Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c(C)noc2C)c1C#N
Temperature: 120 °C
Yield: 39 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (107 mg, 0.395 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (100 mg, 0.593 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.2 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 45% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (62 mg, 39%). 1H NMR (500 MHz, CD3OD) δ ppm 1.31-1.42 (m, 3 H), 2.01 (s, 2 H), 2.15 (s, 1 H), 2.19 (s, 1 H), 2.32 (d, J=4.39 Hz, 5 H), 3.86 (s, 3 H), 5.39-5.48 (m, 1 H), 6.65-6.69 (m, 1H), 7.59 (d, J=3.42 Hz, 1 H), 7.68-7.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C2H22N8O, 403; found 403.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)(=[O:5])=[O:4]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:9]1[CH:8]=[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(NS(=O)(=O)CCl)ccc1F
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A mixture of 12.5 g of iron powder (223 mmol) and 16 mL of an aqueous solution of acetic acid (8%) was heated to 80° C., and a solution of 6 g of 1-chloro-N-(4-fluoro-3-nitrophenyl)methanesulfonamide (22.3 mmol) in 20 mL of glacial acetic acid and 22 mL ethyl acetate was added dropwise to the mixture. After heating for 1.5 h the reaction mixture was filtered through a pad of Celite® and washed with 200 mL of ethyl acetate and water (twice with 25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 5 g (94%) of the title compound as a solid melting at 128-129° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)=[CH:9][C:8]=2[CH:15]([CH3:16])[CH3:17])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg (34%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:52])[NH:39][CH:40]([C:48]([O:50][CH3:51])=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]C=C)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCl>[CH3:51][O:50][C:48]([CH:40]1[NH:39][C:38](=[O:52])[N:15]2[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16]2)[C:12](=[O:13])[NH:11][C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:8]2)[CH:9]=[CH:10][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=[O:49]
Reactant: C=CCCCCCC(NC(=O)N1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C)C(=O)OC
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCC(C(=O)OC)NC(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Yield: 73.5 %

Procedure:
Compound 127 (170 mg, 0.2385 mmol) was dissolved in dichloromethane (40 ml) and degassed by bubbling nitrogen for 20 min. Hoveyda-Grubbs catalyst II generation (10 mg, 0.016 mmol, 6.7 mol %) was then added and the mixture was refluxed under nitrogen atmosphere overnight. The solvent was then evaporated, catalyst and salts were removed by flash chromatography (5% methanol in chloroform) and the crude product (120 mg, 73% yield, 85-90% purity) was used in next step MS (M+H+) 685
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added). The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1([CH3:40])[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH3:27][C:28]1([CH3:40])[CH2:33][CH:32]([N:34]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:36]3[N:37]=[CH:38][N:39]=[C:35]23)[CH2:31][CH2:30][O:29]1
Reactant: CC1(C)CC(Nc2nnc[nH]2)CCO1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 66.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.89 g) and N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.41 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].C(OCC)(=O)C>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)CCCCl)cc(C(C)(C)C)c1O
Temperature: 3 °C
Yield: 78.2 %

Procedure:
To a stirred mixture of 65.2 g (295 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 23.3 g (295 mmol) of pyridine in 700 ml of ether cooled to 3° C. there was slowly added 41.6 g (295 mmol) of 4-chlorobutyryl chloride. Fifteen hours later 700 ml of ethyl acetate was added and the mixture was washed successively with 500 ml of water, 500 ml of dilute sodium bicarbonate solution and again with 500 ml of water. The organic phase was dried over anhydrous magnesium sulfate and concentrated to a solid (85.3 g). This solid was triturated in hexane and filtered to yield 75.2 g of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-chlorobutyramide.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:36]([NH:38][C:39]1([C:43]([NH2:45])=[O:44])[CH2:42][NH:41][CH2:40]1)[CH3:37]>COCCOC.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([N:41]3[CH2:42][C:39]([NH:38][CH2:36][CH3:37])([C:43]([NH2:45])=[O:44])[CH2:40]3)[N:7]2[N:8]=1
Reactant: CCNC1(C(N)=O)CNC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 2.00 g, 5.13 mmol) in DME (30 ml) at 23° C. was added diisopropylethylamine (0.940 ml, 5.36 mmol) over 5 minutes. In a separate flask, a solution of 3-ethylaminoazetidine-3-carboxylic acid amide hydrochloride salt (I-2A-1h; 1.16 g, 5.37 mmol) in water (10 ml) was treated with diisopropylethylamine (1.90 ml, 10.8 mmol) over 5 minutes. The aqueous solution was then added to the DME solution over a 10-minute period while maintaining the reaction temperature below 28° C. After 2 hours, water (20 ml) was added over 5 minutes, and an orange solid precipitated from the reaction. The solid product was collected by filtration, washed with additional water, and then air dried by pulling low house vacuum across the sample to afford 2A-1 (2.15 g, 84%) as an off-white solid: +ESI MS (M+1) 496.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.35 (m, 4H), 7.31 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 5.14 (br d, J=8.3 Hz, 1H), 4.77 (br d, J=8.3 Hz, 1H), 4.61 (br d, J=8.3 Hz, 1H), 4.22 (br d, J=8.3 Hz, 1H), 2.54 (q, J=7.1 Hz, 2H), 2.45 (s, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([N:4]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][CH:20]=[CH:21][C:6]1=2)(=[O:3])[CH3:2].C([N:41](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(N)C=CC1=2)(=O)C>>[C:1]([N:4]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([NH2:41])=[CH:19][CH:20]=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cccc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(N)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-9-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 26, Steps 1-2 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 532 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][O:17][N:18]([CH3:19])[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 79.2 %

Procedure:
2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (6.62 g, 32.6 mmol), O,N-dimethylhydroxylamine hydrochloride (3.50 g, 35.8 mmol), and HATU (14.86 g, 39.1 mmol) were combined in DMF (100 mL). To this solution was added Hunig's Base (17.07 mL, 98 mmol). The reaction was stirred for overnight (17 hours). The reaction was then concentrated under vacuum and the residue was diluted with EtOAc (300 mL) and washed with water (2×80 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50 percent EtOAc-Hexanes) to afford the desired product as a white solid (6.36 g). LCMS m/z 247.2 (M+H)+, Rt 0.61 min.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)pyridin-4-yl)propanoate (71 mg) in THF (1.0 mL) and methanol (0.50 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (1.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (62 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[S:12].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[S:10][C:11](=[S:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
10 g of 4-fluorobenzaldehyde was dropwise added at room temperature to a solution having 10.8 g of rhodanine and 20 g of sodium acetate suspended in 100 ml of acetic acid. The obtained mixture was reacted under reflux for two hours and then cooled to room temperature. Then, this reaction mixture was put into about 500 ml of water, and a solid product thereby obtained was collected by filtration, washed with water and dried to obtain 16.4 g of 5-(4-fluorobenzylidene)rhodanine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([O:13]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([OH:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)c(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of 4-formylbenzene-1,3-diyl diacetate (5.56 g, 25.08 mmol) in ethanol (20 mL) was added a solution of sodium hydroxide (1.00 g, 25.08 mmol) in water (12 mL). The reaction was stirred overnight at room temperature. The reaction was carefully neutralized with 2.0 N aqueous solution of hydrochloric acid (12.8 mL) at 0° C. and diluted with ethyl acetate (400 mL). The organic layer was washed with water (60 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford, the product (2.01 g, 44% yield) as a gray solid: 1H NMR (400 MHz, d-MeOH): δ 9.90 (s, 1H), 7.68 (d, 1H), 6.80 (d, 1H), 6.75 (s, 1H), 4.82 (br s, 1H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[H][H]>O1CCCC1.C(O)C.[C].[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][C:2]=1[OH:1]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)c(O)c1
Yield: 105.9 %

Procedure:
In 30 ml of tetrahydrofuran and 130 ml of ethanol was dissolved 3.32 g of ethyl 3-hydroxy-4-nitrocinnamate. To the solution was added 100 mg of 10% palladium-carbon. The mixture was stirred under normal pressure in a hydrogen flow until absorption of hydrogen was discontinued. The catalyst was filtered off by suction and the filtrate was concentrated under reduced pressure to obtain 3.10 g of crude ethyl 4-amino-3-hydroxybenzenepropionate as an oily substance.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].ClCCl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To the 250 ml 3-necked flask was added 10.0 gm 2-ethyl 1-hexanol, 100 ml dichloromethane, and 6.0 gm pyridine and the contents were stirred for 10 minutes. To this mixture, 14.2 gm 4-nitro benzoyl chloride was added slowly and stirred under reflux conditions for 2 hrs. The reaction mixture was then cooled, washed with 20% aqueous ammonium hydroxide. The organic layer was washed with 1N hydrochloric acid and brine, and dried over anhydrous sodium sulfate to give a crude product (˜65% yield).
Reaction SMILES: C([O:3][C:4](OCC)([C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1)[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1)C.[OH-].[Na+]>C1COCC1.Cl>[CH2:24]([C:19]1[CH:18]=[C:17]([C:4](=[O:3])[CH2:5][NH:6][C:7](=[O:16])[C:8]2[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([CH3:14])[CH:13]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(CNC(=O)c1cc(C)nc(C)c1)(OCC)c1cc(C)nc(CC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCC(=O)c2cc(C)nc(CC(C)C)c2)cc(C)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of N-[2,2-diethoxy-2-(2-isobutyl-6-methyl-pyridin-4-yl)-ethyl]-2,6-dimethyl-isonicotinamide (60 mg, 0.177 mmol) in THF (4 mL), 25% aq. HCl (50 μL) is added and the mixture is stirred at 65° C. for 2 h. Another portion of 25% aq. HCl (50 μL) is added and stirring is continued at 65° C. for 3 h. The mixture is cooled to 0° C., neutralized by adding 1 N aq. NaOH solution and extracted twice with EA. The combined org. extracts are dried over Na2SO4, filtered and concentrated to give crude N-[2-(2-isobutyl-6-methyl-pyridin-4-yl)-2-oxo-ethyl]-2,6-dimethyl-isonicotinamide (48 mg) as an orange oil. Part of this material (22 mg) is purified on prep. TLC plates using DCM containing 10% of methanol to give N-[2-(2-isobutyl-6-methyl-pyridin-4-yl)-2-oxo-ethyl]-2,6-dimethyl-isonicotinamide (9 mg) as a pale yellow oil; LC-MS: tR=0.75*, [M+1]+=330.13; 1H NMR (CDCl3): δ 0.97 (d, J=6.5 Hz, 6H), 2.09-2.21 (m, 1H), 2.64 (s, 6H), 2.67 (s, 3H), 2.75 (d, J=7.3 Hz, 2H), 4.94 (d, J=3.8 Hz, 2H), 7.23 (s br, 1H), 7.38 (s, 2H), 7.42 (s, 1H), 7.49 (s, 1H).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a 3L round bottom flask was added the resultant compound from Example 1E (370.5 g, 1.34 mol) and dichloromethane (2L). The mixture was cooled to 0° C. in an ice water bath and a solution of N-benzyl piperazine (295.8 g, 1.68 mol) was added dropwise with vigorous stirring over 2 h. After the addition was completed, the mixture was stirred in additional 4 h while at 0° C. The solution was then poured into a separatory funnel containing 2L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 1 kg of silica gel using 3:2 hexane/ethyl acetate as an eluant. Concentration gave 467 g (84%) of the desired product: 1H NMR (CDCl3) δ 7.37-7.12 (m, 10H), 3.66 (s, 3H), 3.51 (s, 2H), 3.42 (dd, 1H), 3.29-3.13 (m, 5H), 3.06 (dd, 1H), 2.96-2.84 (m, 2H), 2.50-2.42 (m, 4H).