Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24](O)=[C:23]([CH3:29])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:11][CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]2)=[C:23]([CH3:29])[CH:22]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OC[C@@H]1CCCN(C)C1
Temperature: 25 °C

Procedure:
Alternatively, a solution of (R)-3-tosyloxymethyl-1-methylpiperidine (100 mg, 0.35 mmol), 4-bromo-2,6-dimethylphenol (75 mg, 0.37 mmol), and cesium carbonate (240 mg, 0.74 mmol) in dimethylformamide (4 mL) was heated to 65° C. under a nitrogen atmosphere for 1.5 hours. The solution was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was removed and the aqueous phase extracted once more with ethyl acetate (30 mL). The combined acetate layers were dried over magnesium sulfate and concentrated to afford the (R)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as a clear oil. This material was identical to that prepared in Example 2E when analyzed by chiral HPLC (Chiralpak AD, 97:3:0.1 hexane/2-propanol/diethylamine).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:30])([F:29])[F:18])[CH:5]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(F)(F)F)cn1
Yield: 20 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) instead of 4-fluorophenylboronic acid, to the title compound (37 mg, 20%) which was obtained as a white solid. MS (ESI): m/e=369.9 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH2:32])[C:20]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:21][C:22]=3[O:23][CH3:24])[N:11]=2)=[CH:2]1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:45])[CH:43]=[CH2:44].Cl>C(Cl)Cl.CO.C(Cl)Cl.CC1CCCO1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[C:19]([NH:32][C:42](=[O:45])[CH:43]=[CH2:44])[CH:18]=3)[N:11]=2)=[CH:2]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: Cl
Solvent: CC1CCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 1.9 %

Procedure:
To a stirred solution of N′-[4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 66, 96 mg, 0.22 mmol) in CH2Cl2 (15 mL) at 2° C. was added DIPEA (0.039 mL, 0.22 mmol) and acryloyl chloride (0.018 mL, 0.22 mmol). The resulting solution was stirred at 2° C. for 0.25 h, then allowed to warm to r.t. and stirred for a further 3.5 h. The mixture was then diluted with CH3OH (10 mL), loaded directly onto silica. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 (containing 1% concentrated ammonia (aq) gave the an off-white solid which appeared to contain DIPEA.HCl according to MNR analysis. The solid was then dissolved in a 1:1 mixture of CH2Cl2/2-methyltetrahydrofuran (30 mL) and the resulting solution was washed with NaOH solution (2M, 2×30 mL), water (2×30 mL) and then sat. brine (30 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to give the title compound (2 mg, 2%) as a white solid after trituration with diethyl ether. The liquors from the trituration were concentrated in vacuo to give a second sample of the title compound (10 mg, 9%) as a white solid; 1H NMR: 2.27 (3H, s), 2.55 (4H, s), 2.82-2.95 (4H, m), 3.84 (3H, d), 5.73 (1H, d), 6.24 (1H, dd), 6.62 (1H, dd), 6.89 (1H, s), 7.07-7.21 (2H, m), 7.25 (1H, d), 7.46 (1H, d), 7.89 (1H, s), 8.29 (1H, d), 8.32 (1H, d), 8.42 (1H, s), 8.69 (1H, s), 9.01 (1H, s); m/z: ES+ MH+ 484.62.
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[Cl:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C1CCC(PC2CCCCC2)CC1
Agent: Cl
Product: ClP(C1CCCCC1)C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
19.8 g (0.1 mol) dicyclohexylphosphane was added dropwise at room temperature to 26.1 g (0.11 mol) hexachloroethane. After the exothermal reaction which took place with evolution of HCl was terminated, the reaction mixture was stirred for 3 hours at 100° C. The yields (31 -P-NMR) were as follows: δ P=125.2 ((C6H11)2PCl, 94 wgt %); δ P=194.4 (C6H11PCl2, 2 wgt %); δ P=76.7 ((C6H11)2P(O)Cl, 4 wgt %). The crude product was distilled and 13.7 g (59 wgt %) dicyclohexylchlorophosphane (bp.: 136°-138° C./4 millibars) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[C:13]([Br:24])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (300 mg, 0.96 mmol) and N-bromosuccinimide (180 mg, 1.01 mmol) in CH2Cl2 (3 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo, and the residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 296 mg of the title compound. MS: (+) m/z 390.98, 392.88 (M+H, 79/81Br)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2ccc(Br)cc2c(=O)o1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2-Amino-5-bromobenzoic acid (25 g, 116 mmol) was added in portions to acetic anhydride (150 mL) giving a slightly exothermic reaction to 30° C. The suspension was heated at reflux for 2 h. The product crystallized spontaneously upon cooling. After stirring in ice for 30 min, the crystals were filtered off and washed twice with heptane. The crystals were thoroughly dried at 0.1 mbar/50° C. One obtained 22.4 g (85%) of beige crystals. MS: m/z=239/241 (M).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.[NH2:9][C@H:10]([C:19]([OH:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.FC(F)(F)S(O)(=O)=O>[N+](C)([O-])=O>[NH2:9][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([CH2:7][C:4]2[S:3][C:2]([NH2:1])=[N:6][CH:5]=2)[CH:17]=1)[C:19]([OH:21])=[O:20]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1ncc(CO)s1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Nc1ncc(Cc2cc(C[C@H](N)C(=O)O)ccc2O)s1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
To a suspension of (2-aminothiazol-5-yl)methanol (35 mg, 0.269 mmol) and L-Tyrosine (199.6 mg, 1.102 mmol) in nitromethane (3.00 mL) is added trifluoromethanesulfonic acid (170 μL, 1.914 mmol). The resulting solution is sonicated for 15 sec, then heated at 80° C. for 18 h. The reaction is evaporated to dryness and the residue is purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 0% Solvent B to 60% Solvent B over 12 min, ret. T=5.14 min. The product fractions are poured thru a washed WATERS OASIS® MCX 20 cc (1 g) LP extraction cartridge and washed with additional MeOH (50 mL). Elution with Aldrich 2.0M NH3/MeOH (20 mL) followed by evaporation gives 48.7 mg (55.6%) of the title compound as a light tan solid. LC/MS (Condition A): ret. T=0.63 min, (M+H)+ 294.05. Analytical HPLC: (Condition C): >95%, ret. T=3.26 min, (Condition D): >90%, ret. T=3.00 min. 1H NMR (500 MHz, DMSO-d6+D2O) δ ppm 6.86-7.04 (2 H, m), 6.67-6.76 (1 H, m), 6.58-6.67 (1 H, m), 3.74 (2 H, br. s.), 3.33 (1 H, br. s.), 3.02 (1 H, d, f=10.07 Hz), 2.68 (1 H, br. s.).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[O:25])=[CH:19][CH:18]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.O>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[O:25])=[CH:19][CH:18]=1)#[N:2]
Reactant: CC(C)S(=O)(=O)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropylsulfonylurea (0.085 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate collected via filtration, washed with water and purified on silica gel (CH2Cl2/EtOAc, 8.5:1.5) to provide 1-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-3-isopropylsulfonylurea (0.061 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH:17]=[O:18])=[CH:15][CH:16]=2)[CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CO)n3CC12c1ccc(Cl)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(C=O)n3CC12c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 92.6 %

Procedure:
10a-(4-chlorophenyl)-8-(hydroxymethyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (26 mg, 0.061 mmol) in CH2Cl2 (50 mL) was added MnO2 (26.5 mg, 0.30 mmol) and the reaction mixture was heated at 50° C. for 18 h. LCMS analysis after this time showed complete conversion of the starting material alcohol to the target aldehyde. The reaction mixture was filtered twice with a syringe filter and the filtrate was concentrated in vacuo to give 10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbaldehyde as a white solid (24 mg, yield 92%) The crude product was used in the next step without further purification. ESI-MI m/z [m+H]+ 425.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:23](=[O:25])[CH3:24])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2ccc(C(F)(F)F)cc2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-trifluoromethyl-2-aminonaphthalene (550 mg, 2.60 mmol) and triethylamine (1.09 mL, 7.81 mmol) in dichloromethane (10 mL) at room temperature is added acetyl chloride (0.222 mL, 3.13 mmol) dropwise. After stirring at room temperature for 1.5 hours, the mixture is partitioned between dichloromethane and water. The organic layer is washed with 0.1 M citric acid solution, brine, dried (MgSO4) and concentrated by rotary evaporator to give 7-trifluoromethyl-2-acetamidonaphthalene as a light yellow solid.
Reaction SMILES: [CH:1]([OH:3])=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.Cl.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]2[CH2:39][CH2:40][CH2:41][CH:42]([NH2:43])[C:31]=12.O>O1CCCC1>[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]2[CH2:39][CH2:40][CH2:41][CH:42]([NH:43][CH:1]=[O:3])[C:31]=12
Reactant: Cc1c2n(c3ccccc13)CCCC2N
Reactant: O=CO
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)CCCC2NC=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of formic acid (b 6 mL) and acetic anhyride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-amine hydrochloride (7.5 g, 37.5 mmol), in dry tetrahydrofuran (60 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. for 2 hours, poured into water (150 mL) and extracted with ether (3×100 mL). The combined extracts were washed successively with 5% hydrochloric acid, 5% sodium bicarbonate, and water. The ethereal solution was dried over MgSO4, filtered, and evaporated. The solid residue was crystallized from benzene/hexane to give 8.5 g (99%) of the title formamide as a yellow solid, m.p. 133°-5° C. Analytical sample melted at 136° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].[Br:15]Br.CO>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:15][C:5]1[S:1][C:2]([C:6]([OH:9])([CH3:8])[CH3:7])=[N:3][CH:4]=1
Reactant: CC(C)(O)c1nccs1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
The product of Step 1 (8.97 g, 62.6 mmol) was dissolved in CHCl3 (125 mL), and NaHCO3 (5.79 g, 68.9 mmol) was added. Bromine (15.01 g, 94 mmol) was then added dropwise. After stirring for 2 h at room temperature, LC/MS showed a mixture of starting material and product (50% conversion). Additional NaHCO3 (2.89 g, 34.5 mmol), bromine (7.51 g, 47.0 mmol), and methanol (15 mL) were added, and the reaction was stirred for another 2 h at room temperature. The reaction was diluted with 10% Na2S2O3, neutralized with saturated NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried (MgSO4), filtered and evaporated. Flash chromatography (0-15% ethyl acetate in toluene) afforded 9.38 g (67%) of 2-(5-bromo-1,3-thiazol-2-yl)propan-2-ol as a white solid. ESI: [M+H]+m/z 221.9/223.9.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22](O)(=[O:25])[CH2:23][OH:24]>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:23](=[O:24])[CH2:22][OH:25])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)O
Reactant: O=C(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)OC(=O)CO
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g.) and 1,1'-carbonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g.) and 2.80 ml. of triethylamine in 15 ml. of tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1 N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g., m.p. 150°-157°. The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@H:13]4[CH2:18][CH2:17][NH:16][C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1F
Product: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1

Procedure:
1-tert-butyl 2-methyl (2R,4S)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (17) was reacted with 3-Chloro-2-fluoroaniline analogously as for the equivalent step in Example 7 to give methyl (2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (18): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.56 (2H, m), 2.03-2.12 (1H, m), 2.31-2.38 (1H, m), 2.60-2.67 (1H, m), 3.08-3.15 (1H, m), 3.44-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.55-4.63 (1H, m), 7.23 (1H, s), 7.26-7.32 (1H, m), 7.48-7.58 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]O)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][Cl:14])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(CO)on1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.12 g of (3-t-butyl-isoxazol-5-yl)methanol was dissolved in 35 ml of dichloromethane, and 2.4 ml of thionyl chloride was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was washed with hexane to obtain 1.12 g of 3-t-butyl-5-(chloromethyl)-isoxazole.
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH:21]([O:23]CCCC)=[CH2:22].C1(N(C)C2CCCCC2)CCCCC1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl-].[Li+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC=C)=C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2](/[CH:22]=[CH:21]/[OH:23])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: C=COCCCC
Agent: [Pd]
Agent: C=COC=C
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(C)c2cc(/C=C/O)c(=O)n(C3CCCC3)c2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (336 mg, 1.0 mmole), 1-(vinyloxy)butane (501 mg, 5.0 mmole), N-cyclohexyl-N-methylcyclohexanamine (254 mg, 1.3 mmole), tri-tert-butylphosphonium tetrafluoroborate (8.70 mg, 0.03 mmole), lithium chloride (127 mg, 3.0 mmole), tris(dibenzylideneacetone)dipalladium(0)) (27.5 mg, 0.03 mmole) and 1,4-dioxane (10 ml) were added to a reaction vial equipped with a stir bar. The reaction vial was flushed with nitrogen, capped, and heated at 75° C. for 75 min. LCMS data indicated that both the intermediate vinyl ether and the product were obtained (4:6). The reaction mixture was cooled to ambient temperature, filtered through Celite™ and washed with dioxane (10 ml). The filtrate and washing were combined, and para-toluene sulfonic acid monohydrate (761 mg, 4.0 mmole) was added. The reaction was stirred at ambient temperature for 1 h. At this point LCMS data indicated that all of the intermediate vinyl ether hydrolyzed to the desired product. The solvent was removed under reduced pressure to a residue, and ethyl acetate (120 ml) was added, and washed with aqueous potassium carbonate solution (5 wt/v %), water, and brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to a yellow solid residue, which was crystallized from boiling heptane. Upon cooling to ambient temperature, yellow crystals formed and collected by filtration to give the title compound (190 mg, 62% yield) after two steps.
Reaction SMILES: I[C:2]1C=C[C:5]([N:8]2C[C@H](CNC(=O)OC(C)(C)C)O[C:9]2=[O:22])=[CH:4][CH:3]=1.F[C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]2=[O:41])[CH:27]=[CH:28][C:29]=1I>>[O:41]=[C:32]1[N:31]([C:26]2[CH:27]=[CH:28][C:29]([CH:3]3[CH2:4][CH2:5][NH:8][C:9](=[O:22])[CH2:2]3)=[CH:24][CH:25]=2)[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNC(=O)C3)cc2)C(=O)O1

Procedure:
N-({(5S)-2-oxo-3-[4-(2-oxopiperidin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide is prepared as described in the route described in Example 16 substituting tert-butyl [(5S)-3-(4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylcarbamate for N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide. 1H-NMR (DMSO) δ: 8.25, 7.55, 7.47, 7.30, 4.70, 4.10, 3.73, 3.40, 3.17, 3.02, 2.31, 1.87, 1.83
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].O>C(O)(=O)C>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(=O)Oc2ccc(OS(C)(=O)=O)cc21
Yield: 70 %

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (20 parts) in warm acetic acid (200 parts) was treated with 200 parts of a 20% aqueous solution of chromic oxide. After about 15 seconds the mixture was poured into water and the solution extracted with ether. The extracts were thoroughly washed with aqueous sodium bicarbonate, then dried and the solvent evaporated to give 2-oxo-2,3-dihydro-3,3-dimethyl-benzofuran-5-yl methanesulphonate (14 parts, 70% yield), melting point 120°-121° C. after recrystallisation from benzene-petroleum.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([N:7](C)[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.B.N#N>C(N(CC)CC)C>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)N(C)c1ccc(C)cc1
Agent: B
Agent: N#N
Solvent: CCN(CC)CC
Product: Cc1ccc(N=C=O)cc1

Procedure:
Ethylene glycol was reacted with boron trichloride to form the borane compound of formula ##STR32## (For detailed procedure see Genmarie et. al., Tetrahedron Letters, 1984, 25, 2279). To a solution of p-tolyl methyl urethane there were added the borane compound and triethylamine and the mixture was refluxed for 5 minutes (N2 atmosphere). An instantaneous reaction was observed and a white cloudy suspension appeared in the reaction flask, due to the formation of Et3NH+Cl-. p-Tolyl isocyanate was obtained and IR spectra showed the complete disappearance of urethane moieties and the formation of isocyanate moieties.