Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)(O)[O-].[Na+].IC>CN(C=O)C>[CH3:23][O:20][C:19](=[O:21])[C@H:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:22]
Reactant: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
A suspension of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid (Example 4, 18.0 g, 0.061 mol), sodium bicarbonate (15.36 g, 0.183 mol), and iodomethane (11.40 mL, 0.183 mol) in DMF (164 mL) was stirred at rt for 20 h. The reaction was monitored by reverse phase HPLC. Upon completion, the reaction was quenched by pouring into ice/water (300 mL) followed by extracting with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×150 mL) and brine (150 mL) and was dried over anhydrous sodium sulfate. Filtration and concentration to dryness gave a crude oil which was purified by silica gel chromatography using 10-35% ethyl acetate/hexanes to give 16.38 g (87%) of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester as an oil. 1H NMR (DMSO-d6) δ 7.45 (d, 2H), 7.38 (m, 3H), 7.30 (m, 2H), 7.13 (s, 1H), 6.82 (d, 1H), 6.38 (s, 1H), 5.41 (q, 1H), 5.08 (s, 2H), 3.60 (s, 3H), 1.70 (d, 3H); LC/MS (+esi) m/z 310.2 (M+H)+, RT 3.47 min.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C[O:37][CH2:36]C1>>[OH:16][C@@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][C:8]([O:37][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: C1CCOC1
Reactant: C1CCNC1
Product: COc1nc(Oc2ccc3[nH]c(C)cc3c2)c2ccc(OC[C@@H](O)CN3CCCC3)cc2n1
Temperature: 75 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of (2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2ylmethoxy)quinazoline (250 mg, 0.66 mmol), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-methoxy-4-(2-methylindol-5-yloxy)quinazoline (106 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: OC1CCNCC1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(Cl)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.7 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (5.0 g, 30.7 mmol) in EtOH (100 mL) were added 4-piperidinol (3.1 g, 30.7 mmol) and Na2CO3 (16.3 g, 153.4 mmol). The reaction mixture was stirred at rt for 72 h, after which the reaction mixture was filtered through Celite®. The filtrate was then concentrated under reduced pressure, the residue dissolved in EtOAc, and the organic solution washed with water and brine after which it was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (1:1 EtOAc/hexanes to 100% EtOAc) to give the product (4.8 g, 90%) as a white waxy solid. 1H NMR (400 MHz, CDCl3) δ 1.62-1.70 (m, 2H), 1.70 (d, 1H), 1.98-2.03 (m, 2H), 2.21 (s, 3H), 3.22-3.28 (m, 2H), 3.87-3.92 (m, 2H), 3.97-3.98 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>CN(C=O)C.O>[CH:2]1([N:12]2[C:8](=[O:18])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]2=[O:13])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrC1C=CCCC1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1C=CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 73717.9 %

Procedure:
To a solution of 3-bromo-cyclohexene (500 g, 3.12 mmol) in DMF (2000 mL) was added potassium phtalimide (580 g, 3.12 mmol), and the reaction mixture was stirred at room temperature for 30 h. The reaction mixture was diluted with water (1000 mL), extracted with ethyl acetate (3 times), and the combined organic layers were concentrated to give 2-cyclohex-2-enyl-isoindole-1,3-dione (520 g, 2.30 mol) as a gray solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][S:71]([CH3:74])(=[O:73])=[O:72])=[C:66]([F:75])[CH:65]=1>C1COCC1>[F:75][C:66]1[CH:65]=[C:64]([CH:69]=[CH:68][C:67]=1[NH:70][S:71]([CH3:74])(=[O:73])=[O:72])[CH2:63][NH:62][C:17]([CH:14]1[CH2:13][CH2:12][C:10]2([O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:16][CH2:15]1)=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C2CCC3(CC2)CC(c2ccccc2)=NO3)cc1F
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (400 mg, 1.54 mmol) was slowly added to a solution of N-ethyldiisopropylamine (662 g, 4.6 mmol), 1-hydroxybenzotriazole hydrate (206 mg, 1.54 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (496 mg, 1.54 mmol) and N-(4-aminomethyl-2-fluorophenyl)methanesulphonamide (336 mg, 1.54 mmol) in abs. THF (11 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (75 ml). The precipitate formed was removed by suction-filtration, washed with a small amount of ether and dried. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-3-fluoro-4-methanesulphonylaminobenzylamide was obtained as a cis isomer (89 mg, 13% of the theoretical amount). The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The residue was boiled up in EtOAc (2.5 ml) and DCM (1 ml). The precipitate formed was removed by suction-filtration and washed with a small amount of ether. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-3-fluoro-4-methanesulphonylaminobenzylamide was obtained as a trans isomer (138 mg, 19% of the theoretical amount).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)C.[NH3:23]>>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:23])=[O:3]
Reactant: CCOC(=O)CCCOc1ccc(C)cc1Cc1ncc[nH]1
Reactant: N
Product: Cc1ccc(OCCCC(N)=O)c(Cc2ncc[nH]2)c1
Reaction time: 6 h

Procedure:
A mixture of 4-[2-(1-imidazolylmethyl)-4-methyl-phenoxy]butyric acid ethyl ester (1.0 g) and 0.880 ammonia solution was stirred for 6 hours and allowed to stand for a further 36 hours. The solid was filtered off and crystallised from water to give 4-[2-(1-imidazolylmethyl)-4-methyl-phenoxy]butyramide (0.30 g), m.p. 114°-116° C. Found: C, 65.31, H, 7.23, N, 15.13. C15H19N3O2 requires: C, 65.91, H, 7.01, N, 15.37%.
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4].[CH3:23][NH2:24]>O>[CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:24][CH3:23])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: CN
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (4.6 mMol) of 4-chloro-3-nitrobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide was mixed with 30 ml of 40% methylamine solution and stirred in a sealed flask for four hours at room temperature. Then the mixture was diluted with about 40 ml of water, the product precipitated was suction filtered, washed with water and dried. Yield: 1.5 g (95% of theory), C14H22N4O4S (343.4) Rf value: 0.45 (silica gel; dichloromethane/ethanol=4:1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Br)=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c(C#C[Si](C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A mixture of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.61 g, 6.93 mmol), TMS-acetylene (1.18 mL, 8.32 mmol), Pd(PPh3)2Cl2 (496 mg, 0.693 mmol), CuI (132 mg, 0.693 mmol), and i-Pr2NH (1.95 mL, 13.9 mmol) in THF (11 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 1% to 2% EtOAc in hexanes) to afford the desired product (2.15 g, 79%).
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1>CCOCC>[CH3:3][O:2][P:1]([NH:6][C:7]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)=[O:8])([S:4][CH3:5])=[O:9]
Reactant: COP(=O)(N=C=O)SC
Reactant: COC(=O)C1CCCNC1
Solvent: CCOCC
Product: COC(=O)C1CCCN(C(=O)NP(=O)(OC)SC)C1
Temperature: 25 °C

Procedure:
A solution of 8.36 g of O,S-dimethyl phosphoro-isocyanatidothioate in 100 ml of ether was cooled to 0° C. and to it was added dropwise with stirring 7.15 g of methyl 3-piperidinecarboxylate. The mixture was allowed to warm to ambient temperature and react overnight. The precipitate that formed was collected by filtration, extracted with ether, and dried under reduced pressure to obtain 11.5 g (74 percent of theory) of the title compound as white crystals melting at 65°-67° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:4][C:3]=1[F:20].O[CH2:22][C:23]1C2N=NNC=2[CH:26]=[CH:25][CH:24]=1.C[O:33]/C=C/C(O[Si](C)(C)C)=C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[F:20][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[C:7]([F:8])[C:2]=1[N:1]1[CH:26]=[CH:25][C:24](=[O:33])[CH2:23][CH2:22]1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: CC(=O)NCC1CN(c2cc(F)c(N)c(F)c2)C(=O)O1
Reactant: OCc1cccc2[nH]nnc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
N-[3-(4-Amino-3,5-difluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (0.745 g, 2.61 mmol) and hydroxymethylbenzotriazole (0.390 g, 2.61 mmol) are dissolved in dry EtOH (2.0 mL). This resulting solution is refluxed for 5 h, solvent is removed under vacuum, and the resulted aminal intermediate dried under high vacuum. Danishefsky's diene (75.3 mg, 0.43 mmol) is added with stirring to the suspension of above aminal intermediate (0.091 g, 0.21 mmol) in THF (3 mL) at 0° C., followed by trimethylsilyl triflate (ca. 20 mL). The resulting mixture is allowed to warm up to r.t. over 2 h. Sat. aq. NaHCO3 (10 mL) is added, and the mixture extracted with excess EtOAc several times. Solvent is removed under vacuum, and the crude product purified by PTLC (5% MeOH in DCM) followed by RP HPLC (gradient 0–60% of MeCN—water). MS (m/z): 366 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.50–2.54 (m, 2H), 3.53–3.64 (m, 2H), 3.84–3.92 (m, 3H), 4.22 (t, 1H, J=9.3 Hz), 4.81–4.89 (m, 1H), 5.04 (d, 1H, J=7.8 Hz), 7.25–7.29 (m, 1H) 7.39–7.51 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[C:7]([C:10](=[O:21])[NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C1COCC1.O>[Cl:33][C:30]1[S:29][C:28]([C:26]2[O:25][N:24]=[C:23]([CH2:22][N:6]3[C:7]([C:10](=[O:21])[NH:11][CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[CH:8][CH:9]=[C:5]3[C:3]([OH:4])=[O:2])[CH:27]=2)=[CH:32][CH:31]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(C(C)C)CC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(NC(=O)c2ccc(C(=O)O)n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid methyl ester (example 10, 30 mg) in 5 mL of THF/water(3:1) was added LiOH (9 mg) The mixture was stirred for 2 h at 45° C. after which it was cooled to RT, acidified with TFA and concentrated. 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid was obtained after preparative HPLC(CH3CN/H2O gradient+0.05% TFA) of the residue. MS (ESI+): m/e=477 [M+H]+, chloro pattern.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:19]=[N:20][CH:21]=[N:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]([CH:25]=[CH2:26])(O)[C:6]=2[CH:5]=1.[NH2:27][C:28]([NH2:30])=[S:29]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)=[CH:11][CH:12]=3)[C:7]3([CH2:25][CH2:26][S:29][C:28]([NH2:30])=[N:27]3)[C:6]=2[CH:5]=1
Reactant: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C1(CCSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial charged with Pd2(dba)3 (0.150 g, 0.164 mmol), XPhos (0.391 g, 0.819 mmol), 5-(tributylstannyl)pyrimidine (1.81 g, 4.92 mmol), 2-bromo-7-methoxy-9H-xanthen-9-one (1.000 g, 3.28 mmol) and dioxane (10 mL). The reaction mixture was evacuated and backfilled with nitrogen. The reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with water and EtOAc. A grey solid precipitated out, which was filtered off. The solid was washed with EtOAc and water. The grey solid dried under reduced pressure to afford 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one) (0.600 g, 60.2% yield). Step 2: A solution of vinylmagnesium chloride (1.6M solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF (10 mL) at −78° C. After 30 min, the reaction mixture was allowed to warm to −10° C. and was then quenched with saturated aqueous ammonium chloride. The reaction was extracted with EtOAc, and the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow gum. Step 3: 2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 μL, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In a 25 ml nitrogen-purged flask, with exclusion of air and moisture, 8.28 mmol (1.01 g, 1.00 ml) of (S)-1-phenylethanol (Fluka, 99% ee), 12.4 mmol (1.50 equ., 983 mg, 1.00 ml) of pyridine and 15 ml of dichloromethane are charged and cooled down to 0° C. (ice bath). With stirring, 10.8 mmol (1.30 equ., 1.10 g, 1.02 ml) of acetic anhydride is added dropwise over 10 min. Within a period of 12 h, the mixture is warmed up to room temperature and successively extracted twice each with 20 ml of 1 M aqueous hydrochloric acid solution, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, separated from the desiccant by filtration and freed from solvent in a rotary evaporator. The crude product was purified by chromatography over silica gel (mobile solvent: hexane:ethyl acetate=9:1). The product fractions are combined and freed from solvent in a rotary evaporator. After drying in an oil-pump vacuum, a clear liquid remains (1.25 g, 7.62 mmol, 92%). Analytics: 1H-NMR (CDCl3, 200 MHz): δ=1.52 (d) 3J=6.6 Hz [3H], 2.06 (s) [3H], 5.94 (q) 3J=6.6 Hz [1H], 7.24-7.38 (m) [5H]; 13C-{1H}-NMR (CDCl3, 50 MHz): δ=21.4 (s), 22.2 (s), 72.3 (s), 126.1 (s), 127.9 (s), 128.5 (s), 141.7 (s), 170.3 (s); MS (EI, 70 eV, pos. ions): m/z (% rel. int.): 164 (25) [M+], 122 (77), 107 (36), 105 (69), 104 (100), 103 (24), 79 (27), 78 (27), 77 (43), 51 (24), 43 (90); EA: C: 72.95% (calc. 73.15%), H: 7.28% (calc. 7.37%); GC (Hewlett Packard 5890, 25 m fused silica, 0.25 inner diameter, 2,6-dimethyl-3-pentyl-β-CD (95% methyl-/5% phenylpolysiloxane), FID, 80° C., 4° C. min−1, 120° C. 0.2 min iso, 0.63 bar hydrogen): 99.8% ee.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25]>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[C:7]=1[F:8]
Reactant: NCc1ccccn1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(NCc2ccccn2)n1
Reaction time: 4 h

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (0.2 g, 1.111 mmol) was dissolved in THF (1 mL). To this solution was added triethylamine (0.17 mL, 1.22 mmol), followed by commercially available (2-pyridinylmethyl)amine (0.11 mL, 1.067 mmol), which was dissolved in THF (1 mL). The reaction was left to stir for 4 hours. The reaction mixture was diluted with water and extracted with ether. The organics were dried (MgSO4) and concentrated to provide 6-chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine as a yellow wax (0.2517 g, 90%). LCMS: (M+H)+=253.3.
Reaction SMILES: [F:1][CH:2]([F:19])[CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:19][CH:2]([F:1])[CH:3]([N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[CH2:4][C:5](=[CH2:7])[CH2:6][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)CC(C(F)F)N1C(=O)c2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)CC(C(F)F)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,1-difluoro-2-phthalimido-4-methyl-4-pentene (17.8 g, 67.2 mmoles) prepared as in Step B above, N-bromosuccinimide (14.4 g, 80.6 mmoles), carbon tetrachloride (200 mL) and benzoyl peroxide (4 times one end of spatula during the heating period) is heated under strong reflux (325 W lamp) during 6.5 hours. After cooling, the solution is extracted 3 times with water, dried over magnesium sulfate, and concentrated. The oily residue obtained is used for the next step without further purification.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=[O:4])[O].[K+].[K+].[K].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>O.CC(C)=O>[CH3:14][O:15][C:16]1[C:21](=[O:4])[CH:20]=[CH:19][C:18](=[O:22])[CH:17]=1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: COC1=CC(=O)C=CC1=O
Reaction time: 0.17 h
Yield: 117.5 %

Procedure:
A solution of potassium nitrosodisulfonate (0.75 g) and potassium monobasic phosphate (0.75 g) in water (37.5 ml) was added to m-methoxyphenol (109 mg, 0.9 mmol) in acetone (12.5 ml) and the resulting mixture was stirred vigorously for 10 minutes. Potassium nitrosodisulfonate (0.75 g) was added to the reaction mixture in two portions at 30 minute intervals and the stirring was continued for an additional two hours. After removal of acetone under reduced pressure, the resulting aqueous solution was extracted with dichloromethane (four 10 ml aliquots). The combined organic layers were washed with 0.01 N sodium hydroxide (10 ml) and then with water (10 ml) and then dried over anhydrous magnesium sulfate. The dried solution was filtered and the solvents removed under reduced pressure to yield 146.1 mg of 2 -methoxy-p-benzoquinone.