Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH2:31]>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: NCC1COc2ccccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(NCC2COc3ccccc3O2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 8 μL (0.11 mmol) acetyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[CH3:11][NH:12][CH3:13].O1CCO[CH2:15]1.Cl>>[CH3:11][N:12]([CH3:15])[CH2:13][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: C1COCO1
Reactant: CNC
Reactant: CC(=O)c1ccccc1
Agent: Cl
Product: CN(C)CCC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
30.0 g of acetophenone are mixed with 24.5 g of dimethylamine hydrochloride and 74.1 g of 1,3-dioxolane, 2.5 g of concentrated hydrochloric acid are added, and the mixture is heated to exactly 90° C. and maintained at that temperature for 3.5 hours. Excess dioxolane is distilled off and the residue is cooled to 0° C. The resulting 3-dimethylamino-1-phenylpropan-1-one of formula
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](OC)=[CH:7][CH:8]=2)[N:3]=1.N1CC[O:18][CH2:17]C1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2nc(Cl)cc(Cl)c12
Temperature: 140 °C
Yield: 60.1 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyquinoline (1 g, 4.38 mmol) in 1,4-dioxane (15 ml) was added morpholine (1.9 g, 4.38 mmol) followed by DIPEA (1.7 g, 13.15 mmol) at room temperature. The reaction mass was heated at 140° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.6 g, 49.1%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.89-7.86 (d, J=12 Hz, 1H), 7.07 (s, 1H), 6.97-6.94 (d, J=12 Hz, 1H), 6.89 (s, 1H), 3.91 (s, 3H), 3.85-3.82 (m, 4H), 3.69-3.66 (m, 4H); MS: MS m/z 279.1 (M++1).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]2[O:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:21]=2[CH:20]=1)(=O)=O>C(O)C>[O:28]=[C:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH2:24][O:23][C:22]2[CH:33]=[CH:34][C:19]([CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])=[CH:20][C:21]1=2
Reactant: CNO
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a stirring solution of 13.06 g of N-methylhydroxylamine hydrochloride in 250 ml of absolute ethanol was added 17.48 g of potassium tert-butoxide. To the resulting suspension was added 9.0 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2 -yl)propanol methanesulfonate. The resulting product suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride, and the mother liquor was then treated with 200 ml of water and concentrated in vacuo to remove ethanol. The resulting mixture was partitioned against a total of 450 ml of methylene chloride and 250 ml of water. The organic phase was washed with 250 ml of saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo to a viscous oil which solidified upon triturating the oil, with 10 ml of ethyl acetate and 3 drops of hexane and refrigerating. Thin layer analysis of the solids indicated a mixture, which was separated via HPLC (silica gel). The purified oil solidified upon standing to give 4.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methyl-1-propylamine, m.p. 113-114.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(CC)CC.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([C:9]([OH:11])=[O:10])=[C:6]([NH:20][C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nc(Cl)nc(Cl)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine-5-carboxylic acid (5.69 g, 25.02 mmol) in DMF (60 mL) was added Et3N (8 mL, 57.4 mmol) and m-toluidine (3.2 mL, 29.5 mmol) at 0° C. The mixture was stirred at RT for 12 h. To the mixture was added 1N HCl. The mixture was extracted with EtOAc. The organic layers were basified with saturated aq NaHCO3 and the aqueous layers were washed with EtOAc. The washed aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were washed with 1N HCl, water, and brine, were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure, triturated with hexane, and filtered to give a first batch of the title compound (4.36 g). The filtrate was concentrated, triturated with hexane, and filtered to give a second batch (0.36 g) of the title compound (total 4.72 g, 63%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 7.00-7.02 (m, 1H), 7.25-7.28 (m, 2H), 7.33-7.35 (m, 2H), 10.13 (s, 1H), 1H not detected. [M+H] calc'd for C12H10Cl2N3O2, 298. found, 298.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:16]1(=O)[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>C(O)C.CC(OC)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(O)cc12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Zinc chloride (28.3 g, 0.207 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95° C. (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4-chlorobenzoylacetate (44 g, 0.194 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155° C. and an internal temperature of 75-95° C. maintained throughout most of the addition. Halfway through the addition more anhydrous ethanol (45 mL) was added because the reaction mixture became thick and a loss of some of the original volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (27 g, 44%).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.C(Cl)Cl>[O:18]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C@H:8]3[CH2:9][C@H:7]3[CH2:6][N:19]=[N+:20]=[N-:21])[C:15]=2[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A solution of (cis)-[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl methane sulfonate (5.0 mmol) and sodium azide (10.0 mmol) in 100 mL of dimethylformamide was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and stirred overnight. The crude reaction mixture was then diluted with CH2Cl2 (100×mL) and washed sequentially with water (3×100 mL) and then brine (1×100 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.1 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]/[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]/[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: O=C(O)/C=C/Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C/Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (10 mg, 0.022 mmol), triethylamine (10.9 g, 0.11 mmol), and (E)-3-chloroacrylic acid (2.76 g, 0.026 mmol) in DCM (0.4 ml, 6.22 mmol), cooled to 0° C., was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.023 ml, 0.039 mmol, 50% solution in EtOAc). The resulting mixture was stirred at room temperature for 4 h and concentrated. The remaining residue was purified by silica gel flash chromatography to obtain the title compound (7.2 mg, yield: 61%). 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H) 3.90 (s, 6H) 6.02 (s, 1H) 6.36 (d, J=12.92 Hz, 1H) 6.49 (s, 1H) 7.21-7.33 (m, 2H) 7.36-7.50 (m, 2H) 7.75 (d, J=6.53 Hz, 1H) 7.93 (br. s., 1H) 8.41 (s, 1H) 12.50 (s, 1H); MS (ESI): 551.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[NH2:14][C:15]1[C:16]([Cl:27])=[N:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:27][C:16]1[C:15]([NH:14][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:12])=[CH:20][CH:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]=1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)n1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)n1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
Oxalyl chloride (1.10 ml, 12.5 mmol) was added to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) and DMF (0.18 ml, 2.28 mmol) in methylene chloride (25 ml) and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent to give 1-methylindole-3-carboxylic acid chloride (2.19 g, 99%) as a pale yellow solid. The resulting 1-methylindole-3-carboxylic acid chloride (752 mg, 3.88 mmol) was added in portions to a solution of ethyl 3-amino-2-chloro-6-pyridylacetate (833 mg, 3.88 mmol) and triethylamine (1.08 ml, 7.77 mmol) in methylene chloride (20 ml) under stirring at 0° C. The reaction mixture was heated under reflux for 8 hours. After cooling to room temperature and addition of water, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, ethyl 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetate (859 mg, 60%) was obtained as a yellow solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]2[C:36](=O)[CH2:35][N:34]([CH3:38])[C:33]2=[O:39])=[CH:23][CH:22]=1>O>[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][C:36]=3[C:23]=2[CH:22]=1
Reactant: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CN1CC2=C(C1=O)c1ccccc1Oc1ccc(Cl)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Phosphorus pentoxide (270 g) is added in portions to H3PO4 (270 g) and the mixture is maintained for 1-2 hours at 100-120° C. 3-(2-(4-chlorophenoxy)phenyl)-1-methyl-pyrrolidine-2,4-dione (90 g) is added and the mixture is maintained for three days at 100-110° C. Additional P2O5 (30 g) is added in two portions and the mass is maintained for one day at 100-120° C. The mass is poured into water (900 mL) and the mass is stirred overnight at 25-35° C. The mass is extracted with dichloromethane (1000 mL), the layers are separated, and the aqueous layer is washed with dichloromethane (400 mL). The combined organic layer is washed with water (900 mL), 5% sodium bicarbonate (300 mL), and saturated brine solution (500 mL). After drying over anhydrous sodium sulfate, the solvent is removed under vacuum. The residue is dissolved in methanol (400 ml) and heated at reflux for 30-60 minutes. The solution is cooled to −10 to −15° C. and a solid forms. The solid is collected by filtration, washed with chilled methanol (50 mL), and dried to afford the title compound. Yield: 37.5 g. Purity by HPLC: 89.47%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22]([C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O)(=[O:24])=[O:23].ClC(Cl)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:30][C:26]2[S:27][CH:28]=[CH:29][C:25]=2[S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:23])=[O:24])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1cccs1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.14 g), 3-(thiophene-2-sulfonyl)thiophene-2-carbaldehyde (0.12 g) and dichloroethane (5.0 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (1.4 mL), trifluoroacetic acid (0.35 mL) and dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C., diluted with saturated aqueous sodium hydrogen carbonate solution and the phases separated. The aqueous phase was extracted with dichloromethane and the combined organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume), to afford the title compound as a yellow solid (0.17 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[NH2:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][O:36][C:37](=[O:42])[C:38]([NH:39][C:8]([C:5]1[CH:4]=[C:3]([I:11])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1cc(I)c(Cl)cn1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-4-iodo-2-pyridinecarboxylic acid (CAN 120643-06-3, 100 mg, 353 μmol) in DMF (2 mL) was added TBTU (170 mg, 529 μmol) and 2-methyl-alanine methyl ester hydrochloride (59.6 mg, 388 μmol) to give a light yellow suspension. DIEA (308 μL, 1.77 mmol) was added and the reaction mixture was stirred for 3 h. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to deliver the desired compound (40.5 mg, 30%) as yellow oil. MS (ESI, m/z): 382.9 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C[Si]([C:29]#[CH:30])(C)C.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1)#[CH:30]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Nc2nc(-c3ccc(Br)cc3)nc3ccccc23)[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(-c2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of [2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol) in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol %), Pd(PPh3)2Cl2 (4.2 mg, 1:50 mol %) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120° C. overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mL) and TBAF (1M in THF, 1.leq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 70%): 1H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H, s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: BrCC1CC1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OCC2CC2)cc1
Temperature: 75 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-hydroxybenzamide (5.00 g), bromomethylcyclopropane (2.20 g), cesium carbonate (5.5 g) and DMF (50 ml) was heated to 75° C. for 12 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 400.32 (C21H22BrNO2); MS (ESI): 400 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:38][CH3:39])[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].CC(C)=O.[Cr](O)(O)(=O)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:38][CH3:39])[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[C:14]([C:17](=[O:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(C)O)=CS[C@@H]21
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(C)=O)=CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
To a solution of 0.154 g. of benzhydryl 7-(2-thienylacetamido)-7-methoxy-3-(1-hydroxyethyl)-2-cephem-4-carboxylate in 40 ml. of acetone was added 1.5 eq. of chromic acid. After stirring the mixture at room temperature for 10 minutes, 2 ml. of isopropanol was added. After stirring for an additional 5 minutes, the reaction mixture was evaporated in vacuo to dryness. The residue was dissolved in an ethyl acetate/water slurry. The organic layer was separated, washed successively with water (2X), aqueous sodium bicarbonate solution, 1N.HCl, and brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided product which was chromatographed on 5.0 g. of silica gel using a toluene-ethyl acetate gradient to give 0.073 g. (47.8 percent) of the title product as a white froth: