Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:7].[OH-].[Na+].Cl.CO>O>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:6]([NH:5][CH2:4][C:3]([OH:18])=[O:2])=[O:7]
Reactant: COC(=O)CNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc2ccccc2c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
[(Naphthalene-2-carbonyl)amino]acetic acid methyl ester (10.03 g, 41 mmol, 1.0 eq., see step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 120 mL, 123 mmol, 3.0 eq.). The mixture was heated to 55° C. using an oil bath for 2 hours. The mixture was cooled to 5° C. using an ice/water bath. Concentrated hydrochloric acid (50 mL) was added very slowly to the cooled solution, ensuring that the temperature did not rise above 10° C. A dense yellow precipitate was formed. The mixture was stirred for 10 minutes and was then filtered. The yellow solid was air lo dried for 15 minutes and then dried in vacuo at 40° C. for 16 hours (8.73 g, 93%). Methanol (50 mL, 10 vols) and water (100 ml, 20 vols) were added to a portion of the sub-title compound (5.0 g, 22 mmol). The mixture was heated to 70° C. using an oil bath whilst being stirred. The solution was held at this temperature for 10 minutes, and then was allowed to cool further to 5° C. using an ice/water bath. Crystallisation began at approximately 30° C. The precipitate was collected by filtration, air dried for 15 minutes, then dried in vacuo at 40° C. for 2 hours (3.2 g, 64%). The isolated sub-title compound (3.2 g, 0.014 mol, 64%) was added to water (100 mL, 20 vols) and methanol (50 mL, 10 vols). The mixture was heated to 70° C. to dissolve the solid. The solution was allowed to cool to room temperature, crystallisation occurred on cooling. The mixture was cooled further to 2° C., and then was filtered using a sinter funnel. The solid was air dried for 10 minutes, then dried in vacuo at 40° C. for 16 hours (2.21 g, 44%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11]>CS(C)=O>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CC#N
Reaction time: 1 h

Procedure:
To 5.39 g of NaCN (110 mol), dissolved in 72 ml of DMSO, was added via dropping funnel a solution of 19.57 g of the above prepared 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole in 144 ml of DMSO (slightly exothermic). The reaction mixture was then kept for 1 h at 35° C. and 40° C. for 1 night. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) delivered 8.81 g of the title compound as light yellow crystals of mp. 85-86°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[CH2:23]([Mg]Br)[CH3:24]>>[Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]([OH:18])[CH2:23][CH3:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1c(C=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reactant: CC[Mg]Br
Product: CCC(O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
As described in General Procedure P, 8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-carbaldehyde, (Compound 135, 0.98 g, 3.05 mmol) was treated with ethylmagnesium bromide (3 M in ether, 1.6 mL, 4.9 mmol) to give rise to the title compound as a yellow foam.
Reaction SMILES: [C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:13]=2)=[N:8]1)([O:3]CC)=[O:2].C(O)(=[O:32])C>C(O)C.[OH-].[Na+].O>[C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:32])[CH:13]=2)=[N:8]1)([OH:3])=[O:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cn1nnc(-c2cccc(OCc3ccc4ccccc4n3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1nnc(-c2cccc(OC(=O)c3ccc4ccccc4n3)c2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1.3 g of 2-carbethoxymethyl-5-[3-(2-quinolylmethyloxy)phenyl]tetrazole in 5 ml ethanol and 40 ml of 1N NaOH was stirred at 70° C. for 4 hours. It was cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 1.0 g product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=c1ccc(C2=CCC3(CC2)OCCO3)c[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1ccc(C2CCC3(CC2)OCCO3)c[nH]1
Reaction time: 2 h

Procedure:
5-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-1H-pyridin-2-one from Step A of Example 37 (5.2 g, 22.1 mmol) in ethyl acetate (30 mL) was treated with 5% Pd/C (Aldrich, 2.6 g) at room temperature. The reaction mixture was then charged with a hydrogen balloon and stirred for 2 hours. The catalyst was removed by filtering the reaction through a pad of Celite. The filtrate was concentrated to give the crude product, which was then purified with a CombiFlash® system using silica gel column and 40% ethyl acetate in hexanes as eluent to give the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[OH:18].CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:16]1[C:17]2[C:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:18][C:9]=3[CH:10]=[CH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc2ccccc2c1-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)ccc1oc3ccccc3c12
Temperature: 150 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
Into a 1 L three-neck flask were placed 15 g (63 mmol) of 1-(2-fluorophenyl)-2-naphthol, 300 mL of N-methyl-2-pyrrolidone (NMP), and 18 g (130 mmol) of potassium carbonate. The mixture in this flask was stirred at 150° C. for 6 hours under a nitrogen stream. After that, this mixture was cooled down to room temperature and added to about 500 mL of water. The aqueous layer of this mixture was subjected to extraction with ethyl acetate, and the obtained solution of the extract and the organic layer were combined and washed with water and saturated brine. The organic layer was dried with magnesium sulfate, and after that, this mixture was gravity-filtered. The obtained filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography (developing solvent: hexane) to give an oily substance. The obtained oily substance was dried under reduced pressure, so that 11.8 g of a colorless transparent oily substance of the object of the synthesis was obtained in 86% yield. The reaction scheme of Step 2 is illustrated in (E1-2).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Sc2ccccn2)cc1C#N

Procedure:
10 g of 2-mercaptopyridine, 14.2 g of 4-nitrophthalonitrile, and 22.6 g of potassium carbonate were suspended in 250 ml of acetone and heated at reflux temperature for 4 hours. The solution was filtered through a pad of celite and a course glass filter to remove residual solids. The solution was concentrated to a crude residue and purified by column chromatography on silica gel eluting the product with a gradient of 0-10% ethyl acetate in dichloromethane. 6.4 g of product was recovered; 1H NMR (200Mz, CDCl3) δ=8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[OH:25][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:28][CH2:27][CH:26]([OH:25])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCC(O)c1ccccc1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCC(O)c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-hydroxy-2-phenyl-ethylamine and DIEA to give 4-ethoxy-6-[2-(2-hydroxy-2-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 445 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 1g, by reacting 0.28 g (0.5 mmol) of methyl 4-[5-(4-tert-butylphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthylselanylethynyl]benzoate with 0.28 g (6.6 mmol) of lithium hydroxide monohydrate, a cream-colored powder is obtained (0.08 g; yield=30%; m.p. =231° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[S:25][C:15]=3[N:16]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:3]2[O:18][CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[IH:19].[Na+].[I-]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:19])[C:3]3[O:18][CH2:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: I
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]-pyrimidine (80 mg, 0.28 mmol, 1 eq) in a 57% HI solution in water (2 ml) at rt. was added NaI (206 mg, 1.41 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine that was not further purified.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7](O)[CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>C1(C)C=CC=CC=1.CO.[Pd]>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH2:7][CH2:6][C:5]1=[O:56])[CH2:2][CH3:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Yield: 40.7 %

Procedure:
To a solution of 17-Allyl-1,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg) in toluene (20 ml) was added p-toluenesulphonic acid (5 mg) and the resulting solution was warmed for 90 minutes on a steam bath. Evaporation of volatiles in vacuo and chromatography of the residue on silica eluting with ethyl acetate gave an oil which was dissolved in methanol (5 ml). To this was then added 10% palladium-on-carbon (20 mg) and the mixture was stirred in an atmosphere of hydrogen for 1 hour at room temperature. The reaction mixture was then filtered through celite, concentrated in vacuo and purified by chromatography on silica eluting with ethyl acetate to give the title compound as an oil (40 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30]O)[CH2:27][O:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:21]=[CH:20][C:19]([O:22][CH2:30][C@H:28]5[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]5)=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1c(F)c(Cl)ccc21
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(F)c(Cl)ccc4c2C3=O)O1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
3-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-3, 20.0 mg, 0.061 mmol) was dissolved in THF (0.25 mL), added with ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (9.8 μL, 0.079 mmol), triphenylphosphine (20.7 mg, 0.079 mmol) and diethyl azodicarboxylic acid (35.9 μl, 0.079 mmol), and then stirred at 40° C. for 5 hr. The reaction solution was concentrated under reduced pressure, and the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the intermediate, 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one. This compound was dissolved in THF (0.10 mL) and MeOH (0.08 ml), added with sulfuric acid (0.5 M, 0.045 ml), and then stirred at 60° C. for 1 hr. The reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was washed with methylene chloride/hexane solvent and filtered to obtain the title compound (4.3 mg, 18%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OCC1CC1
Temperature: 70 °C
Yield: 21.3 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl) isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.745 mmol) and isobutylbromide (102 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 21%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC1NCCc2ccccc21
Reactant: Oc1nc(Cl)nc2c1CCCC2
Product: CC1c2ccccc2CCN1c1nc(O)c2c(n1)CCCC2
Yield: 34.5 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 2-chloro-4-hydroxy-5,6,7,8-tetrahydroquinazoline (2.0 g, 10.8 mmol) prepared in the above Step 1 and 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.3 g, 22.4 mmol) were used as starting materials, 1.1 g of the titled compound was prepared. (Yield: 34.5%)
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:30])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:48])[C@@H:15]2[CH2:31][CH2:32][C@H:33]2[O:38][C:37](=[O:39])[CH2:36][C@H:35]([O:40][Si](C(C)(C)C)(C)C)[CH2:34]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:30])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:48])[C@@H:15]2[CH2:31][CH2:32][C@H:33]2[O:38][C:37](=[O:39])[CH2:36][C@H:35]([OH:40])[CH2:34]2)=[CH:10]1
Reactant: CC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 60.2 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 800 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-phenoxypropionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example127, above] and 24.7 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 324 mg of the title compound as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[OH:16]/[N:17]=[C:18](\Cl)/[CH3:19].C(=O)([O-])O.[K+]>COCCOC>[CH3:19][C:18]1[C:4]([B:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7]([CH3:13])([CH3:12])[O:6]2)=[C:3]([Si:2]([CH3:14])([CH3:15])[CH3:1])[O:16][N:17]=1
Reactant: CC1(C)OB(C#C[Si](C)(C)C)OC1(C)C
Reactant: C/C(Cl)=N/O
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Product: Cc1noc([Si](C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of trimethyl[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl]silane (240 g, 1.07 mol) in 1,2-dimethoxyethane (8000 mL) was added (1Z)—N-hydroxyethanimidoyl chloride (120 g, 1.28 mol) and potassium hydrogen carbonate (214.4 g, 2.141 mol). The reaction mixture was heated to 50° C. After 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/hexanes, linear gradient) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trimethylsilyl)isoxazole. MS ESI calc'd. for C13H24BNO3Si [M]+ 281. found 281. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 1.31 (s, 12H), 0.37 (s, 9H).
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:11][C:10]=2[CH:20]=1)#[N:2].[NH:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1)[NH2:29]>CN1CCCC1=O>[C:30]1([N:28]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[O:13][C:12]([CH2:14][N:15]5[CH2:16][CH2:17][CH2:18][CH2:19]5)=[N:11][C:10]=4[CH:20]=3)=[N:29]2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: NNc1nccc2ccccc12
Reactant: N#C/N=C(/Nc1ccc2oc(CN3CCCC3)nc2c1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccc3oc(CN4CCCC4)nc3c2)nn1-c1nccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of (Z)-phenyl N′-cyano-N-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)carbamimidate (36 mg, 0.1 mmol) and 1-hydrazinoisoquinoline in N-methyl-2-pyrrolidone (0.5 mL) was shaken at 100° C. for 3 hours. After cooling to ambient temperature, the volatiles were evaporated under reduced pressure. The residue was purified by HPLC eluting with acetonitrile-water to provide 1-(isoquinolin-1-yl)-N3-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)-1H-1,2,4-triazole-3,5-diamine, compound #1; 1H NMR (CD3OD, 300 MHz) 8.98 (d, J=8.4 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.84-7.58 (m, 4H), 7.26 (dd, J=2.4, 8.7 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 5.05 (s, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.30 (m, 3H), 2.11 (m, 4H) ppm; MS (ES) 427.16 (M+H).