Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:33]1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47](N(CC)CC)C>CN(C=O)C>[N:40]1[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][CH2:34][NH:33][C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][CH2:11]3)=[CH:24][CH:23]=2)=[O:22])[CH:47]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(C(=O)NCCc3cccnc3)cc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)methyl]benzoic acid (Intermediate XIII.1; 3.00 g; 8.97 mmol), TBTU (3.20 mg; 9.97 mmol) and triethylamine (1.40 ml; 10.0 mmol) in DMF (50 ml) is stirred for 5 min. The amine 3-(2-aminoethyl)-pyridine (1.06 ml; 9.00 mmol) is added. After further 3 h stirring, the solvent is evaporated and the residue is taken up in DCM and washed with sodium carbonate solution. The organic layer is dried over sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient DCM/Methanol) to yield tert-Butyl N-[1-({4-[(2-(3-pyridyl)-ethylamino)carbonyl]phenyl}methyl)piperidin-4-yl]carbamate
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:22])[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[O:20][CH3:21])([CH3:5])[CH3:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:21][O:20][C:9]1[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:7]1[O:22][CH2:4][C:3]([CH3:2])([CH3:5])[N:6]=1
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OC)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 5.66 g (17.62 mmol) N-(2-hydroxy-1,1-dimethyl-ethyl)-2,6-dimethoxy-4-trifluoromethyl-benzamide in 60 ml dichloromethane was cooled to 10° C. 3.8 ml (52.85 mmol) thionylchloride was added drop-wise. The temperature rose to 15° C. The mixture was stirred at room temperature for 1 hour. The solution was added drop-wise to 130 ml of a cooled 2M sodium carbonate solution. The emulsion was diluted with water and filtered, to remove the white solid. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude light yellow solid (5.27 g) was purified with flash column chromatography on silica (70 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 50%) to provide 4.8 g (yield: 89.8%) of the title compound as a white solid. MS (m/e): 304.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=2)[CH:5]=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:7]=1[NH2:8].[CH2:24]([NH:26][C:27]([NH:29][C:30](SC)=NC(=O)NCC)=[O:28])[CH3:25]>O1CCOCC1.OS(O)(=O)=O>[CH2:24]([NH:26][C:27]([NH:29][C:30]1[NH:8][C:7]2[C:6]([CH:9]3[CH2:13][CH2:12][CH2:11][O:10]3)=[CH:5][C:4]([C:14]3[CH:19]=[N:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[N:16][CH:15]=3)=[CH:3][C:2]=2[N:1]=1)=[O:28])[CH3:25]
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2)cn1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirring solution of 2-[5-(3,4-diamino-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (9) (32.10 g, 102.1 mmol) in 1,4-dioxane (160.5 mL, Sigma-Aldrich 360481) was added pH 3.5 buffer (240.8 mL), prepared by dissolving NaOAc trihydrate (34.5 g) in 1N aqueous H2SO4 (240 mL). 1-Ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (28.46 g, 122.5 mmol, CB Research and Development) was added to the reaction mixture and stirred at reflux overnight (HPLC showed 99% consumption of starting diamine). The reaction mixture was cooled to room temperature and poured portion-wise (frothing) into a stirring solution of aqueous saturated NaHCO3 (480 mL) and water (120 mL) giving pH 8-9. This was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving (11) as an off-white solid (34.48 g, 82% yield; 99.4% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 411.41 (1.73 min). 1H NMR (300 MHz, MeOD) δ 9.02 (s, 2H), 7.62 (s, 1H), 7.37 (s, 1H), 5.31 (s, 1H), 4.23 (dd, J=14.5, 7.3 Hz, 1H), 4.01 (dd, J=15.0, 7.1 Hz, 1H), 3.38-3.28 (m, 2H), 2.58-2.46 (m, 1H), 2.16-2.05 (m, 2H), 2.02-1.88 (m, 1H), 1.63 (s, 6H), 1.22 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.C(O)(=O)C.N#N>CO.[Pd]>[C:10]([OH:12])(=[O:11])[CH3:9].[NH2:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)COc1ccc(C=NO)cc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(CN)cc1
Reaction time: 12 h
Yield: 162.3 %

Procedure:
To a solution of methyl {4-[(hydroxyimino)methyl]phenoxy}acetate (30 g, 0.14 mol) in methanol (650 mL) was added glacial acetic acid (6.8 g) and passed N2 for 30 min. To this was added Pd/C (10%, 3 g) and hydrogenated under 2 bars of pressure for 12 h. The reaction mixture was concentrated under vacuum. The crude product was treated with EtOAc (500 mL) and the white product filtered off The solid was dried under vacuum to give the title compound (29 g, 81%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1.[Si:14]([O:31][CH2:32][CH2:33][CH:34]=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1.O>[Si:14]([O:31][CH2:32][CH2:33][CH:34]([OH:35])[CH2:6][C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1)([C:27]([CH3:29])([CH3:30])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1=NC(C)(C)CO1
Reactant: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)COC(CC(O)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)=N1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
5.2 ml of a solution of 1.6M n-butyllithium in hexane was added dropwise to a solution of 940 mg of 2,4,4-trimethyl-2-oxazoline in 20 ml of tetrahydrofuran with stirring, at -78° C. The resulting mixture was stirred at -78° C. for 1 hour. After this time, 2.00 g of 3-tert-butyldiphenylsilyloxy-1-propanal [prepared as described in Can. J. Chem., 71, 695 (1993)] in 10 ml of tetrahydrofuran was added to the reaction mixture whilst stirring, maintaining the temperature at -78° C. Stirring was continued at -78° C. for 15 minutes, then the reaction mixture was brought to room temperature and stirred for 30 minutes. At the end of this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate fraction was washed with water, dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a mixture of 50% v/v ethyl acetate and hexane as the eluent, to afford 2.18 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cc(F)c(Cl)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)c(Cl)c2cccnc12)c1ccccc1
Yield: 15.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-chloro-6-fluoroquinolin-8-amine (Intermediate 53) (100 mg, 0.51 mmol), benzenesulfonyl chloride (100 mg, 0.61 mmol) and DMAP (cat.) gave the title compound (27 mg, 16%) after purification by column chromatography with DCM as the eluent followed by preparative HPLC (neutral conditions).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].[CH2:22](I)[CH3:23].O>CC1OC(C)=C(C)C=1C>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:3]1[CH:4]=[C:5]([Cl:16])[CH:6]=[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1])[CH3:23]
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Reactant: CCI
Agent: Cc1oc(C)c(C)c1C
Agent: [Na]
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt in 250 ml of dry tetramethylfuran was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to 1 liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This material was recrystallized from absolute ethyl alcohol to give 1.5 g, yellow needles, m.p. 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-:10].[Na+].[NH2:12]O.Cl>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:12][OH:10])[NH2:9])=[N:6][CH:7]=1
Reactant: NO
Reactant: [OH-]
Reactant: N#Cc1ccc(Br)cn1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccc(Br)cn1
Temperature: 62.5 °C
Yield: 63.1 %

Procedure:
To a solution of 5-bromo-2-cyanopyridine (1.0 g, 5.50 mmol) in EtOH (100.0 mL) was added a solution of NaOH (0.22 g, 5.50 mmol dissolved in 2.0 ml H2O) followed by addition of NH2OH.HCl (0.38 g, 5.50 mmol). The resulting solution was heated to 60-65° C. for 16 h. After the completion of reaction (TLC monitoring), the solvent was evaporated and the residue was acidified with 3% HCl solution (20.0 mL) and heated to 100° C. till a clear solution was obtained. The reaction mixture was then cooled to room temperature and extracted with DCM (2×50 mL) that was later on discarded. The aqueous layer was basified with aqueous NH3 till pH 8 and extracted with EtOAc (3×50 mL). The combined organics was dried (Na2SO4), filtered and concentrated to obtain the desired product (0.75 g, 64%). MS: 216.01 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH:5][P:6](Cl)(Cl)=[O:7].[NH3:10].[NH4+:11].[Cl-]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][NH:5][P:6](=[O:7])([NH2:11])[NH2:10]
Reactant: N
Reactant: [NH4+]
Reactant: O=P(Cl)(Cl)NCCCBr
Agent: [Cl-]
Solvent: ClCCl
Product: NP(N)(=O)NCCCBr

Procedure:
The crude 3-bromopropylphosphoramidic dichloride was added to a solution of 10 g of ammonia in 125 mL CH2Cl2 at -30° C. The resulting mixture of product and NH4Cl weighed 19.4 g. Extraction with CH2Cl2 gave a material which slowly discolored over several days, mp. 60°-65° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:22]([CH3:24])[CH3:23])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine 1 (100 mg, 0.42 mmol) in DMF was treated with sodium hydride 60% dispersion in mineral oil (25 mg, 0.63 mmol) followed by 2-iodopropane (0.04 mL, 0.42 mmol), stirred at room temperature for 2 hrs. The reaction mixture was poured on ice, and extracted with EtOAc three times. The combined organic layers were dried with sodium sulfate and concentrated to dry. The crude was purified by ISCO eluting with 100% EtOAc to give pure 6-(3-fluorophenyl)-N-isopropylpyrido[3,2-d]pyrimidin-4-amine 25. LC/MS (ESI+): m/z 283 (M+H). 1H NMR (400 MHz, DMSO) δ 8.53-8.43 (m, 2H), 8.37 (d, J=10.8 Hz, 1H), 8.21 (t, J=8.4 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 7.60 (dd, J=14.2, 8.0 Hz, 1H), 7.34 (td, J=8.5, 2.5 Hz, 1H), 4.56 (dq, J=13.3, 6.7 Hz, 1H), 1.35 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:30]=[CH:31][CH:32]=1>ClCCl.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([N:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=1)[CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)CNc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C(=O)CNC(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Boc-glycine and triethylamine (1.0 equiv.) in dichloromethane at 0° C. is added oxalylchloride (1.0 equiv). After one hour, a solution of the product from Step F (1 equiv.) in dichloromethane is added to the first solution, followed by triethylamine (1 equiv.). The solution is allowed to warm to room temperature. After complete reaction, the solution is poured into EtOAc and washed with sat. NH4Cl soln., sat. NaHCO3 soln., and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.[NH:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:18]3[N:17]([C:18]4[CH2:19][CH2:20][CH2:21][N:17]=4)[CH2:21][CH2:20][CH:19]=3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: C1=CNCC1
Reactant: Clc1ccc2c(c1)Oc1ccccc1N2
Agent: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 3-chlorophenoxazine with 2-chloro-(1-pyrrolin-;b 2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-270° C. (dec.) (corr.), from ethanol-ether.
Reaction SMILES: CC1C=CC(C)=CC=1.[Cl:9]Cl.C[C:12]1[C:17]([Cl:18])=[C:16](Cl)[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[CH3:22].[C:23](Cl)(Cl)(Cl)[Cl:24]>[Hg]>[CH3:22][C:13]1[C:12]([Cl:9])=[C:17]([Cl:18])[C:16]([CH2:23][Cl:24])=[C:15]([Cl:20])[C:14]=1[Cl:21]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(C)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCl
Agent: [Hg]
Solvent: Cc1ccc(C)cc1
Product: Cc1c(Cl)c(Cl)c(CCl)c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
530 g of p-xylene in 5 liters of CCl4 were chlorinated in the nucleus in the presence of 10 g of FeCl3 by passing chlorine over the reaction solution while stirring the latter, at a pressure of 0.06 atmospheres excess pressure, with the exclusion of light. The first half of the amount of chlorine calculated for dimethyltetrachlorobenzene was introduced into the gas chamber of the reaction vessel while the liquid phase was at a temperature of 20° C, the remainder at 40° C. The reaction time was 3 hours 30 minutes. Then, while the gas chamber in the reaction vessel was irradiated with a 250-watt mercury vapor lamp, the side-chain chlorination was performed at a liquid phase temperature of 70° C and at 0.06 atmospheres excess pressure; this required 6 hours. The total chlorine consumption was 110% of the calculated amount, with respect to xylene. After the solution cooled, 154 g of a substance crystallized, of which 75% consisted of 1,4-di-(chloromethyl)-2,3,5,6-tetrachlorobenzene. The crystallizate was suction filtered and the filtrate was stirred with 400 g of calcium hydroxide, thereby rendering the solution neutral and free of iron. The calcium hydroxide containing iron and chloride was removed on a suction filter and, after removing the CCl4 by distillation, the solution was fractionated in a packed column at 12 Torr. The main fraction distilled at 179°-193° C. 1055 g of 1-methyl-4-chloromethyl-2,3,5,6-tetrachlorobenzene was obtained in a purity of 87.6% (yield 66.7%). After recrystallization from 1,2-dichloroethane, the product had a purity of 98.9% and melted at 11°-113°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mmol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>>[ClH:47].[ClH:47].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH:45][C:28](=[O:30])[CH2:27][O:26][C:25]1[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:21][C:20]2[C:15]([NH:14][C:11]3[S:12][CH:13]=[C:9]([CH3:8])[N:10]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=1
Reactant: CN(C)CCN
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)O)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCCN(C)C)c2)n1
Yield: 56.1 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) ethyl chloroformate (0.035 mL, 0.36 mmol) and N1,N1-dimethylethane-1,2-diamine (0.079 mL, 0.72 mmol) were reacted according to the method of Example 30 to provide N-(2-(dimethylamino)ethyl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamide dihydrochloride (43.8 mg, 56.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.54 (bs, 1H), 10.76 (bs, 1H), 8.54 (t, 1H), 8.00 (d, 1H), 7.66 (d, 1H), 7.32 (m, 2H), 7.18 (m, 2H), 6.97 (dd, 1H), 6.93 (s, 1H), 5.34 (s, 2H), 4.60 (s, 2H), 3.53 (q, 2H), 3.19 (q, 2H), 2.76 (s, 6H), 2.35 (s, 3H). Mass spectrum (apci) m/z 442.1 (M+H-2HCl).
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:6][CH2:5][CH2:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[NH:3]1[CH2:4][CH2:5][O:6][CH:7]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2]1
Reactant: O=C1NCCOC1CC12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 9-(3-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (100 mg) and lithium aluminum hydride (50 mg) in dioxane was stirred at 60° - 70° C. for 3 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 183° - 189° C. Recrystallization gave colorless crystals, M.P. 189° - 190° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:23])[N:7]2[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(Cl)Cl>CCOC(C)=O.CCCCCC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:23])[N:7]2[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1cccc2ccccc12
Yield: 71 %

Procedure:
By the method used in Example 1, Part D, 1.17 g (3.9 mmol) of 4-methoxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole was O-demethylated by treating it with 15.6 mL of 1M BBr3/CH2Cl2 to give a material that was chromatographed on silica gel (eluted with 20% EtOAc/hexane then 50% EtOAc/hexane) to give 796 mg (71% yield) of 4-hydroxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:23][O:24][N:25]=[C:26]([C:30]([O:35][CH3:36])([O:33][CH3:34])[CH2:31][Br:32])[C:27](O)=[O:28].P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:23][O:24][N:25]=[C:26]([C:30]([O:35][CH3:36])([O:33][CH3:34])[CH2:31][Br:32])[C:27]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: CON=C(C(=O)O)C(CBr)(OC)OC
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C(CBr)(OC)OC
Yield: 79.8 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (2.18 g, purity 84.8%), trimethylsilylacetamide (10.5 g.), 2-methoxyimino-3,3-dimethoxy-4-bromobutyric acid (syn isomer, 3.24 g.), N,N-dimethylformamide (1.1 ml), phosphorus oxychloride (1.36 ml) and methylene chloride (50 ml.) were treated in a similar manner to that of Example 25 (1) to give 7-[2-methoxyimino-3,3-dimethoxy-4-bromobutyramido]-3-hydroxycepham-4-carboxylic acid (syn isomer, 3.75 g.).