Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[NH:9]2)=[N:6][CH:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:10]1([CH3:15])[NH:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:23]#[C:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]=2)[C:12](=[O:13])[CH2:11]1
Reactant: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Temperature: 65 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 39 μmol, 0.05 equiv.) was dissolved in 2 ml THF. (210 mg, 770 μmol) 2-(5-Bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (Example 1, step 2) and phenylacetylene (130 mg, 1.24 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (325 μl, 2.33 mmol, 3 equiv.), triphenylphosphine (6 mg, 23.3 μmol, 0.03 equiv.) and copper(I)iodide (4 mg, 23.3 μmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5,5-dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (102 mg, 45% yield) was obtained as a white solid, MS: m/e=292.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.Cl.[NH2:20][OH:21].O>C(O)C>[NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:20][OH:21])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(Oc2ccc(Cl)cc2N)cc1
Temperature: 60 °C
Yield: 41.2 %

Procedure:
To the product from Example 163a (150 mg, 0.57 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (41.8 mg, 0.60 mmol), and disopropylethylamine (82 mg, 0.63 mmol). The reaction was heated at 60° C. for 3 h. The reaction was cooled and poured into water. The solution was extracted with ethyl ether. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (65 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[C:12][Si](C)(C)C)[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CO>C1COCC1>[C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[CH3:1])#[CH:12]
Reactant: Cc1n[nH]c2ccc(C#C[Si](C)(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc2[nH]nc(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
3-Methyl-5-(2-(trimethylsilyl)ethynyl)-1H-indazole (820 mg, 3.55 mmol) was dissolved in 20 mL THF and K2CO3 (4.9 g, 35.5 mmol) and 200 mL MeOH were added. The mixture was stirred for 1 hour at room temperature, filtered and evaporated. The mixture was purified via glass column chromatography (35% EtOAc in hexane) and the title compound (500 mg, 3.2 mmol) was obtained as a light yellow solid. LCMS (API-ES) m/z (%): 157.0 (100%, M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28].CCN(C(C)C)C(C)C.[C:39]1([CH2:45][S:46](Cl)(=[O:48])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([S:46]([CH2:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:48])=[O:47])[C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28]
Reactant: COC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCN(S(=O)(=O)Cc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of the compound of Example 16 (0.48 mmol) and DIEA in CH2Cl2 (2 mL) at −78° C., was added α-toluenesulfonyl chloride (110 mg, 0.57 mmol). The mixture was stirred at −78° C. for three hours and evaporated in vacuo. The residue was dissolved in CH2Cl2 and H2O. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4 and evaporated to give the title compound as a solid (50% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[N:3]=1.[ClH:18]>ClCCl.O1CCOCC1>[ClH:18].[NH:9]1[CH2:10][CH:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH2:8]1
Reactant: Cc1nc(C2CN(C(=O)OC(C)(C)C)C2)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(C2CNC2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)azetidine-1-carboxylate (97 mg, 0.41 mmol; which may be prepared as described in Step 4) in dichloromethane was added dropwise HCl 4N in dioxane (2.0 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (101 mg, quantitative) as a white solid. The product was used in the next step without further analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2C[C@H](CI)CO2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C[C@@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Reaction time: 42 h
Yield: 79 %

Procedure:
A mixture of 5.0 g of trans-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 4.2 g of 1-(4-piperidyl)benzimidazolin-2-one and 2.5 g of potassium carbonate in 80 ml of dimethylformamide is heated with stirring at 60°-70° C. for 42 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed three times with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the residue, and the crystals precipitated are collected by filtration and recrystallized from ethanol to give 5.1 g of 1-[1-(trans-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazolin-2-one as colorless needles, melting at 154°-155° C. The corresponding hydrochloride melts at 239° C. with decomposition.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:10])[CH:3]=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][S:18]([CH3:17])(=[O:20])=[O:19])[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2cc[nH]c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2cc[nH]c12
Yield: 94 %

Procedure:
Stir 1H-indol-7-ylamine with pyridine (1 equivalent) and methanesulfonyl chloride (1 equivalent) in dichloromethane for 12 hrs. Wash the reaction with 1N hydrochloric acid and water, dry over magnesium sulfate, and evaporate. Recrystallize the residue from isopropanol to obtain the title product as a purple solid (94%). MS (ES+), 210 (M), MS (ES−), 209 (M−1). LC/MS shows 95% purity.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.O>C1COCC1>[C:1]([O:5][C:14]([CH:11]1[CH2:13][CH2:12]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butanol (9.4 mL, 100 mmol) in 50 mL of anhydrous THF is added under nitrogen during several minutes n-butyl lithium (69 mL, 110 mmol, 1.6 M solution in hexane). After 30 min, the resulting solution is treated by the drop wise addition of a THF solution (40 mL) of cyclopropanecarbonyl chloride (10 mL, 110 mmol). The reaction mixture is further stirred at reflux for 1 h, cooled to 0° C. by an ice bath, and slowly hydrolyzed by the addition of water. The aqueous layer is extracted twice with ether and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by vacuum distillation (bp=70° C., 76 mmHg) to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1csc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 74 %

Procedure:
To a solution of 2-hydroxymethyl-4-methylthiophene (1.8 g, 14 mmol) (reference literature: J. Heterocycl. Chem., vol. 19, 1125 (1982)) and imidazole (1.9 g, 28 mmol) in N,N-dimethylformamide (20 ml) was added t-butyldimethylsilyl chloride (2.3 g, 15 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:19) as the eluent to afford the title compound (2.5 g) in a yield of 74% as a colourless oily product.
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:41][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:31])(=[O:30])[N:16]=3)=[C:4]([OH:5])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:41][C@@H:7]3[CH2:8][CH2:9]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (3 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (0.51 mL, 1.37 mmol). After stirring at 60° C. for 2 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (131.5 mg, 0.235 mmol, 68% over two steps), as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.28 (2H, d, J=11.0 Hz), 1.47 (1H, t, J=10.8 Hz), 1.57-1.74 (3H, m), 2.56 (1H, d, J=3.2 Hz), 2.75 (1H, d, J=2.3 Hz), 2.96 (1H, d, J=9.2 Hz), 3.02 (3H, s), 3.58 (1H, d, J=9.2 Hz), 4.42 (1H, d, J=15.5 Hz), 5.03 (1H, d, J=15.7 Hz), 7.04 (2H, t, J=8.5 Hz), 7.31 (2H, dd, J1=7.9 Hz, J2=5.5 Hz), 7.37 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J1=8.3 Hz, J2=2.3 Hz), 7.69 (1H, d, J=2.3 Hz). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.4 [M+H+]. ee=98.5% [HPLC-analysis: Chiralpak AS-RH 2.1×150 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.3 mL/min, 312 nm, t1=7.58 min (major), t2=8.95 min].
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)CC(O)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CC(O)C(=O)OCc1ccccc1

Procedure:
2-Hydroxy-4-methylpentanoic acid is reacted with benzyl bromide in ethyl acetate in the presence of triethylamine, to give benzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 64.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, nicotinoyl chloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-3-pyridylcarboxamide (0.47 g, 64%) as a white solid: mp 148-151° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.36 (t, J=5.6 Hz, 1H), 9.09 (d, J=1.25 Hz, 1H), 8.75-8.73 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.76 (m, 3H), 7.57-7.52 (m, 1H), 5.22-5.15 (dd, J=5.4 and 12.7 Hz, 1H), 4.96 (d, J=5.6 Hz, 2H), 2.92-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.94, 165.23, 152.02, 148.44, 138.86, 135.10, 134.83, 133.20, 131.55, 129.48, 127.20, 123.49, 121.95, 48.89, 38.33, 30.93, 21.98; Anal. Calcd. For C20H16N4O5+0.28H2O: C, 60.45; H, 4.20; N, 14.10. Found: C, 60.29; H, 4.28; N, 13.82.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH2:13]([O:15][C:16]([N:18]1[CH2:33][CH2:32][C:22]2[C:23]3[C:24](=[O:31])[CH2:25][CH2:26][C:27]=3[C:28]([I:30])=[CH:29][C:21]=2[CH2:20][CH2:19]1)=[O:17])[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16]([N:18]1[CH2:33][CH2:32][C:22]2[C:23]3[C:24]([OH:31])([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:25][CH2:26][C:27]=3[C:28]([I:30])=[CH:29][C:21]=2[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(O)(c1cccnc1)CC3
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-bromopyridine (0.11 ml, 1.13 mmol) in THF (5 ml) under Ar at −78° C., n-BuLi (2.5 M in hexane, 0.45 ml, 1.13 mmol) was added. The mixture was stirred at −78° C. for 20 minutes, followed by dropwise addition of Intermediate 1 (0.15 g, 0.38 mmol) in THF (5 ml). The mixture was stirred for 2 h at −78° C., allowed to warm to room temperature, and quenched by slow addition of aqueous saturated NH4Cl (50 ml). The mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-title compound as tan oil that was used without further purification. MS: ESI (positive): 479 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)O
Reactant: OCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OCCCCCCO
Temperature: 90 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
1,6-Hexanediol (1000.00 g, 8.46 mol, Sigma-Aldrich) was placed in a 1-liter 3-neck flask equipped with a mechanical stirrer and a narrow tube blowing dry air into the flask. The solid diol was heated to 90° C., at which temperature all the solid melted. With continuous stirring, p-toluenesulfonic acid crystals (18.95 g, 0.11 mol) followed by BHT (2.42 g, 0.011 mol) and methacrylic acid (728.49.02 g, 8.46 mol). Heating at 90° C. with stirring was continued for 5 hours during which time vacuum was applied using tap water aspirator for 5-10 minutes after each half-hour reaction time. The heat was turned off and the reaction mixture was cooled to room temperature. The viscous liquid obtained was washed with 10% aqueous sodium carbonate twice (2×240 ml), followed by washing with water (2×240 ml), and finally with 100 ml of saturated NaCl aqueous solution. The obtained oil was dried using anhydrous Na2SO4 then isolated by vacuum filtration to give 1067 g (67.70%) of 6-hydroxyhexyl methacrylate, a yellow oil. This desired product was formed along with 15-18% of 1,6-bis(methacryloyloxyhexane). Chemical characterization was by NMR analysis.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[N:42][CH:43]=[C:44]([CH:49]=1)[C:45]([NH:47][CH3:48])=[O:46]>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[N:42][CH:43]=[C:44]([CH:49]=2)[C:45]([NH:47][CH3:48])=[O:46])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cncc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cncc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 45.3 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.0 g), 5-bromo-N-methylnicotinamide (1.01 g) and tetrakis(triphenylphosphine)palladium(0) (0.177 g), the title compound (1.26 g) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20])[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccsc2)cc1OC(CCc1ccccc1C#N)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(OCc2ccsc2)cc1OC(CCc1ccccc1C#N)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
A solution of ethyl (RS)-4-[(2-acetyl-5-(3-thienylmethoxy)-phenoxy]-4-(2-cyanophenyl)butanoate (250 mg) in methanol (10 ml) containing 1N sodium hydroxide (3 mL) is stirred at ambient temperature for 16 hours. The reaction mixture is poured into 0.5 N hydrochloric acid (20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases are washed with brine (20 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave a dark yellow oil. Crystallization from a mixture of cyclohexane and ethyl acetate affords (RS)-4-[(2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-cyanophenyl)butanoic acid (20 mg) in the form of a beige solid, m.p. 132-134° C. [Elemental analysis:- C, 66.0, H, 4.87, N, 3.02%. Calculated:- C, 66.2, H, 4.86, N, 3.22%].
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 89.8 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (200 mg, 0.9 mmol) and 3-methyl-4-(pyridin-2-ylmethoxy)aniline (231 mg, 1.08 mmol) to give the title compound as a white solid (317 mg, 90%); NMR Spectrum: 2.27 (s, 3H), 3.79 (s, 2H), 4.30 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.35 (dd, 1H), 7.40 (s+d, 2H), 7.74 (d, 1H), 7.84 (t, 1H), 8.21 (s, 1H), 8.33 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 393 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:23][C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[N:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])=[N:15][CH:14]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])nc2)cc1C
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])nc2)cc1C
Temperature: 85 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitrobenzamide (500 mg, 1.31 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), and piperidine (330 mg, 3.88 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 85° C. in an oil bath. The reaction was then quenched with 100 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum to give 550 mg (98%) of product as a yellow solid.