Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:36])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Yield: 55.1 %

Procedure:
A solution of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(9-pentylthiononyl)thiochroman (178 mg, 0.355 mmol) and sodium periodate (83 mg, 0.390 mmol) in methanol (20 ml) and water (5 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was quenched with water and then diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was purified with preparative chromatography on silica gel plate (hexane:ethyl acetate=1:1) to obtain 101 mg (yield: 55%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:19][CH3:20])=O.O>C1COCC1>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][NH:19][CH3:20]
Reactant: CNC(=O)c1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
LAH (50 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 1-methyl-2-(methylaminocarbonyl)indole (2.33 g, 12.4 mmol) in anhydrous THF (10 mL) with cooling, and the resulting solution was stirred at RT under argon overnight. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3), concentrated, and purified by silica gel flash chromatography to afford the title compound (430 mg, 20% yield) as a yellow solid. MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[C:12]1=2)=O.B.Cl>O1CCCC1.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[C:12]1=2
Reactant: O=C(Cc1ccccc1Cl)N1CCCc2ncc3ccccc3c21
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1ccccc1CCN1CCCc2ncc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 82.6 %

Procedure:
A stirred colorless solution of 1-[(2-chlorophenyl)-acetyl]-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (5.7 g) in tetrahydrofuran (500 ml) was treated rapidly with 1M borane solution in tetrahydrofuran (68 ml, 0.068 mole of BH3, 4-fold excess) under nitrogen. A yellow color appeared within one minute. After stirring overnight at room temperature with exclusion of moisture, the reaction was quenched by dropwise addition of 10% sodium hydroxide solution (100 ml, gas evolution). The mixture was concentrated to remove the tetrahydrofuran and the aqueous residue was extracted with dichloromethane (2×250 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a viscous gum (borane complex) which was dissolved in glacial acetic acid and treated portion-wise with concentrated hydrochloric acid (25 ml, gas evolution). The resultant solution was stirred for 3 hours at ambient temperature, decanted into ice water (500 ml), basified with 50% sodium hydroxide solution and extracted with dichloromethane (2×250 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to an oil (5.43 g). Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated a mixture. The material was purified by HPLC (silica gel, sample applied in 25 ml of dichloromethane, eluted with ethyl acetate, 200 ml/min flow rate), and the appropriate fractions were combined and concentrated to an oil (2.90 g). A solution of the oil in methanol (10 ml) was treated with a slight excess of ethereal hydrogen chloride, followed by dilution with anhydrous ether almost to the cloud point. The solution was seeded with a material obtained from a small scale recrystallization, whereupon crystals precipitated rapidly. After standing 20 minutes (exclusion of light), the precipitate was isolated by vacuum filtration, washed thoroughly with ether and dried in vacuo at 40° C. to give 2.51 g of crystals, m.p. 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1ccccc1-c1ccccc1
Reaction time: 18 h

Procedure:
To a suspension of 85 mg (3.55 mmol) of sodium hydride in 4 mL of benzene was added 326 mg (3.55 mmol) of methyl glycolate and a solution of 200 mg (0.507 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine in 8 ml of benzene. The mixture was heated at 60° C. and monitored by TLC (silica, methylene chloride) for conversion to product. After 70 hours, the reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate. The aqueous phase was extracted twice with 7 mL portions of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated to provide 380 mg of yellow oil containing [[2-(methylthio)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as the major component. The crude oil was dissolved in 30 mL of ethanol, treated with 2.28 g of Raney Ni, then the mixture heated to reflux. After 18 hours, the solids were removed by filtration through a filter aid and the reaction concentrated to an oil. The oil was purified by flash chromatography ( 46 g silica, hexanes-ethyl acetate gradient 100:0 to 2:1) to provide 203 mg (quantitative yield for 2 steps) of [[6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as an oil. nmr (300 MHz, CDCl3) δ1.14 (t, J=7.5 Hz, 3H), 2.32 (q, J=7.5 Hz, 2H), 3.79 (s, 3H), 5.08 (s, 2H), 5.38 (s, 2H), 6.37 (s, 1H), 6.5 (d, J=7.1 Hz, 1H), 7.1-7.6 (m, 8H), 8.37 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:12]([O:14]C)=[CH:13][C:8]=2[S:7][CH:6]=1.CC(O)=O.Br>[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:9]2[C:10]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(OC)cc(C(F)(F)F)c12
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
To a mixture of methyl(6-methoxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate obtained above (405 mg) and AcOH (1.5 mL) was added 48% hydrobromic acid (3 mL) at room temperature. The mixture was stirred at 130° C. for 40 min under microwave irradiation. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. A mixture of the residue, MeOH and conc. H2SO4 (0.071 mL) was refluxed for 1 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine twice, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (232 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24]CC3C=CC(OC)=CC=3)=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
A solution of 1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea (122 μmol, 58 mg) (Example 279) in DCM (2.5 mL) was treated with TFA (2.5 mL). The reaction mixture was stirred at room temperature for 4 hours, then the volatiles were removed under a stream of nitrogen. The oily residue was triturated with ether, the precipitate collected, washed with ether, then dissolved in MeOH and evaporated to gives the desired product (44 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.364 (m, 6H), 1.812 (pentet, J=7 Hz, 2H), 2.943 (br t, 2H), 4.154 (d, J=7 Hz, 2H), 4.131 (t, J=7 Hz, 2H), 5.349 (br. s, 2H), 5.894 (br. s, 1H), 6.607 (d, J=8 Hz, 1H), 6.752 (d, J=8 Hz, 1H), 7.456 (t, J=8 Hz, 1H), 7.824 (br. s, 1H), 8.351 (br. s, 1H), 10.945 (s, 1H). MS 356 (MH+).
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH:10]=3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH:10]=3
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=C(F)F
Yield: 80.7 %

Procedure:
A suspension of 950 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),7-tetraene in 20 ml of methanol and 2.0 ml of water is refluxed with 950 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra-1,3,5(10),7-tetraen-3-ol is obtained as colorless crystals with a melting point of 126-129° C., [α]D22 =+163.7° (c=0.505% in pyridine)
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:20]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:29][CH2:30]1)=[O:24])[CH3:21]
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and piperazine-1-carboxylic acid ethyl ester (0.556 g, 3.52 mmol) were used to afford 0.52 g of the required product. Percentage purity (LCMS): 90.2%, (M+1)=395.1+1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]2[N:28]([CH3:36])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][C:18]=1[CH:19]=O>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]2[N:28]([CH3:36])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][C:18]=1/[CH:19]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CNS(=O)(=O)c1ccc(C(C)=O)cc1
Product: CNS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4n3C)c(OC)cc2OC)cc1
Yield: 57 %

Procedure:
The title compound was prepared using in an analogous way as Ex-1 using 4-acetyl-N-methyl-benzenesulfonamide (Ex-29A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 57% yield, yellow solid, mp 129–131° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz), 1H), 7.47 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.14–7.16 (m, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.42 (br s, 1H) 4.03 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H), 2.69 (d, J=6 Hz, 3H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1646.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of 4-chloro-2-fluoroaniline (5.0 g, 34.3 mmol) in acetic acid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7 mmol) and stirred at RT for 2 h. The mixture was poured onto ice water, stirred for 2 h and the resulting solid collected via filtration and dried to afford N-(4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 7.91 (t, J=8.7 Hz, 1H), 7.45 (dd, J=10.8, 2.4 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 2.07 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27](O)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:30].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27]([N:41]1[CH2:40][CH2:39][N:38]([CH2:37][C:36]3[CH:44]=[C:45]([O:49][CH3:50])[C:46]([O:47][CH3:48])=[C:34]([O:33][CH3:32])[CH:35]=3)[CH2:43][CH2:42]1)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)C1=Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Yield: 69.1 %

Procedure:
Using 6,7-dibenzyloxy-1,2-dihydro-3-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.69 g), triethylamine (0.52 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.75 ml), as amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(6,7-dibenzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless crystals, m.p. 186°-190° C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][CH2:7][CH2:8]/[C:9](/[C:25]1O[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[N:28][N:29]=1)=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[N:1]3[CH2:6][CH2:7][CH2:8]/[C:9](=[CH:10]\[C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:13]([O:23][CH3:24])[CH:12]=4)/[C:25]3=[N:29][N:28]=2)=[CH:31][CH:32]=1
Reactant: COc1cc(/C=C(\CCCCl)c2nnc(-c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCn3c2nnc3-c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
Sodium azide (0.15 g) was added to a solution of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorophenyl)[1,3,4]oxadiazole (366 mg) in DMSO (10 mL) at room temperature, and the reaction solution was stirred at 70° C. for six hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Triphenylphosphine (0.33 g) was added to a mixed solution of the resulting residue in THF (10 mL) and water (0.5 mL) at room temperature, and the reaction solution was stirred at 60° C. for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. THF and toluene were added to the residue, and the solution was again concentrated under reduced pressure. A solution of the resulting residue in acetic acid (5 mL) was stirred at 150° C. for 1.5 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system), solidified with ethyl acetate and hexane and separated by filtration to obtain 188 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][OH:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>O1CCCC1>[O:14]([C:21]1[CH:22]=[C:23]([CH2:24][O:13][N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]([CH3:10])[CH3:11])[CH:26]=[CH:27][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(=NO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=NOCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3.86 g of 1B, 5.2 g of 3-phenoxybenzyl bromide and 30 ml of tetrahydrofuran were mixed and 0.9 g of sodium hydride was added. The mixture was heated to 35°. The mixture was cooled, stirred at room temperature for 21 hours, then filtered, and the solvent was stripped from the filtrate. The liquid residue was chromatographed (silica gel, 1/2 v/v methylene chloride/pentane) to give (1C), 1-(4-chlorophenyl)-2-methyl-1-propanone O-((3-phenoxyphenyl)methyl)oxime as a light yellow liquid, boiling point not determined.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([C:7]2[C:2]([NH:50][C:45]3[C:44]4[CH:43]=[N:42][N:41]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[C:49]=4[CH:48]=[CH:47][CH:46]=3)=[N:3][CH:4]=[C:5]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:6]=2)[N:16]=1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Reaction time: 0.33 h
Yield: 115.7 %

Procedure:
A mixture of 6-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (78.5 mg, 0.163 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (45.5 mg, 0.209 mmol) in THF (1.0 mL) was cooled in an ice/salt bath and treated dropwise with LiHMDS (0.627 mL of a 1.0 M solution in THF). The mixture was stirred for 20 min and then quenched with water (0.1 mL). The mixture was stirred for 3 min and then extracted into EtOAc from saturated aqueous NaHCO3. The EtOAc extracts were dried (MgSO4) and concentrated to give a dark yellow solid (128 mg). This was taken on to the next step without further purification.
Reaction SMILES: C(OC([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:40]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)=[CH:23][CH:24]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N>[CH3:39][O:38][C:34]1[N:33]=[C:32]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[O:26][CH2:27][C:28]2([CH2:29][O:30][CH2:31]2)[C:19]23[CH2:18][O:17][C:16]([NH2:8])=[N:40]2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1cccc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)CO3)n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
The mixture of di-tert-butyl[6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (160 mg, 0.289 mmol) and TsOH.H2O (275 mg, 1.45 mmol) in MeCN (3.2 mL) was stirred for 4 hours at 40° C. After dilution with CHCl3, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=99:1-95:5) and then the residue was washed with EtOAc to afford 6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl.[OH:32][CH:33]1[CH2:36][NH:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[CH2:11][CH2:12][C:13]1[N:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:35]4[CH2:36][CH:33]([OH:32])[CH2:34]4)=[O:30])[CH:23]=3)[NH:19][C:16]2=[N:17][CH:18]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)O)c4)cc3n2)cc(OC)c1
Reactant: OC1CNC1
Agent: Cl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)N5CC(O)C5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 73, Step 3 starting from 4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}pyridine-2-carboxylic acid and 3-hydroxyazetidine hydrochloride (from Oakwood). LCMS calculated for C25H26N5O4 (M+H)+: m/z=460.2. Found 460.2.