Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][CH:119]([CH3:121])[CH3:120].C(Cl)Cl>C(O)C>[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][C:119]([OH:20])([CH3:120])[CH3:121]
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: ClCCl
Solvent: CCO
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% aqueous β-cyclodextrin solution (0.01 M phosphate buffer, pH 7.0), a solution of 1% 1-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of β-cyclodextrin relative to 1 mol of 1α-hydroxyvitamin D3) and a solution of 20% Tween 80 in 1 ml of ethanol. After cultivation for a further 2 hours, methylene chloride was added to the flask, and the determination as described in Example 1 was carried out. The peak fraction having a retention time of 3.8 minutes was collected, concentrated to dryness at 40° C. or below under reduced pressure, and applied to HPLC on Zorbax ODS (made by Du Pont Co.) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak reaction having a retention time of 5.6 minutes was collected, and concentrated to dryness under pressure at 40° C. or below with a nitrogen gas replacement to give 645 μg (64.5% of conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. In case of the same procedure as described above but without β-cyclodextrin, the yield was 350 μg (35% of the conversion ratio from the material).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[OH:16][N:15]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=1)[CH3:11]
Reactant: NO
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=NO)cc1
Temperature: 40 °C
Yield: 96.1 %

Procedure:
A mixture of 4-acetylbenzoic acid methyl ester (1.0 g, 5.6 mmol), hydroxylamine hydrochloride (3.1 g, 45 mmol) and sodium acetate (3.7 g, 45 mmol) in methanol (50 mL) was heated at 40° C. for 2 hours. The mixture was evaporated to dryness and the residue partitioned between EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous MgSO4 and evaporated to dryness to afford the title compound as a white solid (1.04 g, 96%). LC-MS: (FA) ES+ 194; 1H NMR (400 MHz, MeOD) δ 8.02-7.98 (m, 2H), 7.78-7.75 (m, 2H), 3.90 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C@@H:69]([NH2:72])[CH2:70][CH3:71])[CH2:65][CH:64]1[C:73](=[O:75])[NH2:74])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C.CCOC(C)=O>[CH2:53]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C@@H:69]([NH:72][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:70][CH3:71])[CH2:65][CH:64]1[C:73](=[O:75])[NH2:74])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CC[C@H](N)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (360 mg, 1.4 mmol) in DMF (4 mL) was added DIPEA (487 μL, 2.8 mmol). After 10 minutes, HATU (638 mg, 1.68 mmol) was added to the brown solution. After 10 minutes, a solution of 4-((S)-1-amino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester (0.45 g, 1.4 mmol) in DMF (4 mL) and DIPEA (244 μL, 1.4 mmol) was added resulting in a clear solution. After 18 hours, the reaction was diluted with EtOAc (200 mL), washed with NH4Cl (50 mL), water (50 mL), brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% MeOH in DCM to afford 2-carbamoyl-4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid benzyl ester as a light brown foam.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.[Cl:13][CH2:14]Cl.[C:16]([Cl:19])(Cl)=[O:17]>N1C=CC=CC=1>[C:5]([O:17][CH3:16])(=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([O:12][CH3:14])=[O:11])[CH:3]=1.[C:16]([Cl:19])(=[O:17])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([Cl:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: ClCCl
Reactant: O=C(O)c1cccc(C(=O)O)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C(=O)OC)c1
Product: O=C(Cl)c1cccc(C(=O)Cl)c1
Yield: 100 %
Yield: 100 %

Procedure:
Following the general procedure of Example 9, a slurry of 7.46 parts isophthalic acid in 80 parts dry dichloromethane was added to a mixture of 7.91 parts pyridine and 9.77 parts phosgene in 210 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of pyridine base/COOH acid group was 1.10. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1 there was obtained a 100% yield of dimethyl isophthalate corresponding to a 100% yield of isophthaloyl chloride formed initially in the reaction.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])=[CH:40][CH:41]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In a stream of nitrogen and at 0° C., 0.22 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-(4-methoxybenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 6 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 520 mg (yield: 94.6%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:13])([CH:11]=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C(OC(=O)C(NC=O)C(O)(C)C=C)C.S(Br)(Br)=O.[P:32]([O:39]CC)([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:9])/[C:10](/[CH3:13])=[CH:11]/[CH2:12][P:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:39])[CH3:2]
Reactant: C=CC1(C)OC=NC1C(=O)OCC
Reactant: CCOP(OCC)OCC
Agent: C=CC(C)(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC

Procedure:
The starting material is manufactured as follows: 5-Methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester, b.p. 65°-75° (13 Pa) is obtained by reaction of isocyanoacetic acid ethyl ester with methyl vinyl ketone in a manner analogous to that described in Example 30. By hydrolysis of the 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester in the form of a colourless liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1([CH3:14])[C:6](=[O:16])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc([N+](=O)[O-])c2O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=O
Yield: 93.5 %

Procedure:
A mixture of 37.3 g (0.193 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, 156.6 g (0.58 mole) of potassium persulfate, and 48.2 g (0.193 mole) of copper(II) sulfate pentahydrate in 500 mL of acetonitrile and 500 mL of water was prepared. This mixture was heated at reflux for one hour with vigorous stirring. The reaction mixture was cooled and then extracted three times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving 37.4 g of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one as a residue. The NMR and IR spectra of the same product from a previous run of this reaction were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:12])[CH2:10]Cl)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:17]([CH2:10][C:9](=[O:12])[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCc1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN(Cc1c(F)cccc1F)C(=O)c1ccc(Cl)cc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
To N1-(3-chlorophenyl)-2-chloroacetamide (61 mg) in DMF (1 mL) was added 2,6-difluorobenzylamine (38 mg) and triethylamine (0.1 mL) and 4-chlorobenzoyl chloride (58 mg) the reaction mixture was stirred at room temperature for 15 min and then purified by HPLC preparative to yield the title compound (55 mg). MS (m/e): 447.0 (M−H). Procedure E
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2([OH:19])[C:14]([O:16]CC)=[O:15])=[CH:6][CH:5]=1>CS(C)=O.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2([OH:19])[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(O)CCCc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C1(O)CCCc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
NaOH (10M, 1 mL) was added to a solution of 7-chloro-1-hydroxytetraline-1-carboxylic acid, ethyl ester (0.8 g; 3.1 mmol; from step (iii) above) in DMSO (20 mL), and the mixture was heated to 100° C. for 3 hours. The resultant mixture was diluted with crushed ice (40 g) and brine (40 mL), and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with 2M HCl and extracted with EtOAc (2×40 mL). The combined organic layer was dried (Na2SO4) and concentrated. Yield 0.22 mg (30%).
Reaction SMILES: Br[C:2](Br)([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[S:14].CO>O>[NH2:16][N:15]1[C:3](=[O:4])[C:2]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:11][N:12]=[C:13]1[SH:14]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(Br)(Br)C(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 0 °C

Procedure:
A mixture of 2,2-dibromo-3,3-dimethylbutyric acid, 55 parts, and thiocarbohydrazide, 22 parts, in 500 parts of (1:1) methanol and water was heated to reflux for five hours. Upon cooling the reaction mixture to 0° C., a solid formed and was collected. The solid, 4-amino-6-t-butyl-3-mercapto-1,2,4-triazin-5-one, was obtained in 78% of theory (29 parts).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](N(OC)C)=[O:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH3:25][Mg+].[Br-]>C1COCC1>[NH2:1][C:2]1[C:3]([C:19](=[O:20])[CH3:25])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: C[Mg+]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)N(C)OC)n2)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)-N-methoxy-N-methylpyrazine-2-carboxamide (864 mg, 2.411 mmol) was dissolved in THF (10 mL) and cooled to −20° C. under nitrogen. MeMgBr (2.411 mL of 3 M, 7.233 mmol) was added dropwise and the reaction was left to stir at this temperature for 15 minutes after which time the reaction was allowed to slowly warm to ambient temperature. A further MeMgBr (803.7 μL of 3 M, 2.411 mmol) was added and analysis showed after 10 minutes showed no SM remaining. The mixture was quenched with 10 mL 1M HCl, stirred for 5 mins and then extracted with EtOAc (3×), dried (MgSO4), filtered and the solvent removed in vacuo to give the product as an orange solid (510 mg, 68% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, 3H), 2.54 (s, 3H), 3.11 (q, 2H), 3.30-3.32 (m, 4H), 3.47-3.49 (m, 4H), 7.42 (br s, 2H) and 8.34 (s, 1H) ppm; MS (ES+) 314.0
Reaction SMILES: CCOCC.[S:6](=[O:10])(=[O:9])([OH:8])[O-:7].CC(C=CC=C(C)C=CC=C(C)CCCC(C)C)=CC[P+:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)C.CCCCCCC>[C:28]1([P:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1.[OH:9][S:6]([OH:10])(=[O:8])=[O:7]
Reactant: O=S(=O)([O-])O
Reactant: CC(C=CC=C(C)CCCC(C)C)=CC=CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=S(=O)(O)O
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
18.6 g (0.05 mole) of this ether of 20 carbon atoms are reacted, in accordance with German Pat. No. 1,068,709, with 0.05 mole of triphenylphosphine and 0.05 mole of H2SO4 in isopropanol/heptane to give the corresponding 3,7,11,15-tetramethyl-hexadeca-2,4,6,8,10-pentaen-1-yl-triphenylphosphonium bisulfate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[CH:75]=[CH:74][C:73]([N:76]2[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]2)=[CH:72][C:54]=1[C:55]([NH:57][C:58]1[N:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[C:66]([CH3:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O>[CH3:71][C:66]1[CH:65]=[C:64]([C:61]2[CH:60]=[N:59][C:58]([NH:57][C:55]([C:54]3[CH:72]=[C:73]([N:76]4[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:74]=[CH:75][C:53]=3[NH:52][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH:11]=3)=[O:56])=[N:63][CH:62]=2)[CH:69]=[CH:68][C:67]=1[CH3:70]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(C(=O)NCCOCCO)c3)nc2)cc1C
Yield: 8.8 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (227.1 mg, 0.90 mmol, 3.00 equiv) in N,N-dimethylformamide (6 mL), HATU (397.5 mg, 1.05 mmol, 3.50 equiv), N,N-diisopropylethylamine (192.8 mg, 1.49 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.30 mmol, 1.00 equiv) and the resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 100 mL of water and the resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 2×50 mL of brine and then dried over sodium sulfate. The solids were filtered out and the resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 16.8 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.34 (s, 1H), 11.24 (s, 1H), 8.71˜8.68 (m, 3H), 8.38 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.04˜7.99 (m, 2H), 7.66˜7.58 (m, 1H), 7.47˜7.38 (m, 1H), 7.28˜7.19 (m, 2H), 7.15 (d, J=6.3 Hz, 1H), 4.42 (s, 1H), 3.56˜3.44 (m, 9H), 3.31 (m, 4H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 637 [M+H]+.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:37])[CH:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:19]([CH3:21])[CH:20]=1)[C:11](O)=O)[CH3:7].C=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:37])[C:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:19]([CH3:21])[CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCNCC
Product: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Diethylamine (0.26 g, 2.67 mmol) was added a mixture of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 2.2 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) in methylene chloride (2 mL) at 0° C. The mixture was stirred for 16 h at room temperature and ethyl acetate was added. The organic layer was washed with water and 5% NaHCO3 and dried. Concentration under reduced pressure followed by flash chromatography (toluene/ethyl acetate, 3:1→1:2) gave 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.68 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
To a mixture of 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (768 mg, 2.38 mmol) and iodomethane (0.595 ml, 9.52 mmol) in DMSO (15 ml) at 0° C. was added sodium 2-methylpropan-2-olate (343 mg, 3.57 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 11:9) to afford 2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (191 mg, 0.566 mmol, 24% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3 H) 3.17-3.28 (m, 1 H) 3.55 (td, J=12.13, 3.03 Hz, 1 H) 3.68 (d, J=11.62 Hz, 1 H) 3.89-4.07 (m, 3 H) 4.75-5.04 (m, 2 H) 8.31 (s, 1 H). MS [M+H] found 337.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[S:7])[S:4][N:3]=1.CC1C=CC(S(O[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:7][C:5]1[S:4][N:3]=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Reactant: Cc1nsc(=S)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nsc(SCCC=C(F)F)n1
Yield: 32 %

Procedure:
To a solution of 3-methyl-1,2,4-thiadiazole-5(4H)-thione (1.2 g) in acetone (100 cm3) was added 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (2.4 g) and potassium carbonate (1.2 g) and the mixture was refluxed for 4 hours after which tlc indicated complete consumption of starting material. The reaction was poured into ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSO4). The solution of product was then filtered and evaporated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, 7% ethyl acetate in hexane) to give 5-(4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-thiadiazole as a brown oil (0.645 g). M+ =222; 1H NMR: δ 2.56(2H, br q); 2.63 (3H,s); 3.30(2H,t); 4.30(1H,m).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[NH:23][C:22]2=[O:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[O:33].O>C1C=CC=CC=1>[OH:33][CH:32]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:30])[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC#CCSC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=O
Solvent: c1ccccc1
Solvent: O
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
3-(Triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (1.03g) and t-butyl glyoxalate (3.3g) were refluxed in dry benzene (50ml) with provision for the removal of water. After one hour the benzene solution was washed 5 times with water, dried and evaporated. Chromatography of the residue on silica --H gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous white solid (0.978 g).