Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.I[CH3:21]>C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:12]([CH3:21])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CI
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.5 g, 5.7 mmol) and iodomethane (0.9 g, 6.3 mmol) in saturated NaHCO3 (25 mL) was stirred at 60° C. overnight. The mixture was filtered. The solid was concentrated under vacuum to afford ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 69.9% yield). The mixture was used directly without further purification.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21].C(N(CC)CC)C>>[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH:21][C:9]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]1)=[O:11]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(F)cc2F)CC1
Yield: 75 %

Procedure:
1-Carboethoxycyclopropanecarboxylic acid 7.00 grams, 0.04 mole), ethyl chloroformate (4.8) grams, 0.04 mole) and 2.4-difluoroaniline (5.72 grams, 0.04 mole) were reacted sequentially in the presence of triethylamine (4.51 grams, 0.04 mole) in a manner similar to that described in Example XXXIII to give 7.13 grams (0.03 mole) of ethyl 1-(2,4-difluorophenylaminocarbonyl)cyclopropanecarboxylate as a white crystalline solid having a melting point of 79° C.-80.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:18]([F:28])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[CH2:14][N:15]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:18]([F:28])[CH:17]=2)[C:43]([C:39]2[S:38][CH:42]=[CH:41][CH:40]=2)=[O:44])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CC2C(CNc3ccc(N4CCOCC4)c(F)c3)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2CN(C(=O)c1cccs1)c1ccc(N2CCOCC2)c(F)c1
Reaction time: 2 h

Procedure:
To a stirring solution of 6-[(3-Fluoro-4-morpholin-4-yl-phenylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (500 mg, 1.28 mmol) in 10 mL of DCE at room temperature was added DIEA (0.33 mL, 1.92 mmol) and 2-thiophenecarbonylchloride (0.21 mL, 1.92 mmol). After 2 hours, saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was taken up in 50% EtOAc/hexanes and the white solids were filtered off. The remaining filtrate was concentrated under reduce pressure to yield 640 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.26-7.28 (m, 1H), 6.83-7.15 (m, 4H), 6.76-6.78 (m, 1H), 3.79-3.85 (m, 5H), 3.54-3.59 (m, 1H), 3.44 (d, J=11.0 Hz, 1H), 3.39 (d, J=11.0 Hz, 1H), 3.21-3.26 (m, 2H), 3.08-3.10 (m, 4H), 1.36-1.38 (m, 11H), 0.81-0.86 (m, 1H); MS M+1)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:3][C:4]1[N:5]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cccc(O)c1
Reactant: ClCc1nccn1C1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(OCc2nccn2C2CCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a mixture of 2-chloromethyl-1-(tetrahydro-furan-2-yl)-1H-imidazole hydrochloride, (5.7 g, 30.6 mmol), 3-methoxyphenol (7.6 g, 61.2 mmol) and DMSO (30 mL) was added K2CO3 (12.7 g, 91.8 mmol). The mixture was stirred at ambient temperature under N2 overnight. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were washed with 2N NaOH, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2 hexane/EtOAc) to provide the desired 2-(3-methoxy-phenoxymethyl)-1-(tetrahydro-furan-2-yl)-1H-imidazole (3.49 g, 41%) as a colorless oil: ESI MS m/z 275 [C15H18N2O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=Cc2ccc(F)cc2)C(F)(F)F)cc1
Yield: 87 %

Procedure:
4'-Methoxy-2,2,2-trifluoroacetophenone (R. Fuchs: J. Org. Chem. 22, 993-994 (1957)) is reacted with triphenyl(4-fluorobenzyl)-phosphonium chloride (see Example 18) in ethanol in the presence of sodium ethoxide. 3,3,3-Trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene is obtained with a yield of 87%; b.p.: 138°-142° C./0.5 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([NH2:22])=[CH:17][C:16]=1[CH3:23]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:12]=[N:22][C:18]3[C:19](=[CH:20][C:15]([CH3:14])=[C:16]([CH3:23])[CH:17]=3)[N:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCO
Product: Cc1cc2ncc(-c3ccc([N+](=O)[O-])cc3)nc2cc1C

Procedure:
0.50 g (3 mmol) 4-nitrophenyl glyoxal was dissolved in 20 ml ethanol. 0.34 g (2.5 mml) 1,2 dimethyl 4,5 diaminobenzene was dissolved in ethanol. The reaction mixture was stirred and refluxed for 1 hour. Product crystallized after cooling, and filtrated washing with ethanol then ether.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[CH:15][C:14]=1[OH:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[OH:27])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N[C@H](CO)Cc1ccccc1)c1cc(OCc2ccccc2)ccc1O
Solvent: CO
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(O)ccc1O
Reaction time: 2 h
Yield: 85 %

Procedure:
In a flask equipped with a magnetic stirring bar and a rubber septum is dissolved the N-{(S)-1-hydroxy-3-phenyl-2-propyl}-5-benzyloxy-2-hydroxybenzamide in methanol. Nitrogen is bubbled through the solution and 10% Pd on charcoal is added. After flushing with nitrogen, the suspension is placed under hydrogen atmosphere and stirred for 2 hours. The suspension is flushed with nitrogen and filtered and rinsed over Celite. The filtrate is concentrated under vacuum. In this fashion is obtained N-{(S)-1-hydroxy-3-phenyl-2-propyl}-2,5-dihydroxybenzamide (85%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: Cc1ccncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1SCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a solution of 3-bromo-4-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1→1:1) to give the title compound as a yellow oil (yield 740 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(Cl)cc1C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
(Step 1) To a solution of 4-chloro-2-methylbenzoic acid (5.0 g) in methanol (40 ml) was added concentrated sulfuric acid at room temperature. The mixture was stirred at 70° C. for 3 hr, neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19→3:7) to give methyl 4-chloro-2-methylbenzoate (5.05 g) as an oil.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:16])=O>>[Cl:16][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Product: FC1(F)Oc2ccc(CCl)cc2O1
Yield: 89 %

Procedure:
A solution of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (120 g, 0.64 mol) in neat thionyl chloride (500 mL) was stirred for 2 h at 25° C. The excess thionyl chloride was distilled off in vacuo. The residue was partitioned between saturated NaHCO3 (400 mL) and dichloromethane (200 mL). The separated aqueous layer was extracted with dichloromethane (300 mL×3). The combined organic layers were dried, filtered and concentrated in vacuo to give 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole (117.6 g, 89%), which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1C(O)=NC=[N:6][C:7]=1[NH2:8].[OH-].[Na+].Br[CH:13](Br)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>>[F:16][C:15]([F:18])([F:17])[C:14]1[N:1]=[CH:2][C:7]([NH2:8])=[N:6][CH:13]=1
Reactant: Nc1ncnc(O)c1N
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1cnc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
To an ice bath-cooled solution of 5,6-diaminopyrimidin-4-ol (18 g, 143 mmol) in 3M sodium hydroxide (180 mL, 540 mmol), was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (25.2 g, 93 mmol). The reaction was stirred for 3 days at ambient temperature. The solids were filtered, dissolved in 60% sulfuric acid (140 mL), and stirred at 135° C. for 8 h. The reaction was cooled, poured over ice and allowed to sit for 16 hours. The solution was neutralized to pH 8 with conc. ammonium hydroxide and extracted with ethyl acetate (5×100 mL), dried over sodium sulfate, filtered and concentrated. The solid residue was recrystallized from benzene/hexane to afford 5-(trifluoromethyl)pyrazin-2-amine (2.28 g, 14 mmol, 15% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1H, s), 7.99 (1H, d, J=1.26 Hz), 5.02 (2H, br. s.). MS (LC/MS) R.T.=1.56; [M+H]+=164.03.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=O)[NH:8][N:7]=1.P(Cl)(Cl)([Cl:18])=O>ClC(Cl)C>[Cl:18][C:9]1[N:8]=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[C:11]2[S:12][CH:13]=[CH:14][C:10]=12
Reactant: O=c1[nH]nc(-c2cccs2)c2sccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2cccs2)c2sccc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 95.8 %

Procedure:
0.30 g of 7-(2-thienyl)thieno[2,3-d]pyridazine-4(5H)-one and 0.30 g of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 10 hours. The reaction solution was concentrated, and a 1-N aqueous KOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried. The solvent was distilled off, thereby obtaining 0.31 g of 4-chloro-7-(2-thienyl)thieno-[2,3-d]pyridazine.
Reaction SMILES: [C-:1]#[N:2].[K+].[N+:4]12[CH2:11][CH2:10][CH2:9][C:8]=1[CH2:7][CH2:6][CH2:5]2>O>[C:1]([C:8]12[CH2:9][CH2:10][CH2:11][N:4]1[CH2:5][CH2:6][CH2:7]2)#[N:2]
Reactant: [C-]#N
Reactant: C1CC2=[N+](C1)CCC2
Agent: [K+]
Solvent: O
Product: N#CC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of potassium cyanide (0.191 g, 2.86 mmol) in 1.0 ml of water was added over 20 minutes 0.284 g (1.35 mmol) of 1-azoniabicyclo[3.3.0]oct-1(5)-ene (Example 3). The mixture was stirred at 20° C. for 1 hour. To the reaction mixture was added 2 ml of water and extracted with methylene chloride (3×10 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was distilled out in vacuo to afford 171 mg (Yield: 93.3%) of the desired compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (861 mg, 9.7 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 30 mg of the title compound as an off-white solid. MS: (+) m/z 472.41 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[S:17][C:16]3[N:18]=[CH:19][CH:20]=[N:21][C:15]=3[N:14](COC)[C:13]=2[CH:25]=1)(=O)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[N:26]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[NH:14][C:13]=3[CH:25]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: COCN1c2cc(CCCOS(C)(=O)=O)ccc2Sc2nccnc21
Product: c1cn(CCCc2ccc3c(c2)Nc2nccnc2S3)cn1

Procedure:
Similar to Example 1094, 3-[10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propyl methanesulfonate was reacted with imidazole and then treated by the same method as the one of Example 434 to thereby give the following compound.
Reaction SMILES: C([NH:8][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CCOC(C)=O>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(Br)cc1

Procedure:
Prepared according to the method described in Example 1(b) above from crude (R)-N2 (Boc)-N5 -(Cbz)-(S)-N-[1-(4-bromophenyl)ethyl]ornithine amide (9.1 mmol; from step (a) above), EtOAc (100 mL) and HCl/EtOAc (75 mL), 2 hours reaction time. The solution was concentrated to give the crude product as a yellow crushable foam (5.4 g) which was used without purification.
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7](O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)([Br:15])=O>CN(C=O)C>[Br:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:10][C:9](=[O:11])[CH:8]=1
Reactant: CC(C)(C)c1cc(O)cc(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)cc(=O)[nH]1
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To a solution of compound 17a (9.7 g, 60 mmol) in DMF (100 mL) was added POBr3 (17.2 g, 60 mmol) and the mixture was heated at 90° C. for 2 h. Then the resulting mixture was concentrated. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, concentrated and purified by CC (PE/EA=5/1) to give compound 17b (11 g, 80%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][S:29](O)(=[O:31])=[O:30]>C(Cl)Cl>[CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:29]([Cl:28])(=[O:31])=[O:30])=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (−78° C.) solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 19; 2.70 g; 7.41 mmol) in DCM (27 ml) was treated dropwise with a solution of chlorosulfonic acid (2.48 ml; 37.0 mmol) in DCM (2 mL). The reaction mixture was allowed to warm to RT, then it was stirred at RT for 16 hours. The solution was cooled again (−78° C.) and treated with a second aliquot of chlorosulfonic acid (0.99 ml; 14.8 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was cooled to 5° C. and a mixture of ice/water was carefully added. The resulting precipitate was filtered and dried under vacuum to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[I-:11].[Na+].O>CC(C)=O>[I:11][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10]
Reactant: [I-]
Reactant: C=Cc1ccccc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=Cc1ccccc1CI
Yield: 95 %

Procedure:
Dissolve 1-chloromethyl-2-vinyl-benzene (4.0 g, 26 mmol) in acetone (100 mL) and add sodium iodide (4.5 g, 30 mmol). Heat at gentle reflux for 30 minutes. Cool, add water (150 mL) and extract with pentane (200 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (95%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: c1ccc(CCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
3 ml of 50% by volume aqueous dimethylamine were added to a solution of 0.45 g of 2-[2-(3-phenylpropyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.31 g (yield 59%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32](O)=[O:33])=[CH:4][N:3]=1.[CH3:35][O:36][CH:37]([O:40][CH3:41])[CH2:38][NH2:39].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:39][CH2:38][CH:37]([O:40][CH3:41])[O:36][CH3:35])=[O:33])=[CH:4][N:3]=1
Reactant: COC(CN)OC
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COc1cc(-c2csc3c(C(=O)NCC(OC)OC)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (1.0 g, 2.1 mmol) and 2,2-dimethoxy-1-ethanamine (252 uL, 2.3 mmol) were reacted according to General Procedure D. MP-carbonate resin (5 g) was added, and the mixture was shaken for 2 hours. The resin was filtered from the mixture and the filtrate was concentrated in vacuo to yield 1.5 g crude material. Isopropyl alcohol (35 mL) was added and the crude product was triturated and filtered to yield the title compound (830 mg, 71% yield): 1H NMR (DMSO, 400 MHz) δ 9.48 (s, 1H), 8.56 (s, 2H), 7.98 (d, 1H), 7.69 (d, 1H), 7.56-7.58 (m, 2H), 7.31-7.33 (m, 2H), 7.04-7.17 (m, 3H), 4.54 (t, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 3.37 (t, 2H), 3.31 (s, 6H), 2.51 (t, 2H); RP-HPLC (Conditions j) Rt 12.2 min. MS: 560.0 MH+.