Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](Cl)=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32].Cl.C(OCC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:25].[N:1]1([CH2:6][C:7]2([C:34](=[O:35])[CH2:33][C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CC1(C)CNC(CN2CC=CC2)c2ccccc21
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC1(C)CNC(CN2CC=CC2)(C(=O)Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 59.4 %

Procedure:
Prepared as Example No. 1 from 1.4 g (5.78 mmoles) of 1-(3-pyrrolin-1-yl)methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline, 1.6 g (11.59 moles) of anhydrous potassium carbonate and 1.5 g (6.71 moles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform. The work-up of the reaction mixture afforded 1.9 g of the crude product which was dissolved in 60 ml of ethyl acetate and the solution brought to acidic pH with HCl/diethyl ether. The precipitate was filtered, washed and dried, to yield 1.6 g of the title compound. C24H26Cl2N2O.HCl M.P.=254°-257° C. M.W.=465.843 Elemental analysis: Calcd. C,61.87; H,5.84; N,6.01; Cl,22.83; Found C,61.94; H,5.88; N,5.99; C1,22.75. I.R. (KBr): 3450; 2960; 2540; 1630; 1440 cm-1N.M.R. (CDCl3): δ12.5 (s, broad, 1H); 6.9-7.5 (m, 7H); (80 MHz) 6.1 (dd, 1H); 5.8 (s, 2H); 3.9-5.1 (m, 4H);
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].I[CH2:18]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]1[C:3]2[C:4](=[O:5])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:18][O:1][C:2]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1O)c1ccccc1O
Reactant: ICI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OCOc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry N,N-dimethylformamide (180 ml). Dried finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added and the mixture was heated at 105° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo [d,g][1,3]dioxocin-12-one as a solid (9.5 g, 90%).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].C([O:8][CH2:9][CH3:10])C.[NH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:34])[N:25]([CH3:33])[CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:18]=2)=[CH:14][C:13]=1[F:37]>>[F:37][C:13]1[CH:14]=[C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:25]([CH3:33])[CH:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:34])[CH:18]=2)[CH:35]=[CH:36][C:12]=1[NH:11][C:9](=[O:8])[CH2:10][C:3]([NH:2][C:1]1[CH:15]=[CH:14][C:13]([F:37])=[CH:12][CH:36]=1)=[O:4]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ccn2)CC1
Reactant: CN(C)C=O
Reactant: CCOCC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)c(F)c3)ccn2)CC1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 3-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.5 mg) in tetrahydrofuran (20 ml) (Production Example 124) was added N,N-dimethylformamide (2 ml) under a nitrogen atmosphere, followed by evaporating the tetrahydrofuran under a reduced pressure. To the solution thus concentrated were added N-(4-fluorophenyl)malonic acid (42.6 mg), triethylamine (0.030 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (95.5 mg) at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of ammonium chloride (15 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (15 ml), water (15 ml) and brine (15 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate-ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (29.1 mg, 48.8%) as a pale green and yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C=O.[NH3:20]>[Cl-].[Zn+2].[Cl-].CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH:2][CH3:1])=[C:6]([CH:7]=1)[C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: CN(C=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: CNc1ccc(Cl)cc1C(=N)c1ccccc1
Yield: 75.7 %

Procedure:
A mixture of 41.1 g (0.15 mole) of N-methyl-N-(2-benzoyl-4-chlorophenyl)formamide, 90 ml methanol, 90 g anhydrous ammonia, and 0.5 g zinc chloride was heated in a sealed 360 ml Hastelloy® tube at 150° for 15 hr. and then cooled and vented. The solid portion of the residue was collected on a filter and recrystallized from methanol to give 27.8 g (76%) of 5-chloro-2-methylaminobenzophenone imine as long yellow needles: mp 93°-95°; 1H nmr (CDCl3) δ 2.92 ppm (d, J = 5.5 Hz, 3H), 6.65 ppm (d, J = 9 Hz, 1H) 7.4 ppm (m, 7H) and 9.4 ppm (broad, 2NH).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16]O.C([N:28](CC)C(C)C)(C)C>C(O)CCC>[NH2:28][CH2:16][C@@H:15]([N:14]1[CH2:12][C:4]2[C:5](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:6]1=[O:8])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCCCO
Product: NC[C@H](Cc1ccccc1)N1Cc2cc(Br)ccc2C1=O
Yield: 71.5 %

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)benzoate (1.0 g, 3.24 mmol), (2S)-2-amino-3-phenyl-1-propanol (0.49 g, 3.24 mmol) and N,N-diisopropylethylamine (2.06 mL, 11.8 mmol) in 1-butanol (8 mL) was stirred at 140° C. for 2 h under microwave. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (20 mL) and EtOAc (20 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed with water, brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with MeOH/EtOAc (0-5%) to give 0.8 g (71% yield) of the final product as off-white solid. LC/MS found: 346.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a stirred solution of (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (209 g, 0.80 mol) in absolute CH2Cl2 (3 L) at 0° C. under N2 was added dropwise TiCl4 (92.2 mL, 0.84 mol) over 30 min. After 15 min, DIEA (0.864 mol) was added dropwise over 15 min, and stirring was continued for 1 h at 0° C. ((Chloromethoxy)methyl)benzene (222 mL, 1.60 mol) was added dropwise over 90 min at 0° C. After stirring for 20 h at 0° C., the reaction was quenched by addition of 10% aq NH4Cl (800 mL) and H2O (1 L). The aqueous phase was extracted with CH2Cl2 (2×1 L), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel to afford (R)-4-benzyl-3-((S)-2-(benzyloxymethyl)-3-methylbutanoyl)oxazolidin-2-one (152 g, 50%). 1H NMR (400 MHz, CDCl3): 0.99 (m, 6H), 2.05 (m, 1H), 2.67 (m, 1H), 3.23 (m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.14 (m, 3H), 4.52 (m, 2H), 4.72 (m, 1H), 7.26 (m, 10H).
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.CNC.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22]
Reactant: CN(C)C(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CNC
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CN(C)C(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:21](=[O:22])[O:20]/[C:9](=[C:10](/[C:17]([OH:19])=[O:18])\[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:8]=2O)=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[CH:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:17](=[O:19])[O:18][C:8]3=[C:7]([C:4]4[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:21]([O:20][C:9]=23)=[O:22])=[CH:12][CH:13]=1
Reactant: O=C1O/C(=C(/C(=O)O)c2ccccc2)C(O)=C1c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC2=C(c3ccccc3)C(=O)OC2=C1c1ccccc1

Procedure:
Pulvinic acid (19.0 g., 0.0616 m.) is refluxed in 250 ml. of acetic anhydride for 15 minutes. The cooled solution is stirred into 1200 ml. of ice and water and the oily mass crystallized by stirring in 500 ml. of ethanol. The yellow solid is removed, washed with ethanol and dried to yield pulvinic acid lactone, m.p. 221.5° -223° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([N:27](CC)CC)[CH3:26].C(Cl)(=[O:34])C>C(Cl)Cl>[CH3:22][CH:13]([O:12][C:11]1[CH:23]=[CH:24][C:8]([C:4]2[CH:5]=[CH:6][C:7]([NH:27][C:25](=[O:34])[CH3:26])=[CH:2][CH:3]=2)=[CH:9][CH:10]=1)[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17]
Reactant: CCN(CC)CC
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 189.2 %

Procedure:
To a solution of {2-[4-(3-Aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125 mg, 0.3587 mmol, prepared in example 3) in methylene chloride (2.5 mL) in a 10 mL round-bottomed flask, in an ice bath, fitted with a thermometer, and under a nitrogen system was added triethylamine (0.125 mL, 0.8968 mmol). The mixture was cooled to 0° C. and acetyl chloride 0.04 mL, 0.5381 mmol) was added by syringe. The mixture was allowed to warm to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced vacuum, yielding 265 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding the title compound (104 mg, 74%) as a slow crystallizing foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:15])[OH:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[I:21]Cl.O>C(O)(=O)C>[I:21][C:6]1[C:7]2[S:11][C:10]([NH:12][C:13](=[O:14])[OH:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClI
Reactant: COc1cccc2sc(NC(=O)O)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(I)c2sc(NC(=O)O)nc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.31), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydroflirane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.01), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(O)C>[C:25]1([CH2:24][CH2:23][CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccccc2)CC1

Procedure:
To a solution of 7.06 g (37.9 mmol.) of 1-tert-butoxycarbonylpiperazine in ethanol (50 ml) were added, at room temperature, 8.0 ml (57.4 mmol.) of triethylamine and 7.09 g (39.7 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated under reflux for 16 hours under nitrogen atmosphere. To the reaction system was added ethyl acetate. The mixture was washed with water and a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane=25-50%). The solvent was distilled off under reduced pressure to give the object compound as a pale yellow liquid product. The yield was 8.69 g (75%).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([O:4][C:5]([N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:17])[NH:15][OH:16])=[N:12][CH:13]=1)=[O:6])[CH3:3].Cl[C:27]([O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].[Cl-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C.O>[CH3:22][C:21]([CH3:24])([O:20][C:18]([N:7]([C:5]([O:4][C:2]([CH3:25])([CH3:1])[CH3:3])=[O:6])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:17])[NH:15][O:16][C:27]([O:29][CH2:30][CH:31]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:38]3[C:43]2=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:28])=[N:12][CH:13]=1)=[O:19])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NO)cn1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NOC(=O)OCC2c3ccccc3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-hydroxy-2-pyrazinecarboximidamide (77.0 mg, 0.218 mmol) in pyridine (2 mL) at 25° C. was treated with 9-fluorenylmethyl chloroformate (68.0 mg, 0.263 mmol). The reaction mixture was stirred at 25° C. for 45 min. The reaction mixture was then diluted with ethyl acetate, water, and a saturated aqueous sodium chloride solution. The mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/9 to 1/1 ethyl acetate/hexanes) afforded the desired 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-[[[(9H-fluoren-9-yl)methoxy]carbonyl]oxy]-2-pyrazine carboximidamide. This material was dissolved in methylene chloride (0.5 mL). The solution was cooled to 0° C. and then was treated with trifluoroacetic acid (0.16 mL, 2.077 mmol). The reaction mixture was stirred at 0° C. for 30 min and at 25° C. for 30 min. The reaction mixture was then treated with additional trifluoroacetic acid (1.0 mL, 12.99 mmol) and stirred at 25° C. for 2 h. The reaction mixture was further treated with trifluoroacetic acid (1.0 mL, 12.99 mmol) and stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride, washed three times with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then dried under high vacuum to afford 5-amino-N-[[[(9H-fluoren-9-yl)methoxy]carbonyl]oxy]-2-pyrazinecarboximidamide (36.7 mg, 44.9%) as a white solid: LRMS for C20H17N5O3 (M+H)+ at m/z=376
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[N:5](C(OCC1C3C=CC=CC=3C3C1=CC=CC=3)=O)[CH2:4][CH2:3][N:2]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>CCOCC>[CH:1]12[CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][N:2]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C2CC21
Agent: CCCCCCCCS
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCNC2CC21
Reaction time: 4 h

Procedure:
tert-Butyl (±)-9H-fluoren-9-ylmethyl 2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate (1.05 g, 2.50 mmol) was dissolved in Ether (25 mL) and was treated with 1-octanethiol (3.65 g, 24.97 mmol) at room temperature for 10 minutes. Then DBU (0.151 mL, 0.999 mmol) was added. Let mixture stir for 4 hours. Then solvent and extra 1-Octanethiol was removed under reduced pressure. And residue was put on 40 gram silica gel column and eluted on ISCO (0-15% MeOH/EtOAc). Removing solvent gave the title compound. 1H NMR (ppm) (500 MHz, CDCl3): δ 3.51-3.45 (1H, m), 3.05-2.58 (5H, m), 1.71 (1H, s), 1.45 (9H, s), 0.88-0.77 (1H, m), 0.53-0.44 (1H, m).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
4-(Trifluoromethyl)iodobenzene (145 μl, 1.0 mmol), tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.22 g, 1.2 mmol), potassium phosphate (0.43 g, 2.0 mmol), ethylene glycol (0.11 mL, 2.0 mmol), copper(I) iodide (19 mg, 0.10 mmol) and 2-propanol (1 mL) were charged in a threaded test tube, and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked-up according to a conventional method. The obtained crude product was purified by silica gel column chromatography (15% mixed solvent of ethyl acetate/hexane) to give the title compound (0.07 g, 0.21 mmol, 21%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2
Reactant: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a mixture of ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (WO2009144554) (100 mg, 0.34 mmol) and potassium carbonate (95.1 mg, 0.68 mmol) in N,N-dimethylformamide (1 mL) was added methyl iodide (32 μL, 0.51 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (105 mg, 100%) as a yellow oil. +ESI (M+1-THP) 221.2; 1H NMR (400 MHz, CDCl3, δ): 8.07-8.10 (m, 2H), 7.43 (d, J=0.98 Hz, 1H), 6.24 (dd, J=10.24, 2.44 Hz, 1H), 4.38 (q, J=7.15 Hz, 2H), 4.08 (dt, J=11.56, 2.02 Hz, 1H), 4.04 (s, 3H), 3.70-3.78 (m, 1H), 2.54-2.66 (m, 1H), 2.09-2.19 (m, 1H), 2.01-2.08 (m, 1H), 1.71-1.83 (m, 2H), 1.55-1.64 (m, 1H), 1.41 (t, J=7.12 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:44][C:43]([CH3:46])([CH3:45])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]3)=[CH:34][N:33]=2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][C:43]([CH3:45])([CH3:46])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]4)=[CH:34][N:33]=3)=[CH:26][CH:25]=2)[N:7]([CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(N)cc3)nc2)CC1(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4C)cc3)nc2)CC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
A mixture of 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate from Step 1 of this example (65 mg, 0.24 mmol), N-(4-aminophenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide dihydrochloride from Example 49 (90 mg, 0.20 mmol), triethylamine (92 μL, 0.66 mmol), and N,N-dimethylpyridin-4-amine (2 mg, 0.02 mmol) in THF (3 mL) was stirred at rt for 2 d. The solvent was removed under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 9% MeOH/1% NH3 in DCM. The resulting compound was then purified by reverse phase HPLC to afford N-(4-(3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)ureido)phenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide (7 mg, 6% yield). LCMS (ESI) m/z 562 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.76 (br s, 1H), 9.47 (br s, 1H), 8.35-8.34 (d, 1H), 8.11-8.08 (d, 1H), 7.78-7.75 (d, 2H), 7.63-7.59 (d, 1H), 7.47-7.44 (d, 2H), 6.02 (s, 1H), 4.87 (t, 1H), 3.6 (s, 3H), 2.2 (s, 3H), 2.04-1.99 (d, 2H), 1.49-1.42 (t, 2H), 1.21 (s, 9H), 1.13-1.12 (m, 12H).