Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]3[C:14]([C:15]4[C:16]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:17][O:18][C:19]=4[CH3:20])=[N:13][N:12]=[C:9]32)=[CH:5][CH:4]=1.[B].C(OCC)C.O>ClCCl>[CH3:20][C:19]1[O:18][N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[C:14]1[N:8]2[CH2:7][C:6]3[C:10]([C:9]2=[N:12][N:13]=1)=[CH:11][C:3]([OH:2])=[CH:4][CH:5]=3
Reactant: COc1ccc2c(c1)-c1nnc(-c3c(-c4ccccc4)noc3C)n1C2
Agent: [B]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Temperature: -78 °C

Procedure:
8-Methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (4.6 g, 13 mmol) in dichloromethane (70 ml) was stirred with boron tribronide (25 g) for five days. The reaction was cooled to −78° C. and diethyl ether was added dropwise followed by water. The reaction was warmed to room temperature and the organic layer was washed with water and dried, filtered and evaporated. The residue was purified by column chromatography on silica using methanol/dichloromethane to yield the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C=O.[C:6](O)(=O)C.[C:10]([C:14]1[CH:15]=[C:16]([C:25]2[N:26]=[C:27]3[N:31]([CH:32]=2)[CH2:30][CH2:29][S:28]3)[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1>[CH3:1][N:2]([CH2:6][C:32]1[N:31]2[C:27]([S:28][CH2:29][CH2:30]2)=[N:26][C:25]=1[C:16]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:14]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:15]=1)[CH3:3]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: CC(=O)O
Reactant: CNC
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)Cc1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc2n1CCS2

Procedure:
To a mixed solution of 0.9 g of an aqueous 40% dimethylamine solution, 0.5 g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 5 ml of dioxane was added 0.66 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and the resulting mixture was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was mixed with 20 ml of an aqueous 10% potassium carbonate solution and extracted with chloroform. The extract was dried and concentrated, and the residue thus formed was purified by silica gel chromatography using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.3 g of 5-dimethylaminomethyl-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.1/4H2O.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[F:11])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 94.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (8.76 g) and piperazine-1-carboxylic acid tert-butyl ester (8.2 g), the title compound (14.7 g) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([CH:20]=1)[NH2:19].Cl>C(N(CC)CC)C>[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([NH:19][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=1
Reactant: Cc1ccc(I)cc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(I)cc1NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
2.1 mL of benzoyl chloride was added to 70 mL of a methylene chloride solution containing 3.5 g of 5-iodo-2-methylaniline and 2.5 mL of triethylamine at room temperature and stirred at the same temperature for 30 minutes. 1.0 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue and a solid substance was separated by filtration to obtain 4.2 g of N-(5-iodo-2-methylphenyl)benzamide as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O.O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2cccc(NCC3CCOCC3)n2)c(Cl)cn1
Solvent: CS(C)=O
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a solution of 5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (500 mg, 1.55 mmol) in DMSO (7 mL) was added trans-1,4-diaminocyclohexane (710 mg, 6.22 mmol). The mixture was stirred at 110° C. for 19 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 600 mg of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine. LCMS (m/z): 416.1 (MH+), retention time=0.48 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].[H-].[Na+]>C(O)(C)(C)C>[F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:24][CH2:23][CH2:22][CH2:21][NH2:20])[N:8]=1
Reactant: NCCCO
Reactant: CS(=O)(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphonylpyrimidine (0.15 g.) was added to a mixture of 3-aminopropanol (0.075 g.), t-butanol (5 ml.) and a 50% w/w dispersion of sodium hydride in mineral oil (0.05 g.) which was stirred under an argon atmosphere. The mixture was stirred at room temperature for 2 hours, heated under reflux for 4 hours and then evaporated to dryness. The residue was partitioned between 2N aqueous acetic acid and ether, and the aqueous phase basified with 17N NaOH and extracted three times with ether. The combined ether extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidine (0.07 g.) which was used without further purification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Br)o1
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 5.25 mmol) was coupled to 4-chloro-phenylboronic acid (819 mg, 5.23 mmol) acid using Method F to give the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate (17 mg, 0.039 mmol) was dissolved in THF (308 μL) and water (77 μL) before lithium hydroxide monohydrate (1 mg, 0.039 mmol) was added and stirred at 65° C. for 2 h. The reaction mixture was concentrated, acidified with 1 N HCl, and filtered. The solid was dissolved in DMSO and eluted through the frit to give the title compound after concentration. MS (ESI) m/z: Calculated: 427.1; Observed: 427.9 (M++H).
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].[CH:6]1[C:19]2[CH:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CI>O.C(O)C>[CH3:2][O:21][C:20]([CH:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:22]
Reactant: CC[O-]
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CCO
Solvent: O
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is generated from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the resulting suspension is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL of diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and 126.73 mL (2.0 mol) of methyl iodide is added with stirring. The solution obtained is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13](Cl)=[O:14]>C(Cl)Cl>[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13]([N:2]([CH3:3])[CH3:1])=[O:14]
Reactant: CNC
Reactant: O=C(Cl)C(Br)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(Br)CCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of dimethylamine (0.91 ml, 7.18 mmol; 40% solution in water) and 2.75 ml (19.76 mmol) of Et3N in 6 ml of CH2Cl2 cooled at 0° C. was added dropwise a solution of 2,5-dibromo-pentanoyl chloride (1.00 g, 3.59 mmol) in 4 ml CH2Cl2. After stirring 1 h at RT, the reaction mixture was partitioned between CH2Cl2 and water. The organic phases were washed with water and brine and the aqueous layers extracted twice with CH2Cl2. The organic phases were dried over MgSO4, evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1) to afford 0.66 g (64%) of the title product as light yellow oil. MS: 288.1 (2Br, MH+).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].S(=O)(=O)(O)O.[CH2:11]=[CH:12][C:13]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])([CH3:15])[OH:14]>>[C:13]([O:14][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])([CH:12]=[CH2:11])[CH3:15]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: C=COCC
Agent: O=S(=O)(O)O
Product: C=CC(C)(CCC=C(C)C)OC(C)OCC
Yield: 82.3 %

Procedure:
Into an 1 l reaction flask is placed 216 g vinylethyl ether. Under stirring a solution of 0.2 g concentrated sulfuric acid (s.g. 1.84) in 154 g linalool is added over a 2 hour period at 30°C. Then 100 g of a 10-percent soda solution are added to the reaction mixture and the entire mixture is stirred for half an hour. The organic upper layer is separated and fractionated with 0.5 g soda to obtain 186 g acetaldehyde ethyl linalyl acetal. The acetal has a boiling point of 90°-94°C. at 2 mm Hg; nD20 1,4495-1,4485. The addition of soda to the product to be distilled prevents the formation of 5.9-dimethyl-4.8-decadien-1-al during the fractionation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][C:32]([CH2:35][OH:36])([CH3:37])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: CC(N)(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 61.7 %

Procedure:
Following the general procedure outlined in Example 60, the product of Example 121 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (494 mg, 4.7 mmol) were reacted to give the crude material, which was purified as described in Example 126 to give the desired product 130 mg (62%). LC-MS: 449.0 (MH+, m/z), 1.67 (Rt, min)
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[Cl:16][C:17](OC(Cl)(Cl)Cl)=[O:18].C1C=CC=CC=1.C(N(CC)CC)C>O>[Cl:16][C:17]([O:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:18]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(OC(=O)Cl)ccc21
Temperature: 25 °C

Procedure:
4.1 g (20 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol, 1.2 ml of trichloromethyl chloroformate and 40 ml of benzene are introduced into a round-bottomed flask. 3 ml (21 mmol) of triethylamine are added dropwise and the mixture is stirred at room temperature for twelve hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (40:60). After evaporation of the solvents, 4 g (75%) of the expected chloroformate are collected in the form of a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH:33]1([CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCCC1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCC2)c1
Yield: 57 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound (84 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:9][N:8]([C:10]([O:12]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:28]([CH3:30])[CH3:29])(C)C.C1(C(Cl)=O)CC1>Cl.ClCCl.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:7][N:8]([C:10]([CH:28]2[CH2:30][CH2:29]2)=[O:12])[CH2:9]1)[CH3:2]
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC1CN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 115.2 %

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl 3-[2-(ethyloxy)-2-oxoethyl]-1-azetidinecarboxylate (10.55 g, 43.3 mmol) in 4M HCl in dioxane (50 mL, 200 mmol) was stirred at room temperature for 1 h. Analysis by LCMS showed that the reaction was complete; conversion was observed to the des-BOC intermediate [M+H]+=144.0 (by ELS, no UV214 detection) and an unknown [M+H]+=179.9. The reaction was concentrated in vacuo. A solution of this intermediate (as the HCl salt) in dichloromethane (50 mL) was treated with N,N-diisopropylethylamine (15.14 mL, 87 mmol) and stirred for 2 min at room temperature. The pale yellow solution was treated with cyclopropanecarbonyl chloride (4.33 mL, 47.7 mmol) by syringe at room temperature and then stirred for 1 h. The reaction was diluted with water (200 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the title compound as an orange liquid (10.54 g, 65% pure, 75% yield). This product could also be prepared by using 10% TFA in dichloromethane. 1H NMR in DMSO-d6 showed ˜2:1 desired product:by-product. MS(ES)+ m/e 211.9 [M+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[C:8]([CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)CCC.[C:29]([O-:32])(=[O:31])[CH3:30].[C:33]([O-:36])(=[O:35])[CH3:34].[C:37]([O-:40])(=[O:39])[CH3:38].C([O-])(=O)C.[Pb+4:45]>C(Cl)(Cl)Cl>[C:29]([O:32][Pb:45]([O:39][C:37](=[O:40])[CH3:38])([O:35][C:33](=[O:36])[CH3:34])[C:6]1[CH:7]=[C:8]([CH:15]2[O:16][CH2:17][CH2:18][CH2:19][O:20]2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)(=[O:31])[CH3:30]
Reactant: [Pb+4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2OCCCO2)c2occc2c1
Reactant: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(=O)O[Pb](OC(C)=O)(OC(C)=O)c1cc(C2OCCCO2)c2occc2c1
Yield: 82.2 %

Procedure:
A stirred solution of tributyl-(7-[1,3]dioxan-2-yl-benzofuran-5-yl)stannane (9.6 g), lead tetraacetate (9.8 g) and mercuric acetate (350 mg) in chloroform (200 ml) was heated at 45° for 20 h. The mixture was cooled and filtered through Hyflo. The filtrate was evaporated to dryness. The residual gum was triturated under hexane (200 ml) for 2 h to give the title compound as an off-white solid (9.4 g), m.p. 92-94°.
Reaction SMILES: ClN1CCCCCC1=O.Cl[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15].[C:17](OC)(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1C=CC=CC=1>[CH3:15][C:14]1[C:17]([OH:23])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=1[OH:16]
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(=O)CCCl
Agent: O=C1CCCCCN1Cl
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c(C)c1O
Temperature: 30 °C
Yield: 85 %

Procedure:
In a 1-L three-necked flask fitted with a mechanical stirrer and a reflux condenser protected by a calcium chloride drying tube, are placed a solution of 60.5 g of N-chlorocaprolactam in 400 ml of benzene and 75.5 g of methyl 3-methyl-dihydroresorcylate, prepared from 5-chloropentan-3-one (R. B. Woodward et al., J.Am.Chem.Soc. 74, 4223 (1952)) and dimethyl malonate; m.p. 126.5° - 127.9° C. The reaction mixture is stirred at reflux temperature for 8 hours, then cooled to 30° C, transferred to a separatory funnel and washed successively with water, 0.2 molar sodium carbonate solution and again with water. The organic layer is then cooled to 5° C and extracted with cold 0.4N sodium hydroxide solution. The aqueous solution is acidified with a slight excess of 15% hydrochloric acid. The temperature is maintained at 0° C throughout the acidification. The solid product is filtered off, washed thoroughly with water and dried, yielding 63.5 g (85%) of methyl 3-methyl-resorcylate (identified by NMR, IR and mass spectral analysis). M.p. 130.5° - 131.6° C).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:30](=O)[CH2:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(OCC)(=O)C>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (56.0 mg, 0.137 mmol) in 1,2-dichloroethane was treated sequentially with propionaldehyde (0.01 mL, 0.1 mmol) in 1,2-dichloroethane and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperatures under nitrogen for 2 hours, treated with additional propionaldehyde (0.1 mL, 1 mmol) to aid in solubility, stirred at ambient temperatures for 1.5 hours, treated with sodium triacetoxyborohydride (59.8 mg, 0.283 mmol), stirred for 1.25 hours at ambient temperatures, diluted with ethyl acetate and poured into excess 1.0 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo at 81° C. for 20 minutes to yield 3-(1-naphthylsulfonyl)-5-(1-propylpiperidin-4-yloxy)-1H-indazole as a light orange solid, 50.4 mg (81.8% yield). The solid was dissolved in chloroform and methanol, treated with ethereal HCl and concentrated in vacuo at 82° C. for 15 hours to give the title product as a light orange semi-solid, 40.2 mg, Mass spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=3.78 Hz), 9.97-10.10 (m*, 1H), 8.70-8.76 (m, 1H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.02-8.04 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.27-7.37 (s* and s*, 1H), 7.08-7.20 (dd* and m*, 1H, J=9.03 Hz and 2.08 Hz), 4.59-4.80 (m*, 1H), 3.50-3.53 (m, 1H), 3.31-3.34 (m, 1H), 2.97-3.19 (m, 4H), 2.08-2.15 (m, 2H), 1.96-2.00 (m, 1H), 1.80-1.90 (m, 1H), 1.63-1.72 (m, 2H), 0.86-0.91 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([C:23]([O:25]CC)=[O:24])[C:12]2=[O:28])=[CH:2]1.[OH-].[K+].Cl>C(O)C.O1CCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([C:23]([OH:25])=[O:24])[C:12]2=[O:28])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of the compound (0.050 g, 0.13 mmol) of Example 1 in ethanol (1.0 mL), 50% potassium hydroxide solution (0.5 mL, 0.13 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol. The crude material was dissolved in water (0.5 mL) and tetrahydrofuran (0.5 mL), then 2M hydrochloric acid (0.023 mL, 0.046 mmol) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration, washed with water and diethyl ether then dried to afford the titled compound (0.012 g, y. 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])C(Cl)=O)=[CH:4][CH:3]=1.[N-:14]=[N+]=[N-].[Na+].C[C:19](C)=[O:20]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]=[C:19]=[O:20])([CH3:12])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)Cl)c1ccc(Cl)cc1
Reactant: CC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC(C)(N=C=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
The product of Example 76A (4.00 g, 19.4 mmol) in acetone (9 mL) at 0° C. was treated with a solution of sodium azide (1.27 g) in water (9 mL) dropwise over 15 minutes. After stirring for 30 minutes at 0° C., the mixture was extracted with toluene (20 mL). The organic extract was dried with MgSO4, filtered, and the filtrate heated at reflux for 1 hour. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to provide the title compound as a pale yellow oil (3.45 g, 96%).