Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:10])[CH2:6][CH2:5]1.[CH2:18]([N:25]([CH3:35])[C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:11]([C:7]1([OH:10])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:33]([NH:32][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:35])[CH:31]=2)=[O:34])[CH2:5][CH2:6]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(Cc1ccccc1)c1cc(N=C=O)ccn1
Reactant: NCCN1CCC(O)(Cc2ccccc2)CC1
Product: CN(Cc1ccccc1)c1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1

Procedure:
The compound is prepared from 1-(2-amino-ethyl)-4-benzyl-piperidin-4-ol (93 mg, 0.40 mmol) and 2-(benzyl-methyl-amino)-4-isocyanato-pyridine (95.7 mg, 0.40 mmol) using the method described for Example 388D.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1COCC1>[Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]1[S:44][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
To a 25-mL round bottom flask charged with a solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (326 mg, 0.65 mmol) in dry THF (10 mL) and equipped with a magnetic stirbar and septum was added Lawesson's reagent (527 mg, 1.3 mmol) under an atmosphere of nitrogen. This was stirred at room temperature for a period or 20 h. The solvent was then blown off under a gentle stream of nitrogen and the residue was directly purified via silica gel chromatography eluted with 30% EtOAc/hexanes to yield the product as a white solid (246 mg, 76%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.90 (m, 2H), 7.46 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.19 (d, J=7.9 Hz, 1H), 5.00 (dd, J=3.1, 7.9 Hz, 1H), 4.50 (m, 1H), 2.27 (s, 3H), 1.21 (d, J=6.3 Hz, 3H), 1.02 (s, 9H), 0.24 (s, 3H), 0.17 (s, 3H).
Reaction SMILES: [C:1]1([N:11]=[C:12](Cl)[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:11]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:20][N:19]=[N:18]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)C(Cl)=Nc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Four grams (15.5 mmol) of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 13, 1.84 g (27.9 mmol) of sodium azide, 1.08 g (7.76 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was precipitated for 1 hour in 18 ml of n-hexane while being cooled using an ice bath, followed by filtration and drying, thereby giving 3.86 g of 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-tetrazole as a white powder (yield: 94.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:16][O-:17].[Li+].S(=O)(=O)(O)O>CC1CCCC(C)C1=O>[CH3:16][O:17][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: CC1CCCC(C)C1=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a stirred solution of 3,5-dinitrobenzoic acid (2.0 g, 9.42 mmol) in 2,6-dimethylcyclohexanone (20.0 ml) was added lithium methoxide (1.43 g, 37.8 mol). The resulting mixture was stirred at room temperature for 20 hours and poured into cold diluted sulfuric acid aqueous solution. The mixture was extracted with diethylether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.31 g, yield: 70.25%, reddish brown solid).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](C(OC)=O)[C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].[Na+].[Cl-]>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
The solution of dimethyl 2-(5-nitropyridin-2-yl)malonate (10.0 g 41.7 mmol), NaCl (2.58 g, 44.20 mmol) and H2O (1.3 g, 74.23 mmol) in DMSO (50 mL) was stirred at 130 degree for 6 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O.CC(C)=O>[Cl:19][CH2:20][C:21]([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=[O:22]
Reactant: C1CNCC2(C1)CC1CCC2CC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 20 g (0.244 mole) of sodium acetate and 18 g (0.100 mole) of spiro[bicyclo[2.2.2]octane2,3'-piperidine] is dissolved in 100 ml of water and 300 ml of acetone. A two-phase system is formed, to which is added dropwise at 0° to 5° an amount of 10.2 ml (14.4 g, 0.13 mole) of chloroacetyl chloride. An addition is then made to the mixture, at 0° to 5°, of 700 ml of water, whereupon the reaction product precipitates in flake form. Stirring is maintained for a further hour and the reaction product subsequently filtered off. After washing and then drying of the product over phosphorus pentoxide in a desiccator, there is obtained 1'-chloroacetyl-spiro [bicyclo[2.2.2]octane-2,3'-piperidine], M.P. 63° (with decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][C:16](N(OC)C)=[O:17])=[CH:10][CH:9]=1.CC(N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(C)C>C1COCC1.[I-].[Zn+2].[I-]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][C:16]([C:5]2[CH:4]=[CH:3][N:2]=[N:1][CH:6]=2)=[O:17])=[CH:12][CH:13]=1
Reactant: c1ccnnc1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Agent: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)c1ccnnc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.5 %

Procedure:
To a solution of pyridazine (250 mg, 3.12 mmol) and (R)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (1.81 g, 4.99 mmol) in THF (10 mL) was added zinc iodide (996 mg, 3.12 mmol). The suspension was stirred for 10 min. at ambient temperature. The reaction mixture was cooled to −78° C., then N′″-(1,1-dimethylethyl)-N,N′,N″-tris[tris(dimethyl-amino)phosphoranylidene]-phosphorimidic triamide solution (“Schwesinger P4 base”; 1 M in hexane 4.68 mL, 4.68 mmol) was added. The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between sat, aq. ammonium chloride solution and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound 30 mg, 3%), while the most of the starting material was recovered (1.51 g, 83%). Light yellow gum, MS: 381.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:14][CH2:15][CH2:16][C:6]=3[C:5]=2[CH:4]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:14]2[CH2:15][CH2:16][C:6]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(OC)cc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(OC)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 9-methoxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.42 (1H, br s), 7.98 (1H, s), 7.62 (2H, m), 7.28 (1H, m), 7.16 (2H, m), 6.93 (1H, d), 6.88 (1H, dd), 4.24 (4H, m), 3.88 (3H, s), 3.23 (2H, m), 1.23 (3H, t); MS (ES): 409 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([CH:20]2[CH2:22][CH2:21]2)=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH:20]1([C:5]2[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]3[N:43]=[C:39]([CH:36]4[CH2:38][CH2:37]4)[O:40][CH:41]=3)=[O:45])=[C:3]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:27][CH2:28]3)[CH:4]=2)[CH2:21][CH2:22]1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
5-Amino-2-cyclopropyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 5b (89.0 mg, 0.19 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (43.0 mg, 0.28 mmol, 150 mol %) and N,N-diisopropylethylamine (0.10 ml, 0.56 mmol, 300 mol %) were combined in N,N-dimethylformamide (3.0 ml) and HATU (106.7 mg, 0.28 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-cyclopropyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 5c (34.0 mg; 0.06 mmol, 29.8%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)c1ccc2nc(Br)sc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Bromo-6-benzothiazolecarboxylic acid (0.500 g, 1.94 mmol) was suspended in dichloromethane/methanol (12 ml, 6:1) and cooled to 0° C. with an ice-water bath. Then, 2M (trimethylsilyl)diazomethane (2.91 ml, 5.81 mmol) was added dropwise over 5 min. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 hrs. The resulting mixture was concentrated in vacuo to yield methyl 2-bromobenzo[d]thiazole-6-carboxylate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (29.8 g, 0.223 mol) is added in small portions to a stirred solution of 2-(4-chlorophenyl)-1-(4-methoxyphenyl)ethanone (19.4 g, 0.074 mol) in toluene (300 ml). The mixture is heated to 60° C. and stirring is continued for 2 h. Dilute hydrochloric acid is added to the cooled mixture. Ethyl acetate is added to dissolve the product. The layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and the solvents are evaporated. The product is recrystallized from toluene. The yield is 17 g, 93%.
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([NH:26][C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 148 °C
Yield: 61 %

Procedure:
A solution of (1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (500 mg, 1.26 mmole) was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb maintained at 148 ° C. (oil bath) for 48 hours. The bomb was cooled and the resulting pale yellow solution diluted with ethanol containing 1 N sodium hydroxide (1.2 mL). Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform as a colorless oil. The oil was dissolved in absolute ethanol, concentrated to an oil, and triturated with water (3 mL) to give (1R, 2S, 3S, 5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (303 mg, 61%), m.p.: collapses to glass at 116-150° C.; 1H-NMR(DMSO-d6) δ: 7.63 and 7.43 (both s, 2, aromatic CH), 6.15 (s, 1, NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d,J=7.4 Hz, 1, OH), 4.71 (d, J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.2-1.85 (m, 3, CH2 and CH of cyclopentane), 1.47 (s, 9, 3 CH3); mass spectrum (CI): 388(M+1); [α]20 589-4.0°, [α]20 578-4.3°, [α]20 546-6.0°, [α 20 436-22.6°, [α]20 365-82.1° (c=0.420, methanol). [See Examples 25-28, 30 and 31]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(O)cc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F

Procedure:
(RS)-(2-Fluoro-4-hydroxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide. White solid. MS 315.1 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1)[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](I)[CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]1[N:7]=[N:8][C:3]([N:2]([CH3:1])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:4][CH:5]=1)[CH:18]=[CH:17]2)[CH:33]=[CH2:32]
Reactant: C=CCI
Reactant: CN(c1ccc(-c2ccc3cc(O)ccc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (208 mg, 0.53 mmol) in DMF (5.3 mL) was added 60% wt NaH (47 mg, 1.17 mmol) followed by allyl iodide (54 μL, 0.59 mmol). The reaction was stirred at RT for 10 min. The crude reaction mixture was diluted with EtOAc. The organic layer was washed with water (5×) and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via HPLC to give 6-(6-(allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (85 mg). LCMS Rt=1.46 min (condition B); MS (M+1)=431.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.6, 1.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.20-7.25 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H), 6.09-6.23 (m, 1H), 5.51 (dd, J=17.2, 1.5 Hz, 1H), 5.36 (dd, J=10.5, 1.4 Hz, 1H), 5.16-5.31 (m, 1H), 4.66-4.74 (m, 2H), 3.03 (s, 3H), 1.76 (dd, J=12.5, 3.4 Hz, 2H), 1.45-1.53 (m, 2H), 1.41 (s, 6H), 1.24 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[F:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][C:49]=1[F:50].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:46]=[CH:45][C:44]([F:43])=[C:49]([F:50])[CH:48]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(F)c(F)c2)c1
Yield: 61.2 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-(propane-1-sulfonyl)-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (220 mg, 0.33 mmol), 3,4-difluoro-phenylboronic acid (107 mg, 0.66 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol), and cesium carbonate (217 mg, 0.66 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (142 mg, 62%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H48F2O8S (M+Na)+ 725.2930, found 725.2928.
Reaction SMILES: [BH4-].[Na+].CO.[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH3:27])([CH3:26])[N:10]=[C:11]2[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>O>[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]([OH:28])[C:9]([CH3:26])([CH3:27])[N:10]=[C:11]2[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.6 %

Procedure:
Sodium borohydride (103 mg) was added to a methanol (8 mL) solution of 3-(5-fluoro-4-keto-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (300 mg, 0.9 mmol) followed by stirring for 2.5 hours at room temperature, pouring water, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 215 mg (yield 74%) of the target compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26]Br>>[C:2]([C:4]1[C:9]([O:10][CH2:26][CH2:25][Br:24])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])(=[O:3])[CH3:1]
Reactant: BrCCBr
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1c(C(C)=O)c(OCCBr)c(OC)c2occc12
Yield: 83 %

Procedure:
Khellinone (850 mg, 3.6 mmol, 0.4 M), K2CO3 (3 eqs) and 1,2-dibromoethane (3 eqs) were reacted according to General Procedure A. The crude product was purified by flash chromatography, eluting with ethyl acetate:petroleum ether (15:85) to afford the title compound as a clear oil (1.02 g, 83%). 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 3H), 3.57 (t, J=6.3 Hz, 2H), 3.98 (s, 3H), 4.07 (s, 3H), 4.35 (t, J=6.3 Hz, 2H), 6.86 (d, J=2.2 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H). MS (ES+) m/z 342.8/344.8 (M+H+).
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[C:33]([O:39]C)[N:32]=2)=[CH:13]\[C@@H:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:17](=[O:30])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[NH:32][C:33](=[O:39])[C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:30])[N:18]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)nc1OC
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
48% hydrobromic acid (0.6 mL) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (59 mg) in 1,4-dioxane (0.6 mL), and the mixture was stirred at 65° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→3:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridin-2(1H)-one as a colorless oil (49 mg).