Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:16]2[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[N:30]=1)[CH3:11]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][S:2]([CH3:1])(=[O:5])=[O:3])[C:16]2[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[N:30]=1)[CH3:11]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCCCN
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCCCNS(C)(=O)=O
Reaction time: 2.5 h
Yield: 142.1 %

Procedure:
Methane sulfonic anhydride (0.822 g, 4.72 mmol) was added over a period of 5 minutes to a solution of 4-[2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amine (1.5 g, 4.23 mmol) in a mixture of chloroform (35 mL) and triethylamine (0.77 mL). The reaction mixture was allowed to stir for 2.5 hours then it was washed with 1 N sodium hydroxide (10 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 2.6 g of crude N-[4-(2-ethoxymethyl-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:36]4[C:4](=[O:5])[C:3]5[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:1]4=[O:11])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1c2c(c(I)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c2c(c(I)c1-c1ccnc(N3C(=O)c4ccccc4C3=O)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Pthaloyl chloride (0.089 g, 0.437 mmol) was added to a cold (0° C.) solution of 2-(2-Amino-pyrimidin-4-yl)-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 1) (0.158 g, 0.337 mmol) and pyridine (0.069 g, 0.875 mmol) in dry DCM (1.5 ml) and the reaction mixture was stirred at room temperature in argon atmosphere for 4 h. The organic layer was washed with a saturated solution of NaHCO3 (1×2.0 ml), brine (1×2.0 ml), and it was dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography, over silica gel (DCM/MeOH (9.8:0.2) as eluent), to afford 2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrimidin-4-yl]-3-iodo-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.150 mg, 0.25 mmol, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH:37]2[CH2:39][CH2:38]2)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:20][C:21]2[C:22]([CH:37]3[CH2:39][CH2:38]3)=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCCC2
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 5B]) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 9E]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[C:27]([F:28])([F:29])[F:30])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-hydroxy-N-(t-butoxycarbonyl)piperidine (10.0 g) in DMF was added NaH (2.2 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. 4-Flouro-3-trifluoromethyl-1-nitrobenzene (5.3 mL) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3 and aqueous HCl, dried over sodium sulfate, concentrated and purified on silica gel column (hexane/ethyl acetate, gradient) to afford a compound of formula (C), 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene in 80% yield.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[NH:41])[NH2:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)C1CCCC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Yield: 60 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 60% of theory, C27H34N6O3 (490.6) EKA mass spectrum: (M+H)+ =491
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[I-].[Na+].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38]Br)=[O:36])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38][N:2]([CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH3:1])=[O:36])=[CH:31][CH:30]=1
Reactant: CNCC(O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=S(CCBr)c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCS(=O)c1ccc(F)cc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A suspension (50 ml) of 6-(3-methylamino-2-hydroxypropoxy)carbostyril (3.0 g), sodium iodide (11.8 g), triethylamine (2.2 ml) and 2-(4-fluorophenylsulfinyl)ethyl bromide (3.9 g) in dimethylformamide is heated with stirring at 80°-90° C. for 5 hours. After concentration under reduced pressure, the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol:ammonium hydroxide=200:10:1-150:10:1) and recrystallized from dichloromethane-diethylether to give 6-[3-{N-[2-(4-fluorophenylsulfinyl)ethyl]-N-methylamino)-2-hydroxypropoxy]carbostyril (0.7 g), as white powder, m.p. 126°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[N:31]12[CH2:39][CH2:38][CH:35]([CH2:36][CH2:37]1)[NH:34][CH2:33][CH2:32]2.O>O1CCOCC1>[N:31]12[CH2:39][CH2:38][CH:35]([CH2:36][CH2:37]1)[N:34]([C:11](=[O:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=1)[CH2:33][CH2:32]2
Reactant: COc1ccc(C(=O)NCC(=O)O)cc1
Reactant: C1CN2CCC(CC2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)NCC(=O)N2CCN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.42 g (2 mmol) of N-(4-methoxybenzoyl)glycine dissolved in 20 ml of dioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) of dicyclohexylcarbodiimide is added, the mixture is stirred at room temperature for 30 minutes, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further one hour. 20 ml of water are added, the precipitate formed is filtered off, the filtrate is extracted with chloroform, the organic phase is extracted with aqueous 0.1N hydrochloric acid solution and the aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=1[C:21]([O:23]CC)=[O:22]>ClC(Cl)C>[C:1]([C:19]1[C:15]([CH3:14])=[C:16]([C:21]([OH:23])=[O:22])[NH:17][C:18]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1[nH]c(C(=O)O)c(C)c1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
To a mixture of benzoyl chloride (1 equiv.) and aluminum chloride (1 equiv.) in dichloroethane at 0° C. was added ethyl 3,5-dimethyl-2-pyrrolecarboxylate (1 equiv.). The mixture was stirred at 80° C. for 4 hr. The mixture was then extracted with ethyl acetate (EtOAc) and H2O. The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried and concentrated to give (51%) of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C=O.[O:14]1CCOC[CH2:15]1>O>[OH:14][CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: C1COCCO1
Agent: C=O
Solvent: O
Product: O=C1C(=O)N(CO)c2ccccc21
Temperature: 100 °C
Yield: 93 %

Procedure:
Isatin (25 g, 0.17 mol) and 30% formalin (30 ml, 0.3 mol) were added to a mixture of dioxane (10 ml) and water (20 ml) and the mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled and crystals formed were filtered off. N-hydroxymethylisatin (28 g, yield 93%) was obtained. The melting point was 138° C. (decomposed).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21](I)[CH3:22]>CN(C=O)C.O>[CH2:21]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1)[CH3:22]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(-c3ccccc3)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF (1.0 mL) is added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture is stirred for 20 min at 0° C. under N2. Ethyl iodide (14.8 μL, 0.185 mmol) is added dropwise and the reaction mixture is stirred for an additional 3 hours. The reaction mixture is diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase is washed with water (250 mL) and is then dried over MgSO4 and the solvent is removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole is obtained as a yellow powder (40.0 mg, 89.5% yield).
Reaction SMILES: C(C(CCCC)C[OH:5])C.C(N(CC)CC)C.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([CH2:23][C:24]([OH:25])=[O:5])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCC(CC)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g, 0.5 mol) and methylene chloride (50 mL). Add, by dropwise addition, 2-phenylacetyl chloride (5 mol) and warm to 50° C. Stir at room temperature overnight, filter and wash the filtercake with methylene chloride (50 mL). Combine the organic phases and wash with 5% aqueous hydrochloric acid (50 mL) and water. Dry (MgSO4), evaporate the solvent in vacuo and purify by distillation to give 2-phenylacetic acid, 2-(2-ethylhexyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.C1C(=O)N([I:26])C(=O)C1.C(OCC)(=O)C>C(#N)C>[I:26][C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Yield: 99.8 %

Procedure:
In an oven dried nitrogen purged 25 mL round bottom flask, 0.088 g (0.359 mmol) of 2,6-Dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine, in 5 mL of dry acetonitrile is cooled to 0 C. 0.0.81 g (0.359 mmol) of NIS is added and the bath is allowed to expire. TLC in 1:1 Hexanes:Ethyl Acetate indicates SM is gone. Remove solvents to obtain 0.133 g of the title compound, quantitative yield. MS; 1H NMR (DMSO-d6)=6.985 (s, 1H); 3.262-3.190 (m, 1H); 2.502 (s, 3H); 2.480 (s, 3H); 1.823-1.600 (m, 4H); 1.182-0.985 (m, 4H); 0.804-0.768 (m, 6H) ppm.
Reaction SMILES: C(O[C:4]1[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][N:9]=1)C.[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]([NH:25][NH2:26])=O>C(O)CCC>[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]1[N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:5][C:4]2=[N:26][N:25]=1
Reactant: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Reactant: NNC(=O)c1cnccn1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (1.14 g, 5 mmol) in 1-butanol (30 mL) was added pyrazine-2-carbohydrazide (685 mg, 5 mmol). The reaction mixture was heated at reflux for 16 h. After cooling to rt, the reaction mixture was concentrated and purified by chromatography (SiO2; 2.5% MeOH in DCM) to afford the desired product as a white solid (700 mg, 50% over 2 steps). MS (ESI): mass calcd. for C14H18N6O2, 302.2; m/z found, 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3) d 9.57 (d, J=1.4 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.59-8.54 (m, 1H), 4.94 (s, 2H), 4.63-4.50 (m, 2H), 3.89 (t, J=5.4 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.C(N(CC)CC)C.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[CH:4]12[CH2:9][CH:7]([CH:6]=[CH:5]1)[CH2:8][CH:3]2[CH2:2][NH:1][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: CCS(=O)(=O)Cl
Reactant: NCC1CC2C=CC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCC1CC2C=CC1C2
Reaction time: 24 h
Yield: 83.6 %

Procedure:
An oven-dried, nitrogen-flushed 1 L round bottom flask equipped with an addition funnel, nitrogen inlet, reagent inlet, and a teflon-coated stir bar was charged with 116.3 g 5-aminomethylnorbornene (0.944 mol,) 95.5 g triethylamine (0.944 mol,) and 1 L dichloromethane. The addition funnel was charged with 121.4 g ethanesulfonyl chloride (0.944 mol,) and 500 ml dichloromethane. The contents of the addition funnel were added dropwise to the flask over the course of approx. two hours. During this time, the reaction warmed gradually and finally began a gentle reflux. The reaction was left to stir for approx. 24 hours. The mixture was transferred into a separatory funnel, and the organic layer was washed twice with 300 ml water, 2× with 300 mL dilute sodium bicarbonate, and twice more with 300 ml water. The organic layer was dried over magnesium sulfate, then concentrated to yield an oil. Attempts to crystallize the oil from hexane:ethyl acetate failed. Silica gel column chromatography using hexane:ethyl acetate (60:40) as the eluent gave a clear, straw-colored oil that was further purified by vacuum distillation (140° C. at 5 microns of Hg) to provide 170 g of the desired ethanesulfonamide as a mixture of isomers. The product was identified by 1H and 13C NMR and IR spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.[N:36]([Si](C)(C)C)=[C:37]=[O:38].O>C(Cl)Cl>[C:30]([C:27]1[N:28]=[CH:29][C:24]([N:3]2[C:2](=[O:1])[C:6]3([CH2:9][CH2:8][CH2:7]3)[N:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:37]([NH2:36])=[O:38])[CH2:19][CH2:18]4)=[CH:12][CH:11]=3)[C:4]2=[S:23])=[CH:25][C:26]=1[C:32]([F:34])([F:33])[F:35])#[N:31]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCN(C(N)=O)CC4)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (70 mg, 0.14 mmol) and isocyanatotrimethylsilane (23 μL, 0.17 mmol) in DCM (3 mL) was stirred at room temperature overnight. Water was added and the mixture was stirred vigorously for 1 h. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. Column chromatography on silica gel (0 to 20% MeOH/DCM) afforded 55 mg of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.69 (s, 1H), 7.23 (d, 2H), 7.12 (d, 2H), 5.92 (s, 2H), 4.53 (m, 1H), 3.67-3.63 (m, 2H), 3.08-3.04 (m, 2H), 2.44 (m, 2H), 2.39 (m, 2H), 1.88 (m, 3H), 1.46 (m, 3H). LCMS [M+1]+ 545.2
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:36][CH3:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), methanamine-HCl (8.24 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.0 min) to provide (R/S)-2-hydroxy-N-methyl-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.066 mmol, 82% yield): LCMS=444.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.07-8.15 (2 H, m), 7.51-7.71(7 H, m), 5.11(1 H, s), 3.35(1 H, s), 2.79 (3 H, s); HPLC peak RT=7.4 min (Method A).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[C:34]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>O1CCOCC1>[F:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)=[CH:33][C:34]=1[C:35]1[N:36]=[CH:37][CH:38]=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(F)c(-c3ncccn3)c2)OC1(C)C
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Temperature: 110 °C

Procedure:
(S)-3-(4-Iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(2.61 g, 6.64 mmol), sodium carbonate (6.64 mL, 13.28 mmol), 2-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pyrimidine (Intermediate H) (2 g, 6.64 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.542 g, 0.664 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (16.60 mL) and stirred at 110° C. overngight. LC-MS indicated that there was complete conversion to the desired product. The final reaction material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide (S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as yellow solid. m/z (ESI) 441.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:15][CH2:16][CH:17]2[CH:21]3[O:22][C:23]([CH3:26])([CH3:25])[O:24][CH:20]3[CH:19]([N:27]3[CH:35]=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][C:32]=4[NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])[O:18]2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[C:10]([O:15][CH2:16][CH:17]2[CH:21]3[O:22][C:23]([CH3:26])([CH3:25])[O:24][CH:20]3[CH:19]([N:27]3[CH:35]=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][C:32]=4[NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])[O:18]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OC2C(COc3ncccc3OCc3ccccc3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)OC2C(COc3ncccc3O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reaction time: 5 h
Yield: 32.1 %

Procedure:
Dry argon was bubbled through a solution of 1-{9-[6-(3-Benzyloxy-pyridin-2-yloxymethyl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}-3-phenyl-urea (18 mg, 0.03 mmol, prepared as above) in methanol/ethyl acetate (1:1 v/v, 10 mL) at 23° C. for 10 min. Palladium on activated carbon (10%) was added and the suspension was degassed by argon for another 5 min. Hydrogen (H2) was conducted to the solution via a balloon, and the reaction proceeded for 5 h. The mixture was filtered and concentrated in vacuo to give the crude product. Preparative reverse-phase HPLC was used to obtain the pure compound (5 mg, 31% yield) as a white solid. MW calculated for C25H25N7O6 (MH+) 520, found 520 by LCMS.