Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:21]1[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and N-isopropyl-piperazine (commercially available) according to the procedure described for Example A. MS (m/e): 299.3 (MH+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](Cl)=[O:18])[CH:15]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13](=[O:23])[C:14]2[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)=[O:18])[CH:15]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2cccc(C(=O)Oc3ccc(C(=O)OCC)cc3)c2)cc1

Procedure:
A similar procedure to Example 5 is carried out by using ethyl p-hydroxybenzoate and isophthalic dichloride. The reaction product is recrystallized from chloroform-ethyl acetate (1:1) to yield di(p-ethoxycarbonylphenyl)isophthalate, m.p. 123°-125° C., as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3O[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[F:44][C:45]1C=CC=C[C:46]=1C(Cl)=O>>[F:44][C:45]1[CH:46]=[CH:23][CH:24]=[CH:25][C:21]=1[C:19]([NH:18][CH:16]([C:13]1[N:12]=[N:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:15][CH:14]=1)[CH3:17])=[O:20]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3F)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-fluorobenzoyl chloride (0.059 mL, 0.45 mmol) to afford 2-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (100 mg) as a yellow solid. MS m/z 368 (M+1).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@@:28]([CH3:38])([S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([O:31]CC)=[O:30])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1N=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1>>[C:9]([O:8][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C@@:28]([CH3:38])([S:34]([CH3:37])(=[O:35])=[O:36])[C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(-c2ccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc2)cc1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)nc1)(C(=O)O)S(C)(=O)=O
Product: CC(C)(C)OP(=O)(Oc1ccc(-c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)cc1)OC(C)(C)C
Yield: 80.5 %

Procedure:
The title compound (4.44 g, 81%) was prepared from ethyl(2R)-4-{4′-[(di-tert-butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoate (5.8 g, 10.2 mmol) by following a procedure analogous to that described for the preparation of 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (i.e. Example 3, Step D). MS (LCMS) m/z 539.5 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53-1.57 (m, 18H) 1.69 (s, 3H) 2.09-2.18 (m, 1H) 2.38-2.53 (m, 2H) 2.62-2.73 (m, 1H) 3.05 (s, 3H) 7.10 (d, J=8.20 Hz, 2H) 7.25-7.37 (m, 4H) 7.45-7.51 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(N)=S)cc1O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2ccc(C)c(O)c2)n1
Yield: 65 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methylphenyl)thiourea (100 mg, 0.59 mmol) and ethyl 3-bromopyruvate (0.074 mL, 0.59 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 65% yield (105 mg).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=[CH:2][CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCO
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCC[Sn](C=CCO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (1 ml) were added tributyl stannane (5.8 ml) followed by 1,1′-azobis(cyclohexanecarbonitrile) (213 mg). The mixture was heated for 2 h at 80° C., cooled to RT, and directly purified by column chromatography (EA/Hept 4/96 to 5/95) to afford 2.98 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Yield: 49.3 %

Procedure:
To a solution of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.0 g) in ethanol (40 ml) was added bit-by-bit sodium borohydride (113.5 mg) at 5° C. under stirring. The mixture was further stirred at 5° C. for 30 minutes and acidified weakly with 50% acetic acid. After removal of the ethanol, to the residue was added water, and the mixture was made slightly alkaline with an aqueous solution of sodium bicarbonate, allowed to stand and then filtered, when it became clear. The precipitate (1.58 g) was collected by filtration and, recrystallized from a mixture of ethanol and diisopropyl ether to give yellowish-orange granules (0.99 g) of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 167° to 169° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].C1COCC1.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(OCC2CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
A mixture of methyl 5-chloro-6-(cyclopropylmethoxy)nicotinate (2.00 g), THF (15 mL), methanol (1.7 mL) and 2 M aqueous lithium hydroxide solution (8.3 mL) was stirred at room temperature for 20 min. The reaction mixture was neutralized with 1 M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether/hexane to give the title compound (1.68 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)(C)C>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A mixture of 6-chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (25 g) and 1N sodium hydroxide solution (200 mL) in isopropanol (200 mL) was stirred at r.t. for 3 h. The solvent was distilled off, the residue was taken up in a little water and brought to pH 3-4 with 1N hydrochloric acid. A solid precipitated, which was filtered off and dried in air. 22 g (96%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O/[CH:18]=[CH:19]/[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8](/[CH:18]=[CH:19]/[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)CN(/C=C/C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-((4-chlorophenyl)amino)acetate (10.0 g, 46.8 mmol) and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (11.0 g, 65.5 mmol) in DCM (150 mL) was heated overnight at 50° C. The resulting mixture was concentrated and then triturated with 20% EtOAc/heptane and the resulting solid filtered and washed with heptane to yield (E)-ethyl 2-((4-chlorophenyl)(4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:22]([O:24]CC)=[O:23])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19]CC)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:22]([OH:24])=[O:23])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Add diethyl (1S,2S,5R,6S)-2-(tert-butoxycarbonylamino)spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (1.79 g, 4.87 mmol) in tetrahydrofuran (29.2 mL) to a freshly prepared solution of lithium hydroxide monohydrate (1.64 g, 38.97 mmol) in water (19.5 mL) and stir overnight at 60° C. Dilute with water (30 mL), extract with ethyl acetate (2×50 mL). Separate aqueous and organic layers. Wash organic layer with 2M hydrochloric acid. Wash the aqueous layer with 2M hydrochloric acid (25 mL) then extract with ethyl acetate (2×50 mL). Combine the organic layers and wash with brine (15 mL). Dry on magnesium sulfate, filter and concentrate to dryness. Redissolve in dichloromethane and concentrate to dryness to give the title compound (1.49 g, 98%). MS (m/z): 334 (M+23).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:10][CH2:11][C:12]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:13]
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(CCl)c1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 7-azaindole (10 g) and chloroacetyl chloride (7.4 mL, 1.1 eq.) are dissolved in carbon disulfide, treated with aluminum chloride (85 g, 7.5 eq.), heated at reflux temperature for 2 h, treated with chloroacetyl chloride (7.4 mL, 1.1 eq.), continued heating at reflux temperature for a further 2 h, cooled to room temperature and decanted to remove the solvent. The sediment is cooled to 0° C., quenched with ice water, treated with sodium carbonate to pH 9 and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title ethanone, 12.5 g (75% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:26])[C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)[C:3]1=[O:27].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>O1CCCC1>[O:27]=[C:3]1[CH:2]([NH:1][C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=2)=[O:36])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20](=[O:26])[C:21]1[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2cccs2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3cccs3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A mixture of 0.26 g 3-amino-1,3-dihydro-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one, 95 mg 3-tolylisocyanate and 5 ml tetrahydrofuran was stirred at room temperature for two hours. The solvent was distilled off from the reaction mixture under reduced pressure, a 1:1 mixture of toluene and diethyl ether (5 ml) was added to the residue, and the crystals were collected by filtration, thus giving 0.2 g of 1-[2,3-dihydro-2-oxo-5-phenyl-1-(2-thenoyl)methyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].Br[CH2:12][C:13]([OH:15])=[O:14]>O.CC(C)=O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of potassium hydroxide (32.7 g, 0.58 mol) in water (100 mL) was added to a stirred mixture of 4-nitro-1H-pyrazole (30 g, 0.27 mol) in acetone (500 mL) at room temperature. After 30 min, a solution of 2-bromoacetic acid (38.7 g, 0.27 mol) in acetone (100 mL) was added and the reaction was stirred overnight. The solvent was removed in vacuo, the residue was diluted with water then extracted three times with ethyl acetate and the combined organic layer was concentrated in vacuo. The residue was further extracted with dichloromethane and methanol and the combined organic layer was concentrated in vacuo to afford 2-(4-nitro-1H-pyrazol-1-yl)acetic acid (40 g, 88%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.[CH3:15]S(C)=O.CCCCCCC.C(OCC)(=O)C>O>[CH3:15][O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:12])[CH3:11]
Reactant: CS(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: OO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A solution of 17.8 g (64.0 mmol) of ferrous sulfate heptahydrate in 100 ml of water is added dropwise, under nitrogen, over an 8-minute interval to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 14.5 g (128 mmol) of 30% aqueous hydrogen peroxide, and 200 ml of dimethyl sulfoxide. As the ferrous sulfate solution is added, an ice-water bath is used to keep the reaction temperature at 20° C.-40° C. After the addition is complete, the mixture is stirred for 15 minutes at ambient temperature and then extracted with methylene chloride (200 ml, then 100 ml). Purification of the crude product by flash chromatography on silica gel (10:1 heptane/ethyl acetate, then 4:1 heptane/ethyl acetate) affords 5.7 g (52% yield) of the title compound.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][NH:7][N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12>C(O)C>[O:3]=[C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][NH:7][N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12
Reactant: CCOC(=O)c1c[nH]n2cccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]n2cccc2c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M sodium hydroxide aqueous solution was added to a suspension of ethyl 4-oxo-1,4-dihydropyrrolo[1,2,b]pyridazin-3-carboxylate in ethanol (165 mL) and stirred overnight at 100° C. The resulting reaction mixture was cooled to room temperature, distilled under reduced pressure, and concentrated. Then, concentrated hydrochloric acid was added until pH decreased to 2. Thereafter, the solid was filtered, washed with water and dried in vacuum. The target compound obtained was subjected to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([O:16][CH3:17])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH3:17][O:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OC)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1OC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-methoxypiperidine-1-carboxylate (2.00 g, 4.99 mmol) and 10% Pd/C (0.27 g, 0.25 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 98%) as an oil.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C1C[O:20][CH2:19]C1>>[OH:20][CH2:19][C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C(O)C1(CO)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cyclopentanecarboxylic acid (1.10 g, 10.0 mmol) was placed in a round-bottomed bottomed flask, filled with nitrogen, and 30 mL of THF (30 mL) was added. The solution was cooled to −78° C., and LDA (8.8 mL, 2.5 m in hexane) was added dropwise. After being stirred for 30 min., the solution was bubbled by nitrogen stream containing formaldehyde gas (formaldehyde gas was in situ generated by thermal degradation of anhydrouse paraformaldehyde at 160° C.). When the reaction solution turned light yellow, the reaction mixture was quenched with a saturated aqueous NH4Cl solution at −78° C., and the organic material was extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([NH:32]C(=O)OC(C)(C)C)=[CH:27][C:26]=3[F:40])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:41][CH3:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:40])=[CH:27][C:28]([NH2:32])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:41][CH3:42]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylcarbamate (75 g, 0.12 mmol) in DCM (300 mL) was added TFA (300 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 2 h and evaporated to give 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenamine as a light-pink foam (62 g, quant). 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.20-7.23 (d, 1H), 6.92-6.96 (t, 2H), 6.41-6.50 (m, 6H), 3.91 (s, 2H), 3.79 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:26]3[CH2:27][CH2:28][CH:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:24][CH2:25]3)=[O:16])[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2cccc(Cl)c2)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2cccc(Cl)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 98 %

Procedure:
In analogy to the procedure described in Example 18], 1-(3-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 98% yield as light brown solid. MS: 387.3 (MH+, Cl).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Solvent: ClCCl
Product: CC(=O)NCCc1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 min at ambient temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added and the reaction mixture is heated at reflux for 30 hours. After cooling, the reaction mixture is hydrolysed with caution and the dichloromethane is evaporated off. The mixture is then extracted with ethyl acetate, the combined organic phases are washed with a 1M aqueous solution of potassium bicarbonate and then with 1M sodium hydroxide solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[O:40][CH3:41])=[CH:34][C:33]=2[C@H:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([N:44]2[CH2:45][CH2:46][CH2:47][C@@H:43]2[C:33]2[CH:34]=[C:35]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]2[CH2:27][CH2:28]2)(=[O:31])=[O:30])=[O:14])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Reactant: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2)c1
Agent: Cl
Product: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2C(=O)[C@H](Nc2cc(C(N)=O)ccc2F)c2ccc(F)c(OC)c2)c1

Procedure:
Example 87 was prepared according to the general coupling condition using 27A and 85J. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.00-1.08 (m, 2H) 1.13 (m, 1H) 1.36-1.43 (m, 1H) 1.73 (m, 1H) 2.02-2.14 (m, 2H) 2.52 (m, 1H) 3.22-3.29 (m, 1H) 3.71 (s, 6H) 4.16 (ddd, J=10.22, 6.81, 6.70 Hz, 1H) 5.46 (s, 1H) 5.88 (dd, J=7.91, 5.27 Hz, 1H) 6.98-7.06 (m, 4H) 7.08-7.15 (m, 3H) 7.32 (dd, J=8.35, 1.76 Hz, 1H) 7.68 (d, J=9.23 Hz, 1H) 9.44 (s, 1H), LC-MS 643 (M+H).