Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:30])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:32][C:33]#[N:34])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:30])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5587 g, 1.2 mmol), prepared in the previous step, bromoacetonitrile (0.10 mL, 1.44 mmol) and potassium carbonate (0.83 g, 6 mmol) in 10 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a brown oil. The oil was chromatographed on a 90 g KP-SIL 60 Δ Biotage column using 5% ethyl acetate in methylene chloride as the eluent. Isolation of the desired product gave 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.48 g, 79%) as a clear oil, MS m/z: 505 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][NH:7][C:6]=2[N:15]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:11]([N:10]1[C@@H:9]([CH3:14])[CH2:8][N:7]([C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[O:34])[C:6]2[N:15]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]1=2)(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(Br)nc2NC[C@@H]1C
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)nc2N(C(=O)Nc2ccc(F)cc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone (0.1 M solution in 1,2-dichloroethane, 0.30 mL, 0.03 mmol) and N,N-diisopropylethylamine (0.052 mL, 0.300 mmol) was added. 1-Fluoro-4-isocyanatobenzene (0.017 mL, 0.150 mmol) was added neat, followed by the addition of a catalytic amount of DMAP (˜1 mg), and the reaction was shaken at 50° C. overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen and vacuum to yield (S)-1-acetyl-6-bromo-N-(4-fluorophenyl)-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. The crude product was dissolved in 1,4-dioxane (100 μL and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 0.27 mL, 0.054 mmol), potassium carbonate (1.0 M solution in water, 0.090 mL, 0.090 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 150 μL, 0.003 mmol) were added. The reaction was purged with nitrogen, and heated to 80° C. on a heater shaker for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution and brine. The combined organic layers were concentrated in a Genevac. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(4-fluorophenyl)-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[N:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:44][C:45]=2[CH3:46])=[CH:35][CH:34]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:46][C:45]1[O:44][C:43]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:42][C:41]=1[CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH2:19][OH:18])=[CH:34][CH:35]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a mixture of 5-(tert-butyldiphenylsilyloxymethyl)-4-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy]methyl]-2-phenyl-1,3-oxazole (1.44 g) and tetrahydrofuran (30 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 5 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give [4-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-5-yl]methanol as colorless crystals (0.55 g, yield 59%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([CH:18](Br)Br)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].S(=O)(=O)(O)[OH:24]>>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[CH:18]=[O:24]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2F)c(Cl)c1OC(F)F
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 100 °C

Procedure:
68 g (0.14 mol) of 4-chloro-3-(4-chloro-5-dibromomethyl-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were dissolved in 200 ml of concentrated sulfuric acid, with ice-cooling, whereupon the mixture was heated at 100° C. until the evolution of gas had ceased. It was then poured into 4 l of ice-water. The mixture was subsequently extracted three times using ethyl acetate. The combined organic phases were washed with water, then dried over magnesium sulfate and finally concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=8:1). Yield: 35 g; m.p.: 95-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC1C=CC2NN=NC=2N=1.[NH2:51][N:52]1[C:60]2[C:55](=[C:56]([F:61])[CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:61][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:55]=1[CH:54]=[CH:53][N:52]2[NH:51][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][CH:10]=1)=[O:16]
Reactant: Nn1ccc2c(F)cccc21
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1ccc2[nH]nnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nn1ccc2c(F)cccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A solution of 2-(3-fluorophenyl)-pyrimidine-5-carboxylic acid (0.33 g), HATU (0.67 g) and hydroxyazabenzotriazole (0.26 g) in dry DMF (15 mL) is stirred at rt for 30 min under N2. A solution of 1-amino-4-fluoroindole (0.24 g) in dry DMF (5 mL) is added followed by the addition of DIPEA (0.39 mL). The mixture is stirred at 80° C. for 24 h, cooled to rt, and then concentrated in vacuo. The residue is dissolved in EtOAc and washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60% DCM/heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.24 g, 53%) as a solid. MS: 351 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 6.64 (d, 1H), 6.89-6.92 (q, 1H), 7.15-7.22 (m, 1H), 7.31-7.33 (d, 1H), 7.46-7.52 (m, 1H), 7.56 (d, 1H), 7.63-7.70 (q, 1H), 8.18-8.23 (d, 1H), 8.34-8.37 (d, 1H), 9.45 (s, 2H), 12.30 (s, 1H). IC50=11 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.O.NN.Cl>C(O)COCCO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)CCCCCC(=O)O)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(CCCCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a stirring solution of 7.5 gms 9(4-methoxyphenyl)-7-ketononanoic acid in 35 ml diethylene glycol was added 5.1 ml hydrazine hydrate. The mixture was heated to 120° for 4 hrs, cooled to room temperature, connected to a water aspirator, and gently heated to 120° to remove excess water and hydrazine. The reaction mixture was cooled to 70°, 7.2 gm KOH was added, and the mixture was heated up to 220° C. where it was kept for 5 hr, then cooled. The cooled reaction mass was dissolved in 120 ml hot water, acidified with conc. HCl, and 3× extracted with CHCl3. The combined organic phases were dried over MgSO4, filtered, and the solvent was evaporated in vacuo. Attempts to crystallize the product failed, so it was vacuum sublimed twice, dissolved in 300 ml chloroform, filtered through silica gel, and the solvent evaporated to give 38% product, a white solid of m.p. 41°-3° C.
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([CH3:11])[CH2:6][CH2:5]1)[CH3:3].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:18][C:14]1[CH:13]=[C:12]([C:4]2([CH2:2][CH3:3])[O:10][CH2:9][CH2:8][N:7]([CH3:11])[CH2:6][CH2:5]2)[CH:17]=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(c2cccc(O)c2)CCN(C)CCO1
Agent: Cl
Product: CCC1(c2cccc(OC(C)=O)c2)CCN(C)CCO1

Procedure:
2.7 g (0.01 mole) of the 7-ethyl-7-(3-hydroxyphenyl)-4-methyl-hexahydro-1,4-oxazepine hydrochloride obtained as described in Example 2 are boiled with 25 ml of acetic anhydride for 3 hours. The excess acetic anhydride is then distilled off under reduced pressure and the residue is recrystallized from an isopropanol/ether mixture.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:40]=[N:41][N:42](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:43]=4)=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]>C(OCC)(=O)C.C(OCC)(=O)C.CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([N:10]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[N:40]=[N:41][NH:42][N:43]=4)=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(-c4nn[nH]n4)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 194.7 %

Procedure:
A solution of 4N hydrogen chloride in ethyl acetate (15 ml) was to a solution of the title compound of example 357 (263 mg, 0.3 mmol) in ethyl acetate-methanol (2/5, 7 ml) and this solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was crystallized from methanol-ethyl acetate (1/1) to give the title compound (196 mg, 97%) as colorless crystalline powder.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[C:13]([CH3:15])=C)C(C(O)=O)C2.[C:20](SCC(C)C(N1C2C(=CC(Cl)=CC=2)CC1C(O)=O)=O)(=O)[C:21]1C=CC=C[CH:22]=1>>[CH:12]1([NH:8][CH:9]2[CH2:10][CH2:11][CH2:3][CH2:4][CH2:5]2)[CH2:13][CH2:15][CH2:22][CH2:21][CH2:20]1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccc(Cl)cc2CC1C(=O)O
Reactant: C=C(C)C(=O)N1c2ccc(OC)cc2CC1C(=O)O
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
By substituting 5-chloro-2,3-dihydro-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid from Example 34 for 2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid in the procedure of Example 25, 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-5-chloro-2,3-dihydro-1H-indole-2-carboxylic acid, dicyclohexylamine was obtained. The latter salt was then treated with 5% aqueous potassium hydrogen sulfate as in Example 15 to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1I.[CH3:14][C:15]([Si:18]([CH3:30])([CH3:29])[O:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:15]([Si:18]([CH3:29])([CH3:30])[O:19][CH2:20][CH2:21][CH2:22][C:23]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:24]=1[Si:25]([CH3:26])([CH3:27])[CH3:28])([CH3:14])[CH3:16]
Reactant: CCOC(=O)c1ccc(N)c(I)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCC#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Yield: 65 %

Procedure:
A mixture of ethyl 4-amino-3-iodobenzoate {Hirschfeld et al. J. Med Chem. 1992, 35, 2231-2238.}(7.80 g, 26.8 mmol), [5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-pentynyl]trimethylsilane (9.41 g, 34.8 mmol), tetra-n-butylammonium chloride (7.44 g, 26.8 mmol), sodium carbonate (14.20 g, 0.134 mol), triphenylphosphine (0.35 g, 1.3 mmol), and palladium (II) acetate (0.30 g, 1.3 mmol) in 200 mL of DMF, was heated at 98° C. under N2 for 2 h. The solution was cooled, and the bulk of the DMF was removed in vacuo. The mixture was diluted with ethyl acetate, and the organic solution was washed with aqueous NaHCO3, dried (brine, MgSO4), filtered, and concentrated in vacuo. Silica gel chromatography (10:1 hexanes-EtOAc) of the concentrate yielded the title compound (7.49 g, 65%) as a crystalline solid. Recrystallization from hexanes provided an analytical sample as a white crystalline solid: mp 115- 116° C. Anal. Calcd for C23H39N1O3Si2 : C 63.69; H, 9.06; N, 3.23. Found: C, 63.54; H, 9.11; N, 3.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: CC(=O)[O-]
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Intermediate 23 (5 g, 16.17 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.2 g, 82.03 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as off-white solid (3.81 g, 71% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.34(d, J=2.3 Hz, 1H), 7.76(dd, J=8.8, 2.2 Hz, 1H), 7.41(m, 2H), 7.24(m, 2H), 7.18(t, J=8.9 Hz, 1H), 2.30(s, 3H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:25]=1[CH2:26][N:27]1[CH:32]([CH:33]2[CH2:35][CH2:34]2)[CH2:31][NH:30][C:29](=O)[C:28]1=[O:37]>C1COCC1>[Cl:23][C:24]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:25]=1[CH2:26][N:27]1[CH:32]([CH:33]2[CH2:35][CH2:34]2)[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:37]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Solvent: C1CCOC1
Product: O=C1C(=S)NCC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 173.4 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (289 mg, 0.69 mmol) in THF (13 mL) was added Intermediate 5 (480 mg, 1.4 mmol) in one portion. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow solid (434 mg, 86%). MS (ESI): mass calcd. for C15H14ClF3N2OS, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 7.63 (t, J=8.0 Hz, 2H), 7.36 (t, J=7.8 Hz, 1H), 5.23 (d, J=15.8 Hz, 1H), 4.74 (d, J=15.8 Hz, 1H), 3.73 (ddd, J=13.4, 4.0, 2.1 Hz, 1H), 3.57 (ddd, J=13.5, 5.2, 3.1 Hz, 1H), 2.81 (dd, J=8.5, 4.4 Hz, 1H), 1.24-1.11 (m, 1H), 0.79-0.67 (m, 1H), 0.63-0.55 (m, 1H), 0.51-0.45 (m, 1H), 0.21-0.08 (m, 1H).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:15]1[N:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)C(OC)=O.C(O)(=O)C>CO>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:15]1[N:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: COC(=O)C(c1ccc(Cl)nn1)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccccc1Cc1ccc(Cl)nn1
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
An aqueous solution of lithium hydroxide (2 g /10 ml of water) was added to a solution of methyl 2-(2-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetate (4.25 g, 14.84 mmol) [prepared as described above] in methanol (30 ml). After 1.5 h, acetic acid (10 ml) was added and the stirring was continued overnight. The product was extracted into ether, and the extract was washed with water, aqueous NaHCO3, and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude was chromatographed on a silica gel column (10% ethyl acetate in hexanes) to give 6-(2-fluorobenzyl)-3-chloropyridazine (2.56 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([OH:23])=[O:22]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
For the preparation of the starting material, MS: 367 (M-BOC+H), 6-(1-t-butoxyformamido)hexanoic acid and 3-amino-5-nitrobenzoic acid are reacted to give 3-[6-(1-t-butoxyformamido)hexanamido]-5-nitrobenzoic acid, MS: 396 (2, M+H), and the latter is reacted with β-alanine methyl ester to give N-[3-[6-(1-t-butoxyformamido)hexanamido]-5-nitrobenzoyl]-β-alanine methyl ester, MS: 381 (100, M-Boc+H). This is then saponified in methanolic sodium hydroxide solution.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:9][CH:10]=[C:11]([CH:21]=2)[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH:1]1([C:7]2[C:8]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:9][CH:10]=[C:11]([CH:21]=2)[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reaction time: 20 h
Yield: 91.2 %

Procedure:
5-Cyclohex-1-enyl-N-(pyridin-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide (Example 1c, 0.012 g, 31.8 μmol) was dissolved in ethyl acetate (1 mL). Palladium (10% on charcoal, 3.4 mg, 32 μmol) was added; the suspension was degassed and aerated with argon (5×). Then it was degassed and aerated with hydrogen (3×) and stirred for 20 h under hydrogen. The reaction mixture was degassed and aerated with argon (3×) again. Then it was filtered through dicalite, washed with i-propyl acetate and concentrated in vacuo to give the title compound (11 mg, 91%) as white solid; MS (ESI) 380.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN(C)C)c(F)c2)c1
Yield: 11.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (9.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][CH:4]=1>[Pd].O1CCOCC1>[NH2:11][C:6]1[C:7]([NH:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: CNc1nc(OC)ccc1N
Yield: 92.2 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3.45 g of 6-methoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 67), 0.70 g of 10% w/w palladium-on-charcoal and 50 ml of dioxane were used, to give 2.66 g of the title compound having Rf=0.12 (on silica gel thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25].OS1C2C=CC=CC=2N=C1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C(=O)O
Reactant: CC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 125.8 %

Procedure:
To a solution of 400 mg of the butyric acid compound, 175 mg of isobutylamine hydrochloride, 270 mg of 1-hydroxybenzotiazole and 0.22 ml of triethylamine in 20 ml of ethyl acetate was added 300 mg of dicyclohexylcarbodiimide with stirring under ice-cooling, and then the mixture was still stirred for 16 hours. The reaction mixture was cooled, and filtered to remove insoluble materials. The filtrate was washed successively with an aqueous citric acid solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 595 mg of (2RS, 3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexyl-2-hydroxy-N-isobutylbutyramide.