Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([NH:10]C(=O)C)[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.Cl.[N:17]([O-])=O.[Na+]>CC(O)=O.O>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:5]([CH:9]=[N:17][NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(Cl)cc(C)c(C)c1NC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc(C)c2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(3-Chloro-2-methoxy-5,6-dimethyl-phenyl)-acetamide (3.36 g, 17.4 mmol) is dissolved in HOAc (75 mL) and conc. HCl (30 mL) in a 1 L round bottom flask. The reaction is cooled to 0° C. with an ice/salt bath. Although some starting material crystallizes, a solution of NaNO2 (5.9 g, 86 mmol) in water (25 mL) is added portion-wise over 5 min. All material goes into solution and the reacion is stoppered and stirred 45 min. HPLC shows very little sm. Ice cold water (800 mL) is was added slowly and the reaction was stirred 1 h. A precipitate forms. The solid is filtered and washed with ice cold water (500 mL). The material is dried with suction and then pumped to a constant weight 3.3 g. The solid is partially dissolved in toluene (35 mL) and stirred under N2. After stirring 18 h, the reaction is heated for 4 hours and cooled. The reaction is diluted with EtOAc and washed with NaHCO3, brine, dried (MgSO4) and concentrated. The crude product is purified by column chromatography (silica, 30% EtOAc/hexanes) to provide the desired product, 6-chloro-7-methoxy-4-methyl-1H-indazole.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10]([N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1)([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:10]([N:13]1[C:17]([C:2]2[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[N:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: OCc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1-c1nccnc1CO
Temperature: 100 °C
Yield: 36 %

Procedure:
To a mixture of (3-chloropyrazin-2-yl)methanol (200 mg, 1.4 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (393 mg, 1.67 mmol, 1.2 eq.), Pd(dppf)Cl2 (102 mg, 0.14 mmol, 0.1 eq.), and K2CO3 (580 mg, 4.2 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100° C. for 1 h, cooled to rt, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanol (110 mg, 36%) as a yellow oil. LRMS (M+H+) m/z 219.1.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([C:33](O)=[O:34])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH2:19]([O:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([C:33]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:34])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: Cn1nc(C(=O)O)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g, 3.4 mmol), 5-(benzyloxy)-1-methyl-1H-pyrazole-3-carboxylic acid (0.975 g, 4.2 mmol), triethylamine (1.39 mL, 10.0 mmol), EDCI (0.978 g, 5.1 mmol) and HOBt (0.781 g, 5.1 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 0:100). Solvent was removed to obtain a solid (1.75 g, quant.).
Reaction SMILES: [NH3:1].C(O)(=O)C.Cl[C:7]1[C:27](=[O:28])[CH2:26][CH2:25][C@@:24]2([CH3:29])[C:8]=1[CH2:9][CH2:10][C@@H:11]1[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:30])[C@H:12]1[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:19])[CH2:17][OH:18].CCOCC>O>[NH2:1][C:7]1[C:27](=[O:28])[CH2:26][CH2:25][C@@:24]2([CH3:29])[C:8]=1[CH2:9][CH2:10][C@@H:11]1[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:30])[C@H:12]1[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:19])[CH2:17][OH:18]
Reactant: N
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
Ammonia (about 8 mL) was condensed into a Carius tube which contained (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.5 g, 3.69 mmol) and which was cooled to -78° C. The tube was sealed, heated to 70° C. for one hour, and then allowed to stand at room temperature overnight. The contents of the tube were poured into a mixture of ether and water and the two layers were separated. The organic layer was extracted with 0.5N hydrochloric acid and the resulting acidic, aqueous solution was washed with ether and then made alkaline with 1N aqueous sodium hydroxide. The resulting alkaline, aqueous mixture was extracted with ether and the ether extracts were dried over magnesium sulfate and concentrated to a yellow, foamy solid. This residue was dissolved in methanol (25 mL) and 2N hydrochloric acid (2 mL) and the resulting mixture was heated to reflux for 15 minutes and then allowed to cool to room temperature. The mixture was extracted with ether, then made alkaline with solid sodium carbonate, and extracted with ether. The organic extracts of the alkaline, aqueous solution were dried over magnesium sulfate and concentrated to give (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one as an off-white solid (50 mg, 4%). This compound has the following structure: ##STR7##
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>O>[OH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)c1ccc2ccccc2c1O
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a 500-mL, three-neck, nitrogen-purged flask were added 28.8 g (0.20 mole) of 1-naphthol and 90 mL of toluene. To this stirred slurry was added 26.6 g (0.20 mole) of anhydrous aluminum chloride in portions over five minutes. The temperature of the mixture rose to 40°-50° C. during this addition. The orange slurry was heated to reflux, then 32.0 g (0.204 mole) of phenyl chloroformate was added over a period of 30 minutes. After this addition, the mixture was refluxed for 30 minutes then cooled to 30°-40° C. To the red reaction mixture was added 100 mL of water while holding the temperature at 35°-50° C. This addition is very exothermic initially, and ice bath cooling is used. During addition of the remaining water, the bath is lowered or removed in order to avoid cooling below 35° C. After this addition, 20 mL of 32% hydrochloric acid was added quickly at 35° -50° C. The mixture was stirred for 15 minutes, then the layers are allowed to separate. The lower (aqueous) layer was discarded. The top layer was washed (at 40°-50° C.) successively with: two 100-mL portions of 10% hydrochloric acid and two 100-mL portions of 40°-50° C. water. The solvent was then stripped off under vacuum (150-200 mm) to a pot temperature of 90° C. To the resulting amber liquid was added 120 mL of isopropyl alcohol at 70° C. The solution was cooled slowly to 0°-5° C. After stirring at 0°-5° C. for one hour, the slurry was filtered and the solids washed with three 25-mL portions of 0°-5° C. isopropyl alcohol. The yellow solids were air dried at 40° C. to give 31.5 g (59.7%) of phenyl 1-hydroxy-2-naphthoate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C:14]2([C:16]#[N:17])[CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:17][CH2:16][C:14]12[CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]1[CH2:11][O:12][CH2:13]2
Reactant: N#CC12COCC1CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC12COCC1CN(Cc1ccccc1)C2

Procedure:
3.7 g (15.9 mmol) of 7-benzyl-1-cyano-3-oxa-7-azabicyclo[3.3.0]octane in 5 ml of absolute tetrahydrofuran are added dropwise to a mixture of 1.5 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran and the resulting mixture is heated under reflux for 15 hours. Decomposition is effected with 1.5 ml each of water, 15% strength sodium hydroxide solution, and again water, and the mixture is filtered with suction, and the aluminium salts are extracted by boiling on two occasions with 100 ml of tetrahydrofuran. The tetrahydrofuran solutions are concentrated and the residue is distilled. Yield: 3.2 g (86% of theory) Boiling point: 125°-130° C./0.04 mbar
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[C:10]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][C:19]=2[C:20](O)=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:21])[C:19]1[CH:23]=[C:24]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:18]=1[O:17][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cnccc1CO
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cnccc1CO)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Neat (3-aminopyridin-4-yl)methanol (may be prepared as described in Description 81; 103 mg, 0.83 mmol) was added in one charge to a stirred suspension of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 180 mg, 0.59 mmol), EDC (226 mg, 1.18 mmol), HOBT (181 mg, 1.179 mmol) and triethylamine (0.16 ml, 1.18 mmol) in N,N-dimethylformamide (1.5 ml) in air at 15° C. The reaction mixture was stirred at 15° C. overnight. 100 ml of water was added. The solid was filtered, and then purified by prep-HPLC (instrument: Gilson-281, Column: Shimadzu 15 um: 250*20 mm*2, Mobile Phase: A: 10 mMol/LNH4HCO3, B: CH3CN, Flow rate: 30.0 ml/L, Gradient: B: 43-55% in 0-7.2 RT=7.5 min, 10.5) to yield the title compound as a white solid. 57 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CCCCC[Mg]Br
Product: CCCCCC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (3.92 g) and pentylmagnesium bromide (2.0 M diethyl ether solution, 12 ml) to give 1-(3,4,5-trimethoxyphenyl)-1-hexanone (3.27 g).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Br.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([CH:27]=1)[NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)(C)C.O>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:19]2[CH:27]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=2[N+:28]([O-:30])=[O:29])[CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NC1CCNCC1
Reactant: BrCC1COc2ccccc2O1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)C(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
11.5 g of 2-bromomethyl-1,4-benzodioxane, 20.4 g of 4-(5-chloro-2-nitroanilino)-piperidine hydrobromide, 20 g of potassium carbonate and 0.5 g of potassium iodide were dissolved in 120 ml of methyl isopropyl ketone and the solution was heated under reflux for 24 hours. After the mixture had been cooled, water was added and the organic phase was separated off, dried and concentrated.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:35][CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: NC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4CCOCC4)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 0.04 h
Yield: 23.1 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), Tetrahydro-pyran-4-ylamine (145 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 2.5 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 80 mg of 250. (yield=29%). 1H NMR (CDCl3, 400 MHz): δ8.03 (s, 1H), 7.50-7.44 (m, 1H), 7.09-6.99 (m, 4H), 6.18 (d, J=8.8 Hz, 1H), 4.06-4.02 (m, 1H), 3.96-3.90 (m, 2H), 3.84-3.76 (m, 1H), 3.50-3.41 (m, 2H), 3.06-3.03 (m, 2H), 1.48-1.40 (m, 2H). LC-MS (ESI): m/z=482 [M+H]+
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH3:17])[CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:8][CH:7]1[CH:6]([CH3:17])[O:5][S:1](=[O:2])[N:9]1[C:10]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC(O)C(C)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1OS(=O)N(C(=O)OC(C)(C)C)C1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A stirred solution of thionyl chloride (4.1 mL, 56.8 mmol) in acetonitrile (30 mL) is cooled to −45° C. A solution of tert-butyl (3-hydroxybutan-2-yl)carbamate (4.3 g, 22.7 mmol) in acetonitrile (40 mL) is added by syringe over about 10 min, keeping the internal temperature below −40° C. When the addition is completed, 4-dimethylamino pyridine (278 mg, 2.3 mmol) is added. Then pyridine (9.2 mL, 114 mmol) is added dropwise by syringe, keeping the temperature below −40° C. The reaction mixture is stirred at −40° C. for 1 hr. Ethyl acetate (70 mL) is added to the suspension and the mixture is filtered at −35° C. The solid is washed with EtOAc and the filtrates are combined. Saturated Na2HPO4 solution (40 mL) is added and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4, dried (MgSO4) and concentrated to afford the title compound (4.8 g, 90%) as an oil.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:20](=[O:55])[NH:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:31]3[C:36]4[S:37][C:38]([C:40]5[C:45]([F:46])=[CH:44][N:43]=[C:42]([NH:47][CH2:48][CH2:49][N:50]6[CH:54]=[CH:53][N:52]=[N:51]6)[N:41]=5)=[CH:39][C:35]=4[CH:34]=[CH:33][CH:32]=3)[CH3:23])[CH3:19])C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.C(Cl)(Cl)Cl.C(O)(C)C>[N:50]1([CH2:49][CH2:48][NH:47][C:42]2[N:41]=[C:40]([C:38]3[S:37][C:36]4[C:31]([C:25]5[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=5[C@H:22]([NH:21][C:20](=[O:55])[C@H:18]([NH2:17])[CH3:19])[CH3:23])=[CH:32][CH:33]=[CH:34][C:35]=4[CH:39]=3)[C:45]([F:46])=[CH:44][N:43]=2)[CH:54]=[CH:53][N:52]=[N:51]1
Reactant: CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC(C)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: C[C@@H](N)C(=O)N[C@H](C)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Dissolve {1-[1-(4-fluoro-2-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-phenyl)-ethylcarbamoyl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (129 mg, 167 μmol) in piperidine (5 mL). Stir the mixture at RT for 30 min and then dilute with chloroform/IPA (3/1, 100 mL). Wash the organic phase with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by FCC (10% methanol in DCM to chloroform/methanol/ammonium hydroxide (7/3/0.05) as a gradient to give the title compound as a yellow solid (72 mg, 78%). MS (ES) m/z 549 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CS(C)=O.[CH3:14][C@H:15]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16][CH2:17][OH:18]>C(N(CC)CC)C>[CH3:14][C@H:15]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23])[CH2:16][CH:17]=[O:18]
Reactant: C[C@@H](CCO)CCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CC=O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 56.3 g. of oxalyl chloride in 300 ml. of dry methylene chloride cooled to -60° C. and under a nitrogen atmosphere was added dropwise 74.81 g. of dimethylsulfoxide in 100 ml. of dry methylene chloride. After 15 minutes 92.0 g. of 3-(S)-methyl-5-(t-butyldimethylsilyloxy)-1-pentanol in 250 ml. of the same solvent was added dropwise. After 30 minutes 206.1 g. of triethylamine was added to -60° C. followed by the removal of the cooling bath. The reaction was stirred at room temperature for 1.5 hours, and was then poured into water and extracted with methylene chloride. The extracts were washed with 2.5% hydrochloric, a saturated sodium bicarbonate solution, water and a brine solution, and then dried over magnesium sulfate. The solvent was removed and the residue dissolved in ether and rewashed and dried as before. Removal of the ether gave 90.9 g. of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:38][C@@H:39]([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=1)[CH2:40][N:41]([CH3:54])[S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:38][C@@H:39]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[CH2:40][N:41]([CH3:54])[S:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[N+:51]([O-:53])=[O:52])(=[O:43])=[O:44])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CN(C[C@@H](N)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (1.55 g, 4.88 mmol) in DMF (16.28 mL) was added HOAt (0.997 g, 7.33 mmol), EDC (1.498 g, 7.82 mmol) DIEA (2.61 m l, 14.65 mmol) and (S)—N-(2-amino-2-(3-chlorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide (2.084 g, 5.13 mmol). The reaction mixture was stirred at room temperature for 3 h, and LCMS indicated the reaction was completed. The reaction mixture was diluted with EtOAc, and the organic was washed by sat.Na2CO3, water and brine, dried over Na2SO4, filtered off, and concentrated. The crude material was purified by flash chromatography eluting with 50% DCM/EtOAc (10% methanol) to provide (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (2.68 g, 4.01 mmol, 82%). LCMS: 669.1 (MH+), 0.95 min.
Reaction SMILES: [CH3:1]OC1C(OC)=CC2NC(=O)CN=C(C3C=CC=CC=3)C=2C=1.[CH2:23]([O:25][C:26]1[C:43]([O:44][CH3:45])=[CH:42][C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:31][CH2:32][C:33](=[O:35])[NH:34][C:28]=2[CH:27]=1)[CH3:24].C1(=O)OCCO1.IC>>[CH2:23]([O:25][C:26]1[C:43]([O:44][CH3:45])=[CH:42][C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:31][CH2:32][C:33](=[O:35])[N:34]([CH3:1])[C:28]=2[CH:27]=1)[CH3:24]
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Solvent: O=C1OCCO1
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2C
Yield: 69 %

Procedure:
By replacing in the example 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (XXIIaa) by 8-ethoxy-7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIam), and ethylene carbonate by iodomethane, and proceeding in the same manner, the abovenamed product is obtained. Yield: 69%. M: 138–140° C. 1H-NMR (CDCl3, 200 MHz): d 1.54 (t, 3H, CH3), 3.38 (s, 3H, NCH3), 3.74 (s, 3H, OCH3), 4.18 (q, 2H, —OCH2), 4.29 (AB system, ? d=0.98, JAB=10.5, 2H, —CH2), 6.70 (s, 1H Ar), 6.77 (s, 1H Ar), 7.39–7.43 (m, 3H Ar), 7.63–7.68 (m, 3H Ar).
Reaction SMILES: BrCC[Te](Br)(Br)[CH2:5][CH2:6][Br:7].O=O.[C:12]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=[O:14])[CH3:13].[Br:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].C(Br)C[Br:31].C=C.C(O)CO>C(O)(=O)C>[C:12]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=[O:14])[CH3:13].[Br:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].[Br:31][CH:6]([Br:7])[CH3:5]
Reactant: BrCCBr
Reactant: BrCC[Te](Br)(Br)CCBr
Agent: C=C
Agent: CC(=O)OCCBr
Agent: O=O
Solvent: OCCO
Solvent: CC(=O)OCCOC(C)=O
Solvent: CC(=O)O
Product: CC(Br)Br
Reaction time: 1 h

Procedure:
1.05 g. (2.09 mmoles) of bis(2-bromoethyl)-tellurium dibromide, from Example 2, along with 4.0 g. glacial acetic acid (99.5 percent) was charged to a "Fisher-Porter" 35 ml. glass tube reactor equipped with a gas inlet and outlet tube, a pressure gauge and relief valve and a magnetic stirrer. The mixture was heated at a temperature of 150° C. under 16 psig oxygen with stirring for 1 hour. The reaction mixture was cooled and the products analyzed by gas liquid partition chromagraph (glpc.) showed 3.10 mmoles of ethylene glycol diacetate, 0.79 mmoles of 2-bromoethylacetate, 0.12 mmoles ethylene dibromide and a trace amount of ethylene. Based on stoichiometry that one mole of bis(2-bromoethyl)tellurium dibromide yields two moles of ethylene glycol precursors, i.e., ethylene glycol diacetate, 2-bromoethylacetate and dibromoethane, the mass balance was calculated to be 96 mole percent.