Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5]([O:18][CH2:19][CH:20]2[CH2:22][S:21]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:22][CH:20]([SH:21])[CH2:19][O:18][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([S:8][C:7]=2[CH:6]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: O=c1c2ccccc2sc2cc(OCC3CS3)cc(O)c12
Reactant: Cl
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2sc2cc(OCC(S)CCl)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-3-(thiiran-2-ylmethoxy)-9H-thioxanthen-9-one (10 mg, 0.03 mmol) prepared in Example 8, followed by stirring at room temperature for 3 hours, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (8 mg, 71.8%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:14])[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:19]([O:14][CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:12]=[CH2:13])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: C=CC(O)C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(C=C)C1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)prop-2-en-1-ol (414 mg, 2.09 mmol), prepared in the previous step, was added to a suspension of sodium hydride (104 mg, 4.12 mmol, 95%) dropwise at 0° C. under argon. After the complete addition, the reaction mixture was allowed to reach room temperature and stirred for 1 hour. Allyl bromide (0.35 mL, 4.05 mmol) was added dropwise and the mixture stirred overnight at room temperature. It was poured onto ice cooled saturated NaHCO3 solution. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to afford the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27](Br)=[C:26]([CH3:32])[CH:25]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)[CH3:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of racemic 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.200 g, 0.360 mmol) in toluene (2 mL) is added palladium tetrakis triphenylphosphine (0.0267 g, 0.020 mmol), 4-trifluoromethyl phenyl boronic acid (0.135 g, 0.720 mmol), and potassium fluoride (0.0416 g, 0.720 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At reflux, water (1.0 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and celite is added, followed by water. This mixture is then filtered through a pad of celite. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is purified by flash column chromatography (0.150 g, 0.240 mmol).
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][N:8]2[C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[C:35](O)(=[O:37])C>CO.O=[Mn]=O>[O:31]=[C:20]([N:8]1[CH2:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:18][C:19]=2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:37][CH3:35])=[O:30])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnO2 (0.59 g, 14 equiv.), sodium cyanide (0.05 g, 2 equiv.) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (SiO2,DCM:MeOH (95:5), Rf=0.82). The mixture was filtered through a short column of celite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2×20 cm2 column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>CN(C=O)C>[CH2:37]([N:38]([CH3:33])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH2:36][CH2:35][CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-methylbutylamine (581 μL, 4.9 mmol) are added. The reaction stirred at room temperature 2 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1.[NH2:38][C@H:39]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl.CC(C)=O>[NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:2]([C:18]([NH:38][C@H:39]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Fmoc-Phe(4-NHBoc)-OH (210 mg, 418 μmol, 1 equiv.) was dissolved in DCM and HCl.H-Leu-OMe (77 mg, 460 μmol, 1.1 equiv.), HBTU (190 mg, 502 μmol, 1.2 equiv.) and DiPEA (242 μl, 1.46 mmol, 3.5 equiv.) were added and the mixture stirred for 1 hour. after which it was washed with 1M HCl (2×), sat. aq. NaHCO3 (4×) and brine and dried over MgSO4. Column chromatography (10% acetone:PE->20% acetone:PE) yielded the title compound (206 mg, 294 μmol, 70%). 1H NMR (400 MHz, CDCl3): δ ppm 7.76 (d, J=7.5 Hz, 2H), 7.54 (t, J=6.9 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35-7.20 (m, 4H), 7.11 (d, J=7.1 Hz, 2H), 6.54 (s, 1H), 6.29 (d, J=6.6 Hz, 1H), 5.44 (d, J=7.2 Hz, 1H), 4.55 (td, J=8.4, 5.4 Hz, 1H), 4.41 (dd, J=10.3, 7.2 Hz, 1H), 4.32 (s, 1H), 4.18 (t, J=6.9 Hz, 1H), 3.68 (s, 3H), 3.15-2.94 (m, 2H), 1.65-1.39 (m, 3H), 1.51 (s, 9H), 0.97-0.78 (m, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.74, 170.69, 155.89, 152.64, 143.67, 143.60, 141.16, 137.31, 130.58, 129.83, 127.64, 127.01, 124.98, 119.88, 118.55, 80.41, 67.11, 55.88, 52.17, 50.75, 46.95, 41.31, 37.78, 28.25, 24.63, 22.58, 21.81.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)C.[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])C=1N.C(=O)([O-])[O-].[K+].[K+].CI>O>[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:4]=1[NH:2][CH3:1]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CNc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a DMF solution (50 mL) of 2,3-difluoro-6-nitroaniline (3.0 g) were added potassium carbonate (14.3 g), and methyl iodide (3.23 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.66 g).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]1[C:10]2[S:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([NH2:18])=[O:17])=[CH:7][CH:6]=1.[C:19](Cl)(=[O:21])[CH3:20].C(OCC)(=O)C>ClCCl>[C:19]([C:6]1[CH:5]=[C:10]([S:11][CH2:12][CH2:13][CH2:14][Cl:1])[C:9]([OH:15])=[C:8]([CH:7]=1)[C:16]([NH2:18])=[O:17])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cccc2c1OCCCS2
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(SCCCCl)c(O)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
Solid aluminum chloride (9.0g, 67.7 mmol) was suspended in 20 mL of dry dichloromethane at 0° C. The 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid amide (2.7 g, 12.7 mmol) was added as a solution in 20 mL dichloromethane. The deep green solution was stirred at 0° C. for 10 min, then neat acetyl chloride (10 mL, 140.6 mmol) was added dropwise with stirring. The suspension was stirred at 0° C. for 20 min, then at rt for 30 h. The reaction was quenched with 4 N HCl and extracted repeatedly with ethyl acetate. Drying over Na2SO4 and concentration yielded the crude product. Sgc (ethyl acetate) yielded the product as a tan solid (1.6 g, 44%). MS [M−H]− 286.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39]1([NH2:43])[CH2:42][O:41][CH2:40]1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:43][C:39]2([C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[CH2:42][O:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2ncccn2)COC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)COC4)ccc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a yellow solution mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (30 mg, 0.071 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (16 mg, 0.085 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added benzotriazo-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (50 mg, 0.096 mmol), followed by triethylamine (TEA) (0.1 ml, 0.717 mmol), and the reaction mixture stirred for overnight. Ice cooled water was added to the reaction mixture, which was then stirred for 10-15 min. at 0° C. Precipitation was observed. The solid was collected by filtration, washed with cold water, and then dissolved in dichloromethane. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield (12 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>COCCOC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(Br)cc1Br
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(Br)cc1N1CCOCC1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dibromo-1-(methylsulfonyl)benzene (0.3 g, 0.96 mmol) and morpholine (0.25 g, 2.9 mmol) in DME was heated at 90° C. for 16 h, cooled, and concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with brine (2×). The organic layer was dried (MgSO4), concentrated to give a near colorless solid which was ˜1:1 mixture of regioisomers by analytical HPLC and LC/MS analysis. This residue was purified by chromatography on silica gel (EtOAc/hexanes) to afford 4-(5-bromo-2-(methylsulfonyl)phenyl)morpholine as a near colorless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.2 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 3.8-3.6 (m, 4H), 3.4 (s, 3H), 3.1-2.9 (m, 4H). MS (ESI) 322.1, 320.1 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6]/[C:7](=[N:10]\[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[CH2:8][CH3:9].[C:18](=[O:21])([O-])[O-].[K+].[K+].[CH3:24]N(C)C=O>>[CH2:8]([C:7]1[C:6]([CH:18]=[O:21])=[CH:24][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CC/C(C)=N/Nc1ccccc1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nn(-c2ccccc2)cc1C=O
Temperature: 25 °C
Yield: 15 %

Procedure:
To an ice cold solution of N,N-dimethylformamide (4.59 mL, 59.36 mmol) and phosphoryl chloride (5.52 mL, 59.36 mmol) add a solution of N-[1-methyl-prop-(E)-ylidene]-N′-phenyl-hydrazine (3.21 g, 19.79 mmol) in N,N-dimethylformamide (2 mL) dropwise. Warm to room temperature, then heat to 75° C. for 5 hr. Cool to room temperature and pour into an ice-cold solution of saturated potassium carbonate. Extract with DCM (3×20 mL), pass through an IST Phase Separator Frit® and concentrate. Purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:isohexane), to give the title compound as a brown solid (600 mg, 15%). MS (ES): m/z=201 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([OH:17])[CH2:14]CC.BrBr.CC1C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C(O)CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:10][CH2:14][CH2:13][O:17]2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)=O
Reactant: CCCCO
Agent: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Solvent: O
Product: COc1cc(Cl)ccc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 27.5 parts of 1-(4-chloro-2-methoxyphenyl)ethanone in 160 parts of butanol are added dropwise 24 parts of bromine. After stirring for 1 hour at room temperature, there are added successively 9.3 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid and 450 parts of benzene. Stirring is continued overnight at reflux temperature with water-separator. The reaction mixture is evaporated and the residue is taken up in benzene. The mixture is washed with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is crystallized from methanol, yielding 27.6 parts (60%) of 2-(bromomethyl)-2-(4-chloro-2-methoxyphenyl-1,3-dioxolane; mp. 110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12].C(OCC)(=O)C>O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]2[CH2:15][CH:13]2[C:11]#[N:12])=[O:7])=[CH:4][CH:3]=1
Reactant: N#CC1CN1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CC2C#N)cc1

Procedure:
This compound is obtained in the form of an oil in a yield of 1.8 g. from 1.54 g. p-methylbenzoyl chloride and 0.68 g. 2-cyanoaziridine. It still contains a little ethyl acetate and water. The analytical results (elementary analysis, NMR and mass spectra) confirm the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][C:23]#[N:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1-Benzyloxycarbonyl-3-mesyloxymethylpiperidine (WO 0100207; 8.4 g) was dissolved in DMSO (100 ml) and sodium cyanide (1.6 g) was added. The mixture was heated to 100° C. and stirred continuously under an argon atmosphere for 6 hours. The mixture was cooled and poured into water (200 ml). The product was extracted with EtOAc, washed with ferrous sulphate solution (10% w/w), dried and evaporated in vacuo. TLC (40% EtOAc/petroleum ether (60/80) Rf. 0.54.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](C2OC=CC=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[CH3:16][Al](C)C.O.[CH3:21][CH2:22][O:23][C:24]([CH3:26])=O>ClCCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]1[CH:24]=[CH:26][CH:21]=[C:22]1[N:3]1[CH:4]=[C:5]2[C:9](=[N:8][CH:7]=[N:6]2)[N:10]=[C:2]1[CH3:16]
Reactant: CCOC(C)=O
Reactant: C[Al](C)C
Reactant: Clc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCCl
Product: Cc1nc2ncnc-2cn1-c1ccco1
Yield: 30 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-1H-purine (1.1 g, 5.0 mmol) and Pd(PPh3)4 (0.58 g, 0.5 mmol) in 1,2-dichloroethane (50 mL) at room temperature was treated dropwise with trimethylaluminium (3.3 mL, 2.0 M hexane), refluxed for 16 h, treated with water (100 mL) then EtOAc (100 mL), stirred for 60 h and filtered through glass microfibre paper. The organic phase was separated, dried (MgSO4), concentrated in vacuo and the resulting solid recrystallised from 90% ethanol to give the title compound (0.30 g, 30%) as a pale brown solid.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1)[C:4]([F:7])([F:6])[F:5].C(N(C(C)C)CC)(C)C.[CH2:32]([C@@:34]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]1)[CH3:33]>ClCCl>[CH2:32]([C@:34]1([CH2:41][S:42]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:3]([F:2])([F:22])[C:4]([F:7])([F:6])[F:5])=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)(=[O:43])=[O:44])[NH:35][C:36](=[O:40])[NH:37][C:38]1=[O:39])[CH3:33]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(pentafluoroethoxy)phenoxy]piperidine hydrochloride (0.17 g) and diisopropylethylamine (0.19 mL) in dichloromethane (100 mL) was added [(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.13 g). The reaction was stirred at ambient temperature for 18 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH:13]([F:15])[F:14].Cl[C:17]1[N:22]=[C:21]([NH:23][CH3:24])[C:20]([Cl:25])=[CH:19][N:18]=1.Cl.O1CCOCC1>C(O)CCC>[Cl:25][C:20]1[C:21]([NH:23][CH3:24])=[N:22][C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH:13]([F:14])[F:15])=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)c(OC(F)F)c1
Reactant: CNc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNc1nc(Nc2ccc(C(=O)OC)cc2OC(F)F)ncc1Cl
Temperature: 150 °C

Procedure:
Methyl 4-amino-3-(difluoromethoxy)benzoate (70 mg), 2,5-dichloro-N-methylpyrimidin-4-amine, 0.1 mL of 4N HCl/dioxane and 1 mL of n-butanol were placed in a microwave vial. The reaction was heated for 30 minutes at 150° C. and monitored by LCMS. The mixture was concentrated and purified by silica gel chromatography to give 100 mg of pure methyl 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.S(Cl)([Cl:19])=O.[CH3:21]O>>[ClH:19].[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:14]([O:16][CH3:21])=[O:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1
Reactant: Cc1c(C(=O)O)nn2c(N)nnc2c1C
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1nn2c(N)nnc2c(C)c1C
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
3-Amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid hydrochloride (W1.140; 780 mg) was dissolved in methanol (40 ml) and thionyl chloride (1.9 ml) was slowly added dropwise, and then the mixture was stirred at 65° C. After 2.5 h, the mixture was dried and the residue was purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 602 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:10])[C:6]([F:8])([F:7])[F:9]
Reactant: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(CCOC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2′-chloro-4′-[2-((RS)-tetra-hydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (352 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (48 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Ethyl bromoacetate (133 μl) was added to the reaction mixture, and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave ethyl N-[2-chloro-4-[2-((RS)-tetrahydropyran-2-yloxy)ethyl]phenyl]-N-trifluoroacetylamino-acetate (250 mg).