Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P([CH2:17][S:18]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=[O:20])=[O:19])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCCC1.[H-].[Na+].[N:43]1[CH:44]=[C:45]2[N:54]3[C:49](=[CH:50][CH:51]=[CH:52][C:53]=13)[S:48][C:47]([CH:55]=O)=[CH:46]2>C1(C)C=CC=CC=1.CN(C)C=O.O>[C:32]([O:31][C:29]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][NH:21][S:18](/[CH:17]=[CH:55]/[C:47]2[S:48][C:49]3[N:54]4[C:45](=[CH:44][N:43]=[C:53]4[CH:52]=[CH:51][CH:50]=3)[CH:46]=2)(=[O:19])=[O:20])[CH2:28][CH2:27]1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: O=CC1=Cc2cnc3cccc(n23)S1
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)CP(=O)(Oc2ccccc2)Oc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 2.16 g (4.11 mM) of tert-butyl 4-(diphenoxyphosphorylmethanesulfonylaminomethyl)-piperidine-1-carboxylate in toluene (20 ml)-tetrahydro-furan (20 ml) was added 0.33 g (8.23 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature and the mixture was stirred at the prevailing temperature for 1 hour. This reaction mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (10 ml)-toluene (50 ml) at room temperature and the mixture was stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 9/1) to provide crude (E)-N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-(5-thia-1,8b-diazaacenaphthylen-4-yl)vinylsulfonamide. To this crude product was added 1 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added ethanol, followed by stirring, and the resulting precipitate was recovered and washed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:24]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:7][C:8]([N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[NH:12]C(OC(C)(C)C)=O)=[N:9][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CCCCCC>[Cl:4][C:5]1[C:6]([CH:24]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=[O:34])=[O:35])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:7][C:8]([N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[NH2:12])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NN(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)(=O)N(N)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.9 %

Procedure:
To a methylene chloride (5 ml) solution of t-butyl N′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N′-methylsulfonylhydrazine carboxylate (167 mg, 0.268 mmol) was added trifluoroacetic acid (2.5 ml). The resulting mixture was stirred at room temperature for 21 hours, followed by concentration under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride. The organic layer obtained by separation was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to afford the title compound (91 mg, 0.174 mmol, 65%) as a white solid. The resulting solid was washed with ether and collected by filtration to give the title compound (60 mg) as a white powder.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O

Procedure:
(S)-benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (70 g) was dissolved in ethyl acetate (350 ml) and placed in a 500 ml glass pressure vessel. To this dry 5% Pd/C (1.4 g) was added under vacuum and pressurized with hydrogen gas at 2.7 bar overpressure. The mixture was stirred magnetically while remaining connected to the hydrogen source. The catalyst was removed by filtration and washed with a small volume of ethyl acetate (25 ml). The clear filtrate was mixed with water and dilute ammonia. The aqueous phase was isolated and the organic phase extracted with water. The combined aqueous phase was washed with MTBE and degassed under vacuum to remove traces of organic solvent. The mixture was placed in an ice-bath. The cooled aqueous solution was acidified using dilute phosphoric acid to obtain thick suspension. This was filtered, washed with cold water and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:33]1[N:34]=[C:35]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[S:36][CH:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH2:26][CH2:25][C:24]([C:33]2[N:34]=[C:35]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[S:36][CH:37]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(O)CCc3ccccc3)cs2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)CCc3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (15% strength solution in dichloromethane, 8.3 g) was added dropwise to a solution of tert-butyl 4-[4-(1-hydroxy-3-phenylpropyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (790 mg) in dichloromethane (7.9 ml). The reaction mixture was stirred at room temperature overnight. 5 g of silica gel were then added, and the solvent was removed under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-[4-(3-phenylpropanoyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (545 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:36])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.N1C=CN=C1.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:36])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([O:17][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (260 mg, 0.519 mmol) in dry DMF (10 ml), IMIDAZOLE (0.137 ml, 2.078 mmol) and TBDMSCl (0.270 ml, 1.558 mmol) were added and the solution stirred overnight. DMF was removed and residue was dissolved in DCM (50 mL) was washed with 0.5 N HCl aqueous solution. Organic phase was dried and solvent was removed. Crude was purified by silica gel flash chromatography (SNAP 25 g DCM:EtOH from 100:0 to 95:5) affording 3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (210 mg, 0.342 mmol, 65.8% yield) as a yellow pale solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:23]3[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]3)=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CCN1

Procedure:
The title compound (D16) was prepared from 1-(4-cyanophenyl)-piperidine4-carboxylic acid (D3) and (R)-2-methylpiperazine using the procedure of Description D15.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][CH2:28]2)[C:13]1=[O:47])=[O:4].[ClH:48].COC(C1C=CC=CC=1CN1C(=O)C2C(=CC=CC=2)N(CCCCN2CCC(OC(C3C=CC=CC=3)C3C=CC=CC=3)CC2)C1=O)=O.[OH-].[Na+].Cl>CO.O1CCCC1>[ClH:48].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([O:33][CH:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:31][CH2:32]2)[C:13]1=[O:47])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 91 %

Procedure:
A mixture of 3-[(2-methoxycarbonylphenyl)methyl]-2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (0.40 g, 0.63 mmol) which is a free salt of the compound obtained in Example 62, a 2N aqueous solution of sodium hydroxide (1.0 ml), tetrahydrofuran (2.0 ml) and methanol (4.0 ml) was stirred at room temperature for 9 hours. The reaction mixture was made weakly acidic using 1N hydrochloric acid and extracted with chloroform. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was triturated with ethyl ether and filtered to give the title compound (0.39 g, 91%) as a colorless powder.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[CH3:7][O:8][CH:9]([O:18][CH3:19])[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CO>[CH3:7][O:8][CH:9]([O:18][CH3:19])[C:10]1[CH:17]=[CH:16][C:13]([C:14](=[N:2][OH:3])[NH2:15])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(OC)c1ccc(C#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(C(N)=NO)cc1
Reaction time: 0.33 h
Yield: 931.3 %

Procedure:
A suspension of hydroxylamine hydrochloride (31.62 g; 45.5 mmol) in MeOH (350 ml) was treated with sodium methoxide (24.58 g; 45.5 mmol) slowly, in small portions. After stirring for 20 minutes, a solution of 4-(dimethoxymethyl)benzonitrile (67 g; 37.9 mmol) in MeOH (100 ml) was added and the mixture heated to reflux. After 12 hr, it was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 4-(dimethoxymethyl)-N′-hydroxybenzenecarboximidamide (74.2 g) which was used in the next step without further purification. MS: m/z 211 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2ccc(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccc(F)cc21
Yield: 76.1 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF88) (2.54 g, 15.2 mmol), (R)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.07 g, 15.2 mmol) and Cs2CO3 (12.38 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF01) (4.09 g, 76%). 1H NMR (CDCl3) δ 6.93-6.87 (m, 1H), 6.92-6.88 (m, 1H), 6.68-6.63 (m, 1H), 4.56 (m, 2H), 4.01 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 2.11 (m, 1H), 0.92 (s, 12H), 0.06 (d, J=0.8 Hz, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.9 Hz), 141.6 (d, J=2.7 Hz), 130.1 (d, J=10.7 Hz), 117.6 (d, J=9.3 Hz), 109.6 (d, J=23.1 Hz), 103.6 (d, J=28.8 Hz), 67.8, 65.9, 44.2, 34.5, 26.0, 18.4, 14.9, −5.4, −5.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](=[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)/[CH2:6][CH2:7][CH:8]=O)[CH3:2].[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([NH2:40])[CH3:39])[CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])/[C:5](=[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)/[CH2:6][CH2:7][CH2:8][NH:40][CH:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:33]=1)[CH3:39])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC=O
Reactant: CC(N)c1cccc(N2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCNC(C)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a methylene chloride (10 mL) solution of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-benzylidene]-5-oxovaleric acid ethyl ester (173 mg) obtained in Example 398, 1-(3-morpholin-4-yl-phenyl)ethyl amine (157 mg) and acetic acid (0.1 mL) and sodium triacetoxy borohydride (214 mg) were added one by one. The reaction solution was agitated at room temperature for 1 hour, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent: heptane-ethyl acetate=1:2), and 205 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[C:19]1([N+]#N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)C>[C:1]1([C:7]([CH2:9][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
0.97 mmol of (1-phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The resulting mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of a common salt, successively. The organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.68 mmol of benzyl phenyl ketone.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[OH:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[P:21](Cl)(Cl)([O:23][CH3:24])=[O:22]>CCOCC>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:19]2[O:20][P:21]([O:23][CH3:24])(=[O:22])[O:8][C:9]=2[CH:10]=1)=[O:13])[CH3:16]
Reactant: COP(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)OP(=O)(OC)O2
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
Triethylamine (2.211 g, 21.86 mM) was added to a solution of 1.989 g (10.93 mM) of ethyl 3,4-dihydroxybenzoate in 30 ml of ether. The mixture was cooled to -30° C. to -20° C. and a solution of 1.627 g (10.93 mM) of methyl dichlorophosphate in 10 ml of ether was added thereto dropwise with stirring over 10 minutes. The reaction mixture was stirred at the same temperature for 5 minutes, the bath was then removed and the temperature was allowed to rise to 20° C. Filtration and washing were carried out by the procedure of Reference Example 1, and the filtrate and washings were concentrated at room temperature (20°~25° C.) under reduced pressure. There was obtained 2.387 g (84.6% yield) of 5-ethoxycarbonyl-2-methoxy-2-oxo-1,3,2-benzo-dioxaphosphole as a viscous oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(OCC)(=O)C>[CH3:21][S:22]([O:13][CH2:12][C:11]#[C:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC#CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol (701.4 mg) was dissolved in ethyl acetate (15 mL), and the solution was cooled to 0° C. Triethylamine (1.1 mL) and methanesulfonyl chloride (0.3 mL) were added, and the mixture was stirred at 0° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→50:50) to give the title compound (469.7 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][OH:14]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]=[O:14]
Reactant: CN(C)CCNc1c(F)cccc1CO
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CN(C)CCNc1c(F)cccc1C=O

Procedure:
(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)methanol (536 mg, 2.525 mmol) and MnO2 (878.1 mg, 174.7 μL, 10.10 mmol) were heated to reflux in toluene (13 mL) overnight. The suspension was filtered through Celite with CH2Cl2 and concentrated on a rotary evaporator. The crude product was purified on 12 g Redisep ISCO column eluting with 4-55% EtOAc/Hexanes over 30 CV. 2-(2-(Dimethylamino)ethylamino)-3-fluorobenzaldehyde was identified by 1H-NMR and carried on to next reaction.
Reaction SMILES: Cl[CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[H][H]>C1COCC1.[Pd]>[F:6][C:3]([F:4])([F:5])[CH2:2][C:7]1([C:16]([F:17])([F:19])[F:18])[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11]1
Reactant: [H][H]
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1

Procedure:
306.5 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 2a were dissolved in 500 ml of THF, and 101 g of triethylamine and 30 g of palladium on carbon (5% by weight) were added. Hydrogenation was then carried out with 100 bar of hydrogen at 110° C. for 48 h. The mixture was then filtered, the solvent stripped off in vacuo and the residue subjected to fractional distillation in vacuo. The yield was 126 g (46% of theory) and the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorption: 19F-NMR: -59.0 and -84.6 ppm; 1H-NMR: 3.02 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nnn(-c2cc(OS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of 0 5 g (0.0017 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.26 g (0.0026 mole) of triethylamine in 30 mL of methylene chloride was cooled to 0° C. Methanesulfonyl chloride (0.22 g, 0.0019 mole) was added slowly to the reaction mixture. After complete addition, the mixture was allowed to warm to room temperature and was stirred for several days. The mixture was poured into ice water and extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel to yield 0.33 g of 1-(2,4-dichloro-5-methylsulfonyloxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one was a solid, mp 64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([S:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)=[C:2]([NH:1][C:38]3[C:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=4[N:34]=[CH:35][N:36]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4ncccc34)c2)cc1
Yield: 55 %

Procedure:
The product from Example 10E and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 10E for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (49 mg, 55%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.38 (d, J=8.46 Hz, 2H), 7.20-7.29 (m, 1H), 7.12-7.18 (m, 1H), 7.06-7.12 (m, 2H), 6.90-6.99 (m, 3H), 6.62-6.69 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI−) m/z 481.2 (M−H)−.