in a mixture of 1,2-dimethoxyethane (8 mL), ethanol (4 mL) and water (4 mL) is purged with nitrogen and is heated to 97° C. Pyrimidine-5-boronic acid (0.810 g, 6.54 mmol), cesium carbonate (2.56 g, 7.84 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.184 g, 0.261 mmol) is added in a single portion and the reaction is heated at 97° C. for 30 minutes. The reaction is cooled, diluted with water and is extracted twice with ethyl acetate. The organic layer is dried over sodium sulfate and the crude product is purified by silica gel chromatography with a linear gradient of 0% to 40% ethyl acetate in dichloromethane over 20 minutes to give the title compound (0.464 g, 79%). ES/MS m/e: 449 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH3:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22]>C(O)C>[CH3:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH2:22][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: C=C(C)C(=O)OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(C)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 99 %

Procedure:
1-(4-Chloro-phenyl)-piperazine (392 mg; 2.0 mmol) and sodium ethoxide (150 mg; 2.21 mmol) are dissolved in ethanol (2 mL) and irradiated for 5 minutes in a mono-mode microwave oven at 60° C. 2-Methyl-acrylic acid methyl ester (400 μL; 4.0 mmol) is then added and the resulting mixture is irradiated for 50 minutes in a mono-mode microwave oven at 100° C. The reaction is concentrated under reduced pressure, diluted in ethylacetate (10 mL) and extracted with water (2×5 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product (586 mg; 1.98 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[N+:4]([O-:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[N+:4]([O-:17])[CH:3]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [O-][n+]1cc(Cl)nc(NCCc2ccccc2)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [O-][n+]1cc(NCCc2ccccc2)nc(-c2ccncc2)c1

Procedure:
A mixture containing 0.250 g (1.0 mmol) of 6-chloro-N-(2-phenylethyl)pyrazin-2-amine 4-oxide, 0.296 g (2.40 mmol) of 4-pyridine boronic acid, 0.60 mL (1.2 mmol) of a 2M solution of sodium carbonate in water and 0.116 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of a mixture of ethanol/water in the proportions 5/1 was stirred under reflux for 16 h. Cooled water was added and the mixture extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to give after trituration with diethyl ether 0.058 g (20%) of pure product as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6].[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6])=[N+:35]=[N-:36]
Reactant: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, phenylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (31a) (0.44 g, 0.9 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 81 mg (1.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (31b) was purified by silica gel column chromatography and used in the next step. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 6H), 1.98-2.10 (m, 2H), 3.07-3.13 (m, 2H), 3.63-3.65 (m, 2H), 3.81 (s, 3H), 3.85 (s, 1H), 3.94 (d, J=9.2 Hz, 1H), 4.18 (d, J=9.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.37-7.39 (m, 5H) ppm. MS (ESI) m/z 528.15 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[C:15]1=[O:35].[H][H]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[C:15]1=[O:35]
Reactant: [H][H]
Reactant: Cc1cc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1S(C)(=O)=O
Yield: 102.2 %

Procedure:
(S)-Benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (906 mg, 1.80 mmol) was dissolved in EtOH (15 mL) and 10% Pd/C was added and stirred under balloon pressure of hydrogen overnight. The reaction was filtered and concentrated to afford (S)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (680 mg, 1.84 mmol, 102% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28](O)=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:39]C=2C=1.CCN=C=NCCCN(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([NH2:39])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
To a suspension of 2-(6-cyclohexyl-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylic acid (169 mg, 0.405 mmol) obtained above in DMF (8 mL), were added TEA (170 μL, 1.22 mmol), ammonium chloride (65.0 mg 1.22 mmol), HOBT (82 mg, 0.61 mmol) and EDCI (120 mg, 0.61 mmol), and the mixture was stirred at rt for 12 h. To the mixture was added DMF (8.0 mL), and the mixture was stirred 40° C. for 2 h. The reaction mixture was allowed to cool to rt, DMF (30 mL) was added, and the mixture was warmed to 60° C. The solution was concentrated until ca 10 mL under reduced pressure. The residue was subjected to basic silica gel column chromatography (EtOAc/hexane=20/80→100/0; then MeOH/EtOAc=30/70). Concentration of the appropriate solution afforded crude product, which was suspended in saturated aqueous solution of sodium bicarbonate (10 mL) and water (10 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the titled compound (104 mg, 62%) as a orange solid,
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Yield: 57.3 %

Procedure:
A mixture of 2 g (0.0088 mol) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 3.39 g (0.0088 mol) of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester and 1.8 g (0.013 mol) of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 20 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for a total of 35 hours. The hot reaction mixture was filtered and filtrate was concentrated in vacuo to an oil which was dissolved in ethyl acetate and washed with 1N sodium hydroxide and sodium chloride solution. The crude oil obtained on concentration of the ethyl acetate solution was purified by HPLC, eluting with 30% ethyl acetate in hexane to yield 2.7 g (58% yield) of [4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CC)CO
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
2-Ethylhexanol (50.51 g, 0.384 mol) and pyridine (260 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -5° C. and to it is added p-toluenesulfonyl chloride (89.63 g, 0.416 mol) in portions via Gooch tubing so as to maintain the reaction temperature -5°-5° C. After 3 h, water (40 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 540 mL of ether. The layers are separated and the organic layer is washed with 5M H2SO4 (2×140 mL), saturated CuSO4 solution (140 mL), water (2×140 mL) and saturated NaHCO3 solution (140 mL). After drying over MgSO4, the organic layer is filtered, and concentrated to leave a light yellow liquid as 2-ethyhexanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: Oc1nc2ccccc2[nH]1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1nc2ccccc2n1C(=O)N(C)c1ccccc1)c1ccccc1

Procedure:
The title product was prepared from 2-hydroxybenzimidazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (14%, white crystals). HPLC-MS: m/z=401.2 (M+1); Rt: 3.88 min, purity: 83%.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19]O)=[C:15]([CH3:17])[N:16]=1)[CH3:11].[OH-].[Na+]>CCCCCC.O>[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19][O:2][N+:1]([O-:4])=[O:3])=[C:15]([CH3:17])[N:16]=1)[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(C)c(CCO)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCc1nc(C)c(CCO[N+](=O)[O-])s1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Fifteen (15) ml of nitric acid of (85-90%) were added dropwise to 15 ml of sulfuric acid (95-98%) over a time period of 20 minutes while keeping the temperature at 0-5° C. After 2 hours, 14.3 grams (83.60 mmole) of 2-ethyl-4-methyl-5-thiazoleethanol, prepared as described above, were added, while the temperature was still maintained at 0-5° C., the reaction mixture was stirred for 2 hours at the same temperature, and was then poured carefully onto 125 ml of cold water. The water solution was made basic with a 20% aqueous solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined and dried over sodium sulfate, filtered and evaporated to dryness. Chromatography of the crude product on silica gel (using a mixture of 75:25 ethyl acetate:hexane as an eluent) yielded 10.5 grams (58% yield) of colorless liquid having a purity of 98%, as determined by gas chromatography.