Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:48])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([N:35](COCC[Si](C)(C)C)[CH2:36][C:37]([NH2:39])=[O:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.O>C(O)(=O)C.CO.ClCCl>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:48][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][C:37]([NH2:39])=[O:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)(=O)N(COCC[Si](C)(C)C)CC(N)=O)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NC(=O)CNS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 49.3 %

Procedure:
N2-[(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N2-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide (0.091 g) was stirred under a reflux condenser at 80° in acetic acid (2 ml) and water (1 ml) for 3.5 h. The solution was evaporated to dryness and re-evaporated twice with methanol to give a gum. The residue was dissolved in methanol and loaded onto two 20×20cm preparative silica gel coated plates (1 mm layer). The plates were run in dichloromethane:ethanol:0.880 ammonia solution, 25:8:1 and elution of the main band and evaporation gave a gum. This was dissolved in acetic acid (2 ml) and evaporated to dryness and re-evaporated with methanol to give the title compound (0.019 g) LCMS RT=2.31 min, ES+ve 552 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC)(C)(C)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:13][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: Cc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Product: Cc1ccccc1OC(CCN(C)C)c1ccccc1
Temperature: 130 °C
Yield: 89.1 %

Procedure:
A mixture of N,N-dimethyl-3-hydroxy-3-phenylpropylamine (0.9 g, 5 mmol), 2-iodotoluene (1.31 g, 6 mmol), cuprous iodide (0.2 g) and cesium carbonate (1.8 g, 5.5 mmol) was stirred under nitrogen at 130° C. until the reaction was complete as determined by 1H NMR. The reaction mixture was cooled to room temperature, diluted with methyl t-butyl ether (10 mL), filtered, and rinsed with more methyl t-butyl ether. The filtrate was extracted with diluted hydrochloric acid solution and the aqueous layer was washed with more methyl t-butyl ether. The aqueous was adjusted to pH>10 by the addition of sodium hydroxide solution, then extracted with methyl t-butyl ether twice. The combined extracts were washed with water and then evaporated to dryness to give 1.2 g of N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine as a light yellow oil. 1H NMR (CDCl3) δ 7.45-7.2 (m, 5H), 7.12 (d, J=6.8 Hz, 1H), 7.0 (dd, J=8.0, 7.6 Hz, 1H), 6.78 (dd, J=8.4, 6.8 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.24 (dd, J=8.1, 4.8 Hz, 1H), 2.46 (t, J=7.3 Hz, 2H), 2.33 (s, 3H), 2.24 (s, 6H), 2.3-2.1 (m, 1H), 2.05-1.9 (m, 1H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[C:10]1([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1csc(-c2ccccc2)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (2.07 g, 10 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (15 mL). Phenyl boronic acid (14 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.5 mmol) and caesium carbonate (14 mmol) were added and the reaction mixture refluxed under nitrogen overnight. The solvent was evaporated under vacuum, and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was dissolved in hot ethyl acetate, filtered and the solvent evaporated to give the title compound as a pale brown solid. LCMS m/z 203.20 [M−H]−R.T.=3.23 min (Analytical Method 5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:30]>C(O)C>[ClH:30].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)CCC1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNCC1=O)N2

Procedure:
A solution of the product from Example 2B (0.25 g) in ethyl alcohol (20 mL) was treated with 6M HCl (20 mL) and heated to reflux for 1.5 hours. The ethyl alcohol was evaporated and the aqueous portion basified with 1N sodium hydroxide. The basified solution was extracted with methylene chloride (3x). The combined methylene chloride extractions were concentrated and the residue was purified by flash chromatography over silica gel (10:90:1 ethanol/methylene chloride/saturated ammonium hydroxide) to provide the title compound (0.10 g) which was converted to the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:4](=[O:11])[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27].CO>C(Cl)Cl>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:4](=[O:11])[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=c1c2ncsc2nc(Cl)n1-c1ccc(F)cc1
Solvent: CO
Solvent: ClCCl
Product: O=c1c2ncsc2nc(Oc2ccc(F)cc2F)n1-c1ccc(F)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
5-Chloro-6-(4-fluorophenyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (0.2 mmol) and 2.4-difluorophenol (0.4 mmol) are added to a vial, and the sealed mixture is heated with stirring at 140° C. for 48 h. Silica gel column chromatography (MeOH:CH2Cl2=0.5:99.5) gives the title compound as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) 8.70 (1H, s), 7.36 (2H, m), 7.26 (2H, m), 7.14 (1H, m), 6.94 (2H, m). MS (M+1): 376.03; RT=1.33 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([OH:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2].Br[CH2:14][CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([CH3:10])=[CH:8][C:7]=1[O:11][CH2:14][CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c([N+](=O)[O-])cc1C
Yield: 58.8 %

Procedure:
A mixture of 16.7 g (100 mmol) of 4-nitro-2,5-xylenol, 24.5 g (110 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 15.3 g (110 mmol) of anhydrous potassium carbonate in 200 mL of acetonitrile is stirred at reflux for 18 hours overnight. The inorganic solid is removed, washed thoroughly with fresh acetonitrile and the filtrate is evaporated. The solid residue is stirred with a mixture of diethyl ether and 100 mL of 2N potassium hydroxide solution. The aqueous layer is removed and the organic layer washed with 50 mL of 2N potassium hydroxide solution, brine, dried, and evaporated. The crystalline residue is taken up in hexane (hot), treated with charcoal to assist in removal of some insoluble material, concentrated to 200 mL, and cooled to afford 18.2 g of the title compound as pale yellow needles; mp 73°-75° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)nn1C(C)(C)C

Procedure:
92 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2,3-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=[C:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:28])[C:16]2=[O:17])=[CH:38]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 77.2 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (293 mg, 0.608 mmol) was condensed with 1H-indole-3-carbaldehyde (106 mg, 0.729 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 286 mg of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.25 (s) and 7.90 (s, total 1H), 8.16 (s, 1H), 7.58-7.67 (m, 4H), 7.37-7.53 (m, 6H), 7.07-7.17 (m, 3H), 6.94 (m, 2H), 4.90 (m, 1H), 4.55 (m, 1H), 4.25 (m, 1H), 3.96 (m, 4H), 1.10 (m, 6H); MS 610.8 (M+1), 608.5 (M−1)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=2)[CH2:30][CH2:31]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 40 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 40%). MS (m/e): 502.0 (M+H+, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[Cl-].[NH4+]>O1CCCC1.O>[O:7]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cc(Oc2ccccc2)ccn1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Oc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
Next, to a solution of lithium aluminum hydride (725 mg, 19.1 mmol) in tetrahydrofuran (6.0 mL) was portionwise added a solution of the resulting 4-phenoxy-pyridine-2-carbonitrile (1.5 g, 7.65 mmol) in tetrahydrofuran (3 mL) on an ice bath, and the solution was stirred at room temperature for 15 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated to obtain the title compound (730 mg, 48%) as a pale brown oil. This was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].ClCC(Cl)(Cl)Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1.Cl>C(Cl)Cl.C1CCCCC1.O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][C:4]([C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)c2ccc(-c3ccccc3)cc2)cc1

Procedure:
KY-560 In a round bottom flask equipped with gas inlet and magnetic stirrer were placed Biphenyl (2.1 gr, 13.65 mmol), Aluminum trichloride (1.5 gr, 11.25 mmol), and 150 ml of tetrachloroethane (TCM). While the TCM solution was stirring, a solution of 25 ml of tetrachloroethane and 0.830 ml of (4-Methoxy-phenyl)-acetyl chloride (5.5 mmol) was dropwise over five minutes by syringe. The reaction mixture was stirred 3-4 h. 150 ml of water and 5 ml of HCl were slowly added. The layers were separated. The aqueous layer was extracted with DCM. The combined DCM and TCE solution was washed with a saturated solution of NaCl in water. The organic solution was dried over Na2SO4. filtration followed by rotary evaporation produced a dark yellow solid. Chromatography on flash chromatographic (CycloHexane:DCM). Yield 1.2 gr (71%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Oc2ccccc2)cc1
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2ccccc2)cc1

Procedure:
In ethanol (5.0 mL), was combined 4-phenoxybenzonitrile (200 mg, 1.02 mmol) and hydroxylamine (250 μL, 4.09 mmol). The mixture was refluxed for 3 hours. The reaction was cooled and then concentrated in vacuo to give the product, which was taken to the next step without further purification (quantitative yield). 1H NMR (500 MHz, CDCL3) δ(ppm): 4.87 (2H, bs), 7.01 (2H, d, J=9.0 Hz), 7.03 (2H, dd, J=8.7, 1.1 Hz), 7.15 (2H, tt, J=7.4, 1.1 Hz), 7.36 (2H, dd, J=8.6, 7.3 Hz), 7.59 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 118.6 (CH), 119.6 (CH), 124, 127.3, 127.6 (CH), 130.1 (CH), 152.5, 156.6, 159.3. MS (FAB+): 229 (MH+). HRMS for C13H12N2O2 (MH+): calculated: 229.0977; found 229.0977.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:30]=[CH:29][C:21]([O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[C:20]([CH3:31])[CH:19]=3)[N:12]([CH3:32])[C:11]2=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36]O>S(=O)(=O)(O)O>[CH3:36][O:25][C:24](=[O:26])[C:23]([O:22][C:21]1[CH:29]=[CH:30][C:18]([CH2:17][CH2:16][CH2:15][CH:13]2[CH2:14][N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[C:11](=[O:33])[N:12]2[CH3:32])=[CH:19][C:20]=1[CH3:31])([CH3:27])[CH3:28]
Reactant: Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionic acid (0.610 g, 1.27 mmole) in methanol (10 mL) was added 15 drops of concentrated sulfuric acid. The mixture was stirred at room temperature overnight. After evaporated the solvent, the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed by saturated sodium bicarbonate (50 mL), then brine (3×50 mL), dried over Na2SO4, filtered and concentrated in vacuo to produce an oil (0.624 g, 99%). Mass [EI+] 495 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:12]2[C:11]([CH3:10])=[CH:15][C:14]([CH3:16])=[N:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: Cc1cc(C)[nH]n1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc(-n2nc(C)cc2C)c1
Temperature: 110 °C
Reaction time: 84 h

Procedure:
A mixture of 1-iodo-3-methoxybenzene (7.15 mL, 60 mmol, 1.0 eq), 3,5-dimethyl-1H-pyrazole (6.92 g, 72 mmol, 1.2 eq), CuI (0.46 g, 2.4 mmol, 0.04 eq), K2CO3 (17.41 g, 126 mmol, 2.1 eq), trans-1,2-cyclohexanediamine (1.37 g, 12 mmol, 0.2 eq) in dioxane (45 mL) was stirred at a temperature of 110° C. for 3.5 days under a nitrogen atmosphere and then cooled to ambient temperature. The solid was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-3:1) as an eluent to obtain the desired product, 1-(3-methoxyphenyl)-3,5-dimethyl-1H-pyrazole 1, as a brown liquid (7.12 g in 59% yield). 1H NMR (DMSO-d6, 400 MHz): δ 2.18 (s, 3H), 2.30 (s, 3H), 3.80 (s, 3H), 6.06 (s, 1H), 6.95 (dd, J=8.0, 2.4 Hz, 1H), 7.02-7.06 (m, 2H), 7.39 (t, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (1.65 g, 6.65 mmol) in CH2Cl2 (200 mL) was added Et3N (1.35 g, 13.3 mmol), followed by acetyl chloride (0.573 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 5 minutes, washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated, to afford ethyl 4-(4-acetamidopiperidin-1-yl)benzoate as a white solid (1.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:12].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12]
Reactant: COc1cc(Cl)c(C(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c(C(O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone (1.0 g, 2.8 mmol) was dissolved in MeOH (15 mL) and cooled to 0° C. NaBH4 (318 mg, 8.4 mmol) was added. The reaction mixture was quenched by aq. NH4Cl (15 mL) and extracted with EtOAc (100, 30, and 20 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (5:1, hexanes:EtOAc) to provide 3d (980 mg, 97%) as a white powder. 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J=8.4 Hz, 1H), 7.38 (d, J=3.0 Hz, 1H), 7.31 (dd, J=8.2, 3.0 Hz, 1H), 6.91 (s, 2H), 6.61 (d, J=2.1 Hz, 1H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.6, 137.8, 136.3, 133.9, 133.0, 130.5, 129.6, 129.6, 128.0, 126.6, 115.4, 115.4, 70.2, 55.9; IR (film): 3482 cm−1, 1438, 1410, 1325;
Reaction SMILES: [Li].C(NC(C)C)(C)C.C=CC1C=CC=CC=1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>O1CCCC1>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:23][C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[CH:33][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(OCCCCCCBr)cc1
Reactant: Cc1cc(C)on1
Agent: [Li]
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a suspension of 301 mg of lithium wire (1/4 inch portions) in 10 ml of tetrahydrofuran under nitrogen was added 6.72 ml of diisopropylamine and 3.44 ml of styrene while maintaining the temperature at 25° C. The mixture was stirred until all the lithium had dissolved (about four hours) and then cooled to -55° C. 3,5-Dimethylisoxazole (4.3 g) in 10 ml of tetrahydrofuran was then added dropwise and the mixture stirred for an hour at -55° C. 4-(6-Bromohexyloxy)benzonitrile (12 g) in 10 ml of tetrahydrofuran was then added dropwise over a period of one hour, and the mixture was allowed to warm to room temperature and stirred for three days. The solvent was removed in vacuo, the residue treated with 5% ammonium chloride solution and extracted with ether. The ether extracts were dried and concentrated, and the residue subjected to high pressure liquid chromatography with etherhexane (1:1) mixture to give 3.9 g of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole, used directly in the next reaction.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[CH2:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[OH:27])[N:18]([C:28]([C:30]4[S:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)=[CH:33][CH:34]=4)=[O:29])[N:17]=3)[CH:13]=[N:14][CH:15]=2)=CC=1.Cl>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[N:18]([C:28]([C:30]3[S:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:33][CH:34]=3)=[O:29])[N:17]=2)[CH:13]=[N:14][CH:15]=1
Reactant: COc1ccc(COCc2cncc(C3=NN(C(=O)c4ccc(-c5ccccn5)s4)C(c4ccccc4O)C3)c2)cc1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc(-c2ccccn2)s1)N1N=C(c2cncc(CO)c2)CC1c1ccccc1O
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a suspension of 2-{3-(5-{[(4-methoxybenzyl)oxy]methyl}pyridin-3-yl)-1-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5-dihydro-1H-pyrazol-5-yl}phenol (0.070 g, 0.12 mmol) in MeOH (6 mL) was added HCl. The reaction mixture was allowed to stir at 65° C. for 6 h and then at rt overnight. Reaction was incomplete, so the mixture was allowed to stir at 65° C. for an additional 10 h and then cooled to rt and concentrated. The residue was purified by column chromatography to give 2-{3-[5-(hydroxymethyl)pyridin-3-yl]-1-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5-dihydro-1H-pyrazol-5-yl}phenol (I-273). LCMS: (FA) ES+ 457.4, ES-455.5.