Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP(OCC)(OCC)=O)C.[CH3:12][O:13][C:14]1[CH:23]=[C:22]([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[C:20]=2[Cl:25])[N:15]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N+:42]([O-])([O-:44])=[O:43].[K+]>CO>[N+:42]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([Cl:25])=[C:21]2[C:16]=1[N:15]=[C:14]([O:13][CH3:12])[CH:23]=[C:22]2[CH3:24])([O-:44])=[O:43]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(C)c2c(Cl)c(OC)ccc2n1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: CO
Solvent: CCOP(=O)(OCC)OCC
Product: COc1cc(C)c2c(Cl)c(OC)cc([N+](=O)[O-])c2n1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 20-liter reactor equipped with a mechanical stirrer, thermowatch, and condenser was charged with triethylphosphate (6.3 liters) and 2,6-dimethoxy-5-chloro-4-methylquinoline (5) (500 g, 2.11 moles). Phosphorous pentoxide (1.052 kg, 7.11 moles) was added in one portion and the resulting slurry stirred for 60 minutes. Reaction temperature was adjusted to 35° C. and solid potassium nitrate (0.423 kg, 4.21 moles) added in one portion. N-hexane is added and the reaction temperature was maintained at 35-40° C. for 2 hours. Methanol (4.2 liters) was added and the mixture heated to reflux and held for 1 hour. The yellow slurry was cooled to 0-5° C. and held for 2 hours. The product was collected by suction filtration, washed with water to neutral pH, then methanol, air dried and oven dried at 60-70° C. to yield the title compound 350 g (68%); mp 199-200° C.;
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:34]=2)[CH:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:32]3[CH:31]=[C:30]4[CH:29]=[CH:28][NH:27][C:35]4=[N:34][CH:33]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([CH3:20])[N:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1noc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccccc2-c2nc3cc(-c4cnc5[nH]ccc5c4)ccc3n2C(C)(C)C)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 10.2 %

Procedure:
To a solution of 5-bromo-1-tert-butyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-1H-benzimidazole (100 mg, 0.24 mmol) in DMF (5 mL) and H2O (1 mL) are added 7-azaindole-5-boronic acid pinacol ester (89 mg, 0.37 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and K2CO3 (34 mg, 0.24 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The mixture is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is (MgSO4), filtered and concentrated and the residue is purified by preparative HPLC to afford the title compound (11 mg, 10%) as a white foam. LCMS (ESMS): m/z 449.77 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:22](C(=O)CC)[C:23](=[O:26])[CH2:24][CH3:25])=[C:14]([CH3:21])[C:15](=[O:20])[N:16]2[CH3:19])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.CO.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:10]2[CH:11]=[C:12]3[C:17](=[N:18][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:16]([CH3:19])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]3[NH:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:32][CH:33]=1
Reactant: CCC(=O)N(C(=O)CC)c1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)Nc1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of step A (1.56 g) in THF (12 mL) was added methanol (3 mL) and Cs2CO3. The reaction stirred overnight at room temperature before it was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel with an EtOAc/hexane gradient elution affording the title compound. HPLC/MS: 499.8 (M+1), 501.8 (M+3); Rt=3.95 min.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.C([O:20][C:21]([CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)=[O:22])C.[OH-].[Li+]>CC(O)CC>[C:21]([CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]2[N:32]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:33]=2)[CH:27]=[CH:28][CH:29]=1)([OH:20])=[O:22]
Reactant: CCOC(=O)Cc1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: O=C(O)Cc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.05 g, 5.0 mmol), 3-ethoxycarbonylmethyl-phenyl-guanidine nitrite (1.42 g, 5.0 mmol), lithium hydroxide (0.12 g, 5.0 mmol) in 2-butanol (15 mL) is heated to reflux for 24 hours. After cooling to room temperature, the solvent is evaporated under reduced pressure. Water (40 mL) is added and extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over sodium sulfate, filtrated and concentrated. The residue is dissolved in ethanol (30 mL) and treated with lithium hydroxide (0.48 g, 20 mmol). The reaction mixture is heated to reflux for 1 hour. After cooling to room temperature, the mixture is concentrated. The residue is dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxymethyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (1.34 g); ESI-MS (m/z): 341.0 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COCCOCCO
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Product: COCCOCCOc1cc2ncnc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Yield: 42.2 %

Procedure:
Using an analogous procedure to that described in Example 91, 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reacted with 2-(2-methoxyethoxy)ethanol (70 mg) to give 4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (50 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:24][CH2:23][CH2:22][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.67 g, 12.67 mmol) in N,N-dimethylformamide (6.5 ml) and dichloromethane (65 ml) was added with 2-piperidin-1-yl-ethylamine (1.78 g, 13.9 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (4.84 g, 25.34 mmol) and 1-hydroxybenzotriazol (1.71 g, 12.67 mmol) in an ice/water-bath. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then added with cold water (50 ml), and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate (50 ml), water (50 ml), brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[(2-piperidin-1-yl-ethyl carbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.46 g, 85%) as a brown oil which was used as such.
Reaction SMILES: [OH:1][C:2]1[C:3](C)=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[C:28](O)(C(F)(F)F)=[O:29].O.C(O)(C(F)(F)F)=O.CC#N>>[OH:1][C:2]1[C:3]([O:29][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 76 %

Procedure:
The title compound (26 mg, 76%) was prepared from Example 398 (38 mg, 0.092 mmol) by a route analogous to that used for the preparation of compound 397A. It has a retention time of 6.08 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M+H)+=373.2
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:30][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
3-(Hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.735 g) was stirred with ice-water cooling in dichloromethane (32 ml) under nitrogen and carbon tetrabromide (0.962 g) and triphenylphosphine (0.646 g) were added successively. After 5 min the cooling bath was removed and the mixture was stirred at 21° for 4 h. The mixture was poured onto an SPE silica cartridge (10 g). The cartridge was eluted with dichloromethane to give the title compound (0.21 g) LCMS RT=4.31 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2C=O)c1
Temperature: 100 °C

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (0.75 g, 4.8 mmol), 5-chloro-2-fluorobenzaldehyde (1.0 g, 4.8 mmol), and potassium carbonate (1.0 g, 7.5 mmol) were combined in 1,4-dioxane (30 mL) and heated to 100° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CC1C(C#N)=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)C=2C=1.[CH3:19][Mg+].[Br-].[C:22]([OH:34])(=O)[CH2:23][C:24]([CH2:29][C:30](O)=O)([C:26](O)=O)O>C1COCC1>[CH3:26][C:24]1[C:23]([C:22](=[O:34])[CH3:19])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:30]=2[CH:29]=1
Reactant: Cc1cc2c(cc1C#N)ncn2C1CCCCO1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc2ncn(C3CCCCO3)c2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (1.1 g, 4.6 mmol) in anhydrous THF (20 mL) under nitrogen at 0° C. was dropped a solution of CH3MgBr in THF (8 mL, 24 mmol) at a rate that the internal reaction temperature remained below 10° C. After the addition, the reaction mixture was stirred at RT overnight. The mixture was slowly poured into ice-water (20 mL) and stirred at RT for 0.5 h. The solution's pH was adjusted to 5.0˜6.0 by using citric acid, and mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (1:1) to afford 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone as a yellow solid (1.1 g, 90.1%). MS (ESI): m/z=259.2 [M+1]+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].COCCOC.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:36].[Na+]>O>[F:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=1[I:36]
Reactant: [I-]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a stirred solution of T10.3 (1.00 g, 3.6 mmol) in DME (10.00 mL, 96 mmol) at 23° C. was added sulfuric acid (0.19 mL, 3.6 mmol) in water (8 mL), followed by dropwise addition of a solution of sodium nitrite (0.38 g, 5.4 mmol) in water (2 mL) at 0° C. over 30 minutes. The reaction was then stirred for 20 minutes. To the mixture was added a solution of sodium iodide (3.0 g, 20 mmol) in water (7 mL) at 0° C. The resulting mixture was then stirred for 1 hour. The reaction was quenched with sodium thiosulfate and extracted three times with diethyl ether. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-40% EtOAc in hexanes) to yield a colorless solid T10.4 (0.820 g, 58% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C@@H:13]([NH:22]C(=O)OC(C)(C)C)[CH2:14][CH:15]1[CH2:20][CH2:19][CH:18](C)[CH2:17][CH2:16]1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[H][H].[CH3:32]O>[Pd]>[NH2:22][CH:13]([CH2:14][C:15]1([CH3:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:12][N:2]([CH3:1])[C:3](=[O:4])[O:5][CH2:6][CH2:7][Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: [H][H]
Reactant: CC1CCC(C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: [Pd]
Product: CN(CC(N)CC1(C)CCCCC1)C(=O)OCC[Si](C)(C)C
Yield: 100 %

Procedure:
A 250 mL round bottom flask was charged with 0.2479 g (0.54 mmol) of (S)-tert-butyl 1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(4-methylcyclohexyl)propan-2-ylcarbamate, 0.2784 g of 10% Pd/C, and 20 mL of MeOH. The reaction mixture was stirred at rt under a balloon of hydrogen for 5 h. The mixture was then filtered through filter agent, Celite® 545, washed with MeOH. The filtrate was evaporated under reduced pressure to afford 0.1799 g (100%) of 2-(trimethylsilyl)ethyl 2-amino-3-(1-methylcyclohexyl)propyl(methyl)carbamate, which was used in the next step without further purification. MS ESI +ve m/z 329 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-fluorobenzoic acid (7.92 g, 36.2 mmol) in N,N-dimethylformamide (75 mL) was added potassium carbonate (6.91 g, 50.0 mmol) as a solid in one portion at room temperature. The mixture was stirred for 5 minutes and iodomethane (6.39 g, 45.0 mmol) was added in one portion. The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with additional ethyl acetate (3×) and the combined organic extracts were washed successively with 10% potassium carbonate solution, water and brine. The organic portion was dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3H) 7.41 (td, J=8.56, 3.22 Hz, 1H) 7.65 (dd, J=8.99, 3.22 Hz, 1H) 7.81 (dd, J=9.16, 5.09 Hz, 1H); MS (+DCI/NH3) m/z 250.0 [M+NH4]+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11]CC2C=CC=CC=2)=[C:4]1[CH2:19][O:20][CH3:21]>CO.O.[Pd]>[ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([OH:11])=[C:4]1[CH2:19][O:20][CH3:21]
Reactant: COCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COCc1c(O)c(=O)cc(C)n1C
Yield: 86.5 %

Procedure:
1,6-Dimethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one hydrochloride (1.55 g, 5 mmol) was dissolved in methanol (40 ml)/water (10 ml) and hydrogenated for 4 hours in the presence of 5% Pd/C (0.3 g). Following filtration the filtrate was concentrated in vacuo and the crude material recrystallised from methanol/diethyl ether gave the pure title compound (0.95 g, 86.5%) as a white crystalline solid. m.p. 156-159° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)=O)(C)(C)C.Cl.C(Cl)Cl.C(OCC)(=O)C>O1CCOCC1>[NH2:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(CN)o1
Reaction time: 12 h
Yield: 8.4 %

Procedure:
Crude, unpurified compound 8 (5 g) is added portionwise to a 0° C. commercially available solution of hydrogen chloride in 1,4-dioxan (Aldrich, 4 M, 35 ml.) Compound 8a slowly dissolves to afford a clear yellow solution. After stirring for approximately 12 hours, the reaction mixture turns cloudy. TLC on silica using methylene chloride:ethyl acetate (9:1) as the eluent shows the starting material has been consumed. The reaction mixture is filtered and a white solid is obtained. The solid is washed exhaustively with ether (50 mL) to afford 266 mg of compound 9.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].C(N(CC)CC)C>C1COCC1.[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>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cccc(I)c1NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C#C[Si](C)(C)C)c1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
To tert-butyl 2-iodo-6-methoxyphenylcarbamate (10.36 g, 29.67 mmol), ethynyltrimethylsilane (3.20 g, 32.63 mmol), copper(I) iodide (0.28 g, 1.48 mmol), and PdCl2(PPh3)2 (1.04 g, 1.48 mmol) in THF (100 mL) was added triethylamine (3.60 g, 35.6 mmol), followed by overnight stirring. The crude reaction was then concentrated and the mixture was flashed through silica gel with 10:1 Hex/EtOAc to give the desired product (98%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH2:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=4)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C:17]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N+:1]4([CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:9][CH:10]=2)=[O:16])=[CH:25]3)=[CH:31][CH:30]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)C3)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)C3)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 86 h

Procedure:
In DMF (10 ml) was dissolved N-[4-(piperidinomethyl)-phenyl]-5-(4-methylphenyl)indene-2-carboxamide (400 mg), and to the mixture was added methyl iodide (177 μl). The mixture was stirred at room temperature for 86 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-[4-[5-(4-methylphenyl)indene-2-carboxamido]-benzyl]-1-methyl-piperidinium iodide (Compound 61) (516 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH2:40][CH3:41])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:42]1([P:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[I-].[Na+]>C(OCC)(=O)C>[Cl-:19].[CH:23]([O:22][C:20]([C:14]1[N:13]2[C:36](=[O:37])[CH:11]([NH:10][C:8](=[O:9])[C:7]([C:4]3[N:3]=[C:2]([NH2:1])[S:6][N:5]=3)=[N:38][O:39][CH2:40][CH3:41])[C@H:12]2[S:17][CH2:16][C:15]=1[CH2:18][P+:48]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:21])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1nsc(N)n1
Product: [Cl-]
Yield: 59.4 %

Procedure:
A mixture of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (36.7 g) in ethyl acetate (600 ml), triphenyl phosphine (18.8 g) and sodium iodide (1 g) were boiled under reflux for 100 minutes. The precipitates were collected by filtration and washed with ethyl acetate to give [4-benzhydryloxycarbonyl-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-cephem-3-ylmethyl]triphenylphosphonium chloride (syn isomer)(31.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[O:13]1COCO[CH2:14]1.O>CS(C)=O.C[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C1OCOCO1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a stirred solution of methyl (4-fluorophenyl)acetate (5.5 g) in DMSO (220 mL) was added 1,3,5-trioxane (3.24 g) and sodium methoxide (88 mg). The mixture was stirred at room temperature for 16 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.8 g of the title compound.