Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]=[CH:7][C:8]1[N:12]([CH3:13])[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:10][C:9]=1[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[C:1]([CH2:6][CH2:7][C:8]1[N:12]([CH3:13])[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:10][C:9]=1[CH3:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=Cc1c(C)nc(SCc2ccc(OC)cc2)n1C
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCc1c(C)nc(SCc2ccc(OC)cc2)n1C

Procedure:
A mixture of 5-[2-(carbethoxy)ethenyl]-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (600 mg, 1.7 mmole) and potassium azodicarboxylate (29 g, 0.17 mole) in methanol (50 ml) was stirred and treated with acetic acid (7 g, 0.12 mole). The mixture was concentrated in vacuo, partitioned between methylene chloride and 5% aqueous sodium carbonate, and the organic phase was concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate to give 5-[2-(carbethoxy)ethyl]-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (mp 63° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].S(Cl)(Cl)=O.O.[NH2:22][NH2:23]>>[N+:14]([C:6]1[CH:7]=[C:8]([C:9]([NH:22][NH2:23])=[O:10])[CH:12]=[CH:13][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]

Procedure:
From 4-methoxycarbonyl-3-nitrobenzoic acid, thionyl chloride and hydrazine monohydrate, 758 mg of the desired product was obtained in the same manner as in Reference Synthetic Example 39 as a white solid (yield 79%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:40]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)C1CCCC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopentanecarboxylic acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(cyclopentanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (113 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[C:30](Cl)(=[O:32])[CH3:31].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 56.9 %

Procedure:
A stirred mixture of (3R)-3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (400 mg, 1 mmol) and acetyl chloride (0.1 mL, 1.4 mmol) in tetrahydrofuran (5 mL) was heated to reflux for 2 h. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 20 mL), brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silica Gel, 1.5:1 ethyl acetate:methylene chloride) to give (3R)-3-[7-(acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (0.25 g, 57% yield); mp, 88-90° C.; 1H NMR (CDCl3)˜1.43 (t, J=6.9 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.04 (dd, J=5.5, 16 Hz, 1H, CHH), 3.09 (s, 3H, CH3), 3.52 (dd, J=9.5, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.26 (d, J=17 Hz, 1H, CHH), 4.44 (d, J=17 Hz, 1H, CHH), 5.58 (dd, J=5.5, 9.4 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 6.92-7.01 (m, 3H, Ar), 7.41 (t, J=7.8 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 10.37 (s, 1H, NH); 13C NMR (CDCl3)˜14.65, 24.84, 35.47, 36.16, 37.31, 48.71, 53.54, 55.85, 64.44, 111.35, 112.44, 116.83, 117.40, 117.97, 119.10, 131.72, 132.84, 137.65, 141.53, 148.46, 149.06, 168.98, 169.41, 169.57; Anal Calcd for C24H29N3O5+0.7H2O: C, 63.76; H, 6.78; N, 9.29; H2O, 2.79. Found: C, 63.89; H, 6.64; N, 9.14; H2O, 2.70.
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][C@@H:24]([CH:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28]3)[CH2:25][OH:26])C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:23][C@@H:24]([CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)[CH2:25][OH:26]
Reactant: O=C(N[C@H](CO)C1Cc2ccccc2C1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N[C@H](CO)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 225.2 %

Procedure:
20% Piperidine in DMF (15 mL) was added to a solution of 9H-fluoren-9-ylmethyl-(1S)-1-(2,3-dihydro-1H-inden-2-yl)-2-hydroxyethylcarbamate (1.05 g, 2.63 mmol) in DMF (5 mL). The reaction was stirred at 25° C. for 19 h. After solvent evaporation, the crude product was dissolved in ethyl acetate (50 mL) and dried over MgSO4, filtered and concentrated to obtain a crude yellow oil (1.05 g). Mass Spectrum (+ESI): 179 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.[ClH:32]>C(O)C>[ClH:32].[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:6]2[O:5][C:4]([NH:7][CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]2=[O:1])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NCCc2ccccc2)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NCCc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of ethyl 4-oxo-2-(phenethylamino)-4,5-dihydrofuran-3-carboxylate (0.041 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 32%).
Reaction SMILES: [CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[NH:24]([C:7]([C:6]1[CH:11]=[CH:12][C:3]([N:2]([CH3:1])[C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1)=[O:8])[NH2:25]
Reactant: NN
Reactant: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate (1600 mg, 5.38 mmol) in EtOH (14 mL) was added hydrazine hydrate (4.0 mL). The resulting mixture was stirred for 16 h at reflux and evaporated under vacuo to give the title compound (1600 mg, 100%) as a gummy colorless oil, which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>N1CCCCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=[C:25]2[C:24]3[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[NH:27][C:26]2=[O:31])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c(C(=O)OCC)c1C
Yield: 85.7 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 5-chloro-2-oxindole (168 mg), and piperidine (2 drops) in ethanol (2 mL) were refluxed for 2 hours. The reaction mixture was cooled and the precipitate that formed was filtered, washed with ethanol and hexanes, and dried to give 369 mg (86%) of 4-(2-ethoxycarbonylethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as a light yellow needle crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=O)=[CH:3]1.[S:23]([NH:33][NH2:34])([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CO>[S:23]([NH:33][N:34]=[C:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH2:20][OH:21])[C:4](=[CH:3][CH:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)([C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CCC5=CC(O)CC[C@]5(CO)[C@H]4CC[C@]23C)cc1
Reaction time: 16 h

Procedure:
3,19-Dihydroxyandrost-4-en-17-one (19) is heated under reflux in methanol with one equivalent of p-toluenesulfonylhydrazide (TsNHNH2, a) for 16 hours. After cooling, the mixture is evaporated to give the crude product. Purification yields the tosylhydrazone (20).
Reaction SMILES: O.[C:2]1([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH:18]([O-])=O.[NH4+]>[Pd].CO>[CH3:18][NH:15][C:14]1[C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Pd/C (10%, 11.49 g) was added to a three-neck flask. A gentle nitrogen flow was applied to the flask. Water (40 mL) and methanol (800 mL) were added to the flask. Then, N2-phenylpyridine-2,3-diamine (20 g, 108 mmol), formaldehyde (8.76 g, 108 mmol), and ammonium formate (136 g, 2160 mmol) were added. The reaction was stirred at room temperature overnight. The solution was filtered through a Celite® plug. The filtrate was concentrated and water was added. The solution was extracted with dichloromethane. The combined organic layer was concentrated and purified by column chromatography (30% ethyl acetate in hexanes) to give N3-methyl-N2-phenylpyridine-2,3-diamine (12 g, 55.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19]SC(O)C[S:15]1.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:15][CH:14]=[CH:19][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: OC1CSC(O)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 116.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2,5-dihydroxy-1,4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50° C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.O>CS(C)=O>[CH:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)=[CH:27][CH:28]=1)=[O:31]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Oc2ccc(C=O)cc2)cc1C(F)(F)F
Yield: 44 %

Procedure:
A solution of N-[4-fluoro-2-nitro-6-(trifluoromethyl)phenyl]acetamide (1.5 g, 5.63 mmol), Cs2CO3 (4.59 g, 14.09 mmol), and 4-hydroxybenzaldehyde (0.757 g, 6.20 mmol) in dimethylsulfoxide (10 mL) was heated to 80 degrees Centigrade for 2 h and then cooled. H2O was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed 1× brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel, using 2:1 hexanes/ethyl acetate eluted N-[4-[(4-formylphenyl)oxy]-2-nitro-6-(trifluoromethyl)phenyl]acetamide as an orange solid. (0.922 g; 44% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[C:27]([O:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)C(C)=O
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)C(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 63.1.1) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=486 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.28 (m, 1H), 8.18-8.06 (m, 2H), 8.04-7.91 (m, 1H), 7.85-7.69 (m, 1H), 7.54-7.41 (m, 1H), 4.52-4.33 (m, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.08 (s, 3H), 1.93 (s, 3H), 1.75 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: [Li+].CCC[CH2-].[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[NH2:9].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]2[N:24]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:26]=[C:19]2[N:18]=1>CCCCCC.C1COCC1>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]2[N:24]=[C:25]([S:27]([NH:9][C:8]3[C:7]([Cl:6])=[CH:13][C:12]([Cl:14])=[CH:11][C:10]=3[Cl:15])(=[O:28])=[O:29])[N:26]=[C:19]2[N:18]=1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cc(Cl)cc3Cl)nc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
A solution (10.7 ml, 17.1 mmol) of 1.60M N-butyllithium in hexane was added to a solution of 3.20 g (16.3 mmol) of 2,4,6-trichloroaniline in 20 ml of dry THF cooled to -78° C. The resultant solution was then allowed to warm to room temperature. This solution was added to a solution of 2.00 g (8.11 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride in 30 ml of dry THF cooled to -10° C. The temperature of the reaction mixture was maintained between -13° C. and -9° C. during to course of the addition. After the addition was complete, the reaction mixture was stirred for 30 minutes and warmed to room temperature. After 1 hour at room temperature, THF was removed from the reaction mixture by evaporation. The residue was triturated with H2O and filtered. The filtrate was treated with charcoal and filtered through celite. The filtrate was washed with Et 2 O, and the aqueous phase was separated and acidified with 3N HCl to precipitate a solid. The solid was collected by filtration, washed with water and dried in vacuo to yield 0.70 g (21%) of the desired product as a tan solid, m.p. >200° C. (decomp.) 1H NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14]O)=[N:3]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])=[N:3]1
Reactant: Cn1cc2c([C@H]3C[C@H]3CO)cccc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cc2c([C@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)cccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon gas atmosphere, to a solution of cis-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (130 mg, 0.643 mmol) in tetrahydrofuran (6.5 mL) were added a solution (40%, 0.351 mL, 0.771 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (219 mg, 0.835 mmol) and phthalimide (123 mg, 0.836 mmol), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added a solution (40%, 0.176 mL, 0.386 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (110 mg, 0.419 mmol) and phthalimide (61.5 mg, 0.418 mmol) were added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound as a crudely purified product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of (3R)-tert-butyl 3-((R)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (86 mg, 0.2 mmol) in anhydrous CH2Cl2 (8 mL) was added Et3N (0.5 ml, 20 mmol). The mixture was cooled with an ice bath and acetyl chloride (15 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was stirred at rt for 0.5 h, then washed with water, dried over MgSO4, filtered and concentrated to give (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (80 mg, 85%), which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.C(O)COCCO.[OH-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[N:5][CH:4]=1
Reactant: CCCCCCCCc1ccc(-c2ncc(OC)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: OCCOCCO
Product: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To 5-methoxy-2-(4-octylphenyl)pyrimidine (53.9 g, 0.18 mol) were added diethylene glycol (500 ml) and NaOH (43.4 g, 1.08 mol), followed by agitating the mixture at about 200° C. for 2 hours, pouring the resulting material in acetic acid (700 ml), collecting deposited crystals and recrystallizing the crystals from a mixed solvent of heptane (100 ml) with ethyl acetate (10 ml) to obtain 5-hydroxy-2-(4-octylphenyl)pyrimidine (45.2 g) (m.p.: 147.3-148.7 ° C.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C:3]1([F:15])[F:14].[CH3:16][S:17]([CH2:20][CH2:21][C:22](O)=[O:23])(=[O:19])=[O:18].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:14][C:3]1([F:15])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1
Reactant: CS(=O)(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100% heptane to 100% ethyl acetate to give the title product as a white foamy solid (1.65 g, 76% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 6.45 (br. s., 1 H) 4.68-4.89 (m, 1 H) 3.94 (dd, J=10.70, 8.62 Hz, 1 H) 3.62-3.86 (m, 2 H) 3.43 (t, J=7.15 Hz, 2 H) 3.18 (br. s., 1 H) 2.97 (s, 3 H) 2.84 (td, J=7.15, 1.96 Hz, 2 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −112.79-−110.52 (m, 1 F) −114.51-−113.30 (m, 1 F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+.