Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.O>CN(C=O)C>[F:16][C:6]1[C:5]([C:3](=[O:4])[CH2:2][N:35]2[CH2:34][CH2:33][C:32]([OH:38])([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:37][CH2:36]2)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:15])[NH:11]2
Reactant: COc1cccc(C2(O)CCNCC2)c1
Reactant: O=C1CCc2c(ccc(C(=O)CBr)c2F)N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3F)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To a cooled solution of 6-(Bromoacetyl)-5-fluoro-3,4-dihydro-2(1H)-quinolinone (900 mg, 3.1 mmol) and triethylamine (0.88 ml, 6.3 mmol) in DMF (15 ml) was added dropwise a solution of 4-(3-Methoxyphenyl)-4-piperidinol (650 mg, 3.1 mmol) in DMF(15 ml) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was added water and the resulting precipitate was filtered to afford 5-Fluoro-6-[[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-3,4-dihydroquinolin-2(1H)-one (360 mg) as a brown solid. The filtrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/methanol=20/1) to afford 5-Fluoro-6-[[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-3,4-dihydroquinolin-2(1H)-one as a yellow solid (270 mg). The obtained products were combined and used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)=[O:3]
Reactant: O=C(NC1CNC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC(NC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Add methyl chloroformate (60 μL, 73 mg, 0.78 mmol, 3.1 equiv) to a suspension of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (108 mg, 0.250 mmol, 1 equiv) and triethylamine (140 μL, 100 mg, 1.0 mmol, 4.0 equiv) in anhydr (CH2Cl2 (3 mL). Observe a vigorous gas evolution. After stirring 4 h, rotary evaporate the reaction solution. Transfer the resultant material to a column of silica gel (80 mm×20 mm dia.) and elute (20-60% EtOAc/hex) to yield 84 mg (69%) of 3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylic acid methyl ester as an off-white foam. MS (m/e): 489.96 (M+1); 488.09 (M−1).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]ethoxy}-5-chloro-pyridine 917 mg (2.13 mmol) dissolved in toluene (20 mL) were added 0.69 mL (6.39 mmol) of 1-chloroethyl chloroformate and 1.09 mL (6.39 mL) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (20 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column-chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 464 mg (64%) of the title compound as a light yellow oil. ES-MS m/e: 339.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzonitrile, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (M.P. 86°-87° C.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O.I[C:28]1[CH:36]=[C:35](C([O-])=O)[CH:34]=[CH:33][C:29]=1C([O-])=O>>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:29]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])c(I)c1
Reactant: COC(=O)c1ccc(OCc2cccnc2)cc1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared according to the method of Example 158A, except substituting 4-(3-pyridylmethyloxy)-2-trifluoromethanesulfonyloxybenzoic acid methyl ester, prepared as in Example 240C for 2-iodoterephthalate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A 250-mL round-bottomed flask was charged with 4-iodo-1H-pyrazole (17 g, 87.63 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) To this was added sodium hydride (3.6 g, 105.00 mmol, 1.20 equiv, 70%) in several batches at 0° C., followed by addition of 1-(bromomethyl)benzene (16.5 g, 96.49 mmol, 1.10 equiv) dropwise at 0° C. The resulting solution was allowed to warm up to room temperature and stirred for 2 hours at room temperature. The reaction was then quenched by the addition of water/ice (200 mL). The resulting solution was extracted with ethyl acetate (3×200 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 1-benzyl-4-iodo-1H-pyrazole as yellow solid (22 g, 80%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.[F-].[Cs+].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.COCCOC.CO>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2ccsc2)ccc1O
Temperature: 80 °C

Procedure:
0.15 g of tetrakis(triphenylphosphine)palladium catalyst (1.3 10−4 mol) is added to a solution of 5-bromosalicylaldehyde (0.86 g, 0.0043 mol) and of 3-thiopheneboronic acid (0.6 g, 0.0047 mol) in 10 ml of 1,2-dimethoxyethane and 5 ml of methanol. 1.3 g of cesium fluoride are added and the mixture is heated at 80° C. for 20 hours. The reaction mixture is cooled to room temperature and poured into water. The resulting mixture is extracted with dichloromethane and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate. 0.62 g of a pale yellow solid is recovered.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:11])[C:6]=2[CH:20]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:23].C(Cl)(Cl)Cl.CO>CS(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:7]2[C:6]3[C:20](=[O:23])[C:2](=[O:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)c2coc3ccc(O)cc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 9 (100 mg, 0.371 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (315 mg, 0.743 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-02 (50 mg, 50%) as a red solid. Rf=0.6 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.85 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 7.40 (d, J=10.3 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.32 (d, J=10.3 Hz, 1H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[N:27]=1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nsc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2nc(C)ns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 1, 102 mg, 0.40 mmol) in dichloromethane (2 mL) was treated with oxalyl chloride (218 μL of 2M solution in dichloromethane), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 0.5 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in N,N-dimethylformamide (2 mL) and treated with 5-amino-3-methyl-1,2,4-thiadiazole (48 mg, 0.41 mmol), and 2,6-lutidine (64 mg, 0.60 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with methylene chloride, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 35% methanol/dichloromethane) to afford ((S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-propionamide (30 mg, 22% as a white powder: LR-ES-MS m/z calculated for C16H22N4O3S [M]+ 350, observed [M+H]+ 351; 1H NMR (300 MHz, CDCl3) δ ppm 0.74-0.96 (m, 1H) 1.03-1.42 (m, 3H) 1.38-2.15 (m, 7H) 2.53 (s, 3H) 3.83 (s, 3H) 3.98 (d, J=17.8 Hz, 1H) 4.13 (d, J=17.8 Hz, 1H) 5.24 (t, J=7.7 Hz, 1H) 5.38 (s, 1H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCCl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(COc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1cc(O)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6′-((4-Methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 3.3 g, 8.59 mmol) was dissolved in 1,2-dichloroethane (25 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at 50° C. for 2 h. After completion, solvent was evaporated under reduced pressure. Obtained crude was washed with water (50 mL) followed by n-pentane and dried under reduced pressure to afford 6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4) as yellow solid. Yield: 0.85 g, 90%; MS (ESI) m/z 249.07 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:43]6[CH2:42][CH2:41][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:45][CH2:44]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.4 %

Procedure:
A suspension of 1-cyclopropyl-3-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea (47, 3 g, 5.90 mmol, acetate salt), 1-boc-piperazine (1.65 g, 8.85 mmol) and acetic acid (675 μL, 11.80 mmol) in NMP (50 mL) at RT under nitrogen was sonicated for 3 h in order to obtain a solution, then NaBH(OAc)3 (3.95 g, 17.70 mmol) was added. The reaction mixture was stirred at RT for 3 days then quenched by addition of water. The pH was adjusted to 12-13 with 4N NaOH and the suspension was stirred and sonicated for 1 h. The solid was collected by filtration, rinsed with water and air-dried. The residue was purified twice by Biotage (SNAP 50 g KP-Sil cartridge; MeOH/DCM: 1/99 to 10/90 over 20 CV). The desired fractions were collected, concentrated, and co-precipitated with AcOEt with traces of methanol/hexanes to afford the compound 48 (1.511 g, 2.44 mmol, 41% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (bd, J=2.0 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.87 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bdd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 6.57 (bd, J=2.5 Hz, 1H), 3.57 (s, 2H), 4H are hidden by water's peak, 2.59-2.51 (m, 1H), 2.42-2.27 (m, 4H), 1.39 (s, 9H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 619.4 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]([NH2:25])[CH3:24])=[N:21][CH:22]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:25][C@@H:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][N:21]=2)[CH3:24])=[O:13])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc([C@@H](C)N)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(C(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-isopropylphenylacetic acid (2.5 g, 14.0 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethylamine hydrochloride (3.2 g, 16.8 mmol), EDC (3.24 g, 16.9 mmol), and 1-hydroxy-7-azabenzotriazole (2.3 g, 16.8 mmol) in DMF (60 mL) was added N,N-diisopropylethylamine (5.2 mL, 29.6 mmol). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated to 20 mL and diluted with CH2Cl2 (100 mL). The solution was washed with water (100 mL) and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The combined organic layer was washed with water (100 mL), dried over MgSO4, concentrated and purified by normal phase chromatography (10-100% EtOAc/Hexanes) to give of 2-(4-isopropylphenyl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.14 (d, J=2.56 Hz, 1H), 7.20 (m, 4H), 7.13 (m, 2H), 6.69 (d, J=6.78 Hz, 1H), 5.08 (quint., J=6.96 Hz, 1H), 3.84 (s, 3H), 3.55 (s, 2H), 2.90 (sept., J=6.96 Hz, 1H), 1.39 (d, J=6.77 Hz, 3H), 1.25 (d, J=6.96 Hz, 6H); MS (Electrospray): m/z 313.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Cl)ccc1S(C)(=O)=O
Reactant: Nc1ccn(CCCO)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCO)n2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 30 mg, 0.21 mmol), 2,6-lutidine (34 μL, 0.29 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride in methylene chloride (prepared in example 81, 0.096 M solution, 2 mL, 0.19 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic extracts were then combined and washed with a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (59 mg, 67%) as a white foam: [α]31589=−21.2° (c=0.17, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2109; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 1.78-1.90 (m, 2H, CH2), 2.03-2.16 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.27-3.39 (m, 2H, OCH2), 3.82-3.94 (m, 1H, ArCH), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.56 (t, J=5.0 Hz, 1 H, OH), 6.40 (d, J=2.1 Hz, 1H, Ar), 7.41-7.49 (m, 2H, Ar), 7.54 (d, J=2.1 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>[Zn]>[OH:22][C:20]([CH3:21])([CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C=CCCCc1ccc(OCc2ccccc2)cc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCCc1ccc(OCc2ccccc2)cc1

Procedure:
Using 0.68 g of 7-(p-benzyloxyphenyl)-3-hepten-2-one, 0.37 ml of ethyl bromoacetate and 0.19 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 25 (a) affording 0.84 g of ethyl 3-hydroxy-3-methyl-8-(p-benzyloxyphenyl)-4-octenoate.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[CH3:22][O:23][N:24]=[C:15]([C:13]1[S:14][C:10]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:11][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CON
Reactant: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCC(=NOC)c1ccc(-n2cnc3ccccc32)s1

Procedure:
To the solution of compound (84) (0.703 mmoles) in Ethanol (10 ml) was added N-methoxy amine HCl (2.878 m.moles) and Pyridine (2.844 m.moles) at ambient temp. The reaction mass was heated to reflux for 2.0 hrs. After completion of reaction, distilled off the solvent completely, added Water (20 ml) and the product was extracted in ethyl acetate (2×100 ml), washed with 10% brine and dried over sodium sulphate. The solvent was distilled completely under reduced pressure to get the crude compound. This crude compound was purified by preparative HPLC to get the pure isomers (88 & 89).
Reaction SMILES: [I:1][C:2]1[C:10](I)=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[C:5]([CH3:13])=[N:6]2.I[CH3:17]>>[I-:1].[I:1][C:2]1[CH:10]=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:15])[C:5]([CH3:13])=[N+:6]2[CH3:17]
Reactant: CI
Reactant: CC1=Nc2cc(I)c(I)c(I)c2C1(C)C
Product: CC1=[N+](C)c2cc(I)cc(I)c2C1(C)C
Product: [I-]

Procedure:
1.05 g (2.5 mmol) of 4,5,6-triiodo-2,3,3-trimethyl-3H-indole and 2 mL of iodomethane were heated at 45° C. for 6 hours in a sealed tube. The formed precipitate was filtered, washed with acetone. Yield: 900 mg. 1H-NMR (300 MHz, DMSO-d6), δ, ppm: 8.37 (2H, d, 5.4 Hz, arom.), 3.92 (3H, s, NCH3), 2.79 (3H, s, CH3), 1.61 (6H, s, C(CH3)2).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCCCCC>CN(C)C=O>[C:13]1([O:21][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCCCCC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCCCCCC1
Yield: 79.4 %

Procedure:
To a solution of 42 g (0.38 mol) of chlorotrimethylsilane and 78 g of triethylamine in 100 ml of dimethylformamide, a solution of 32 g (0.254 mol) of cyclooctanone in 40 ml of dimethylformamide was added. The resultant mixture was stirred at 100° to 115° C. for 48 hours. At the end of the reaction, the reaction mixture was combined with 240 ml of n-hexane and washed twice with 300 ml of a saturated aqueous sodium bicarbonate solution. The mixture was washed under cooling with 180 ml of 1.5N hydrochloric acid, then washed sequentially with an aqueous sodium bicarbonate solution, water, and saline and then dried with magnesium sulfate. The mixture was concentrated and distilled under a vacuum, to afford 40 g (80% in yield) of 1-cyclooctenyloxytrimethylsilane having a boiling point of 82° to 84° C./5 mmHg.