Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cccc(F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11].F[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])=[CH:6][C:5]=1[F:11]
Reactant: O=[N+]([O-])c1ccncc1F
Reactant: Nc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccncc1Nc1ccc(Cl)c(F)c1
Reaction time: 18 h
Yield: 22 %

Procedure:
NaH (422 mg, 60% dispersion in mineral oil, 10.6 mmol) was suspended in THF (20 mL) and 4-chloro-3-fluoroaniline (1.54 g, 10.6 mmol) and 3-fluoro-4-nitropyridine (500 mg, 3.52 mmol) were added. The reaction mixture was stirred for 18 h, quenched with sat aq NH4Cl (2 mL), and concentrated in vacuo. The residue was partitioned between water (50 mL) and DCM (50 mL) and the organic fraction was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (207 mg, 22.0%) as an orange solid. LCMS (ES+): 268.0 [MH]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])(O)[CH3:3]>C(OC(=O)C)(=O)C>[C:8]([O:12][C:6]1[CH:7]=[C:8]([O:11][C:6](=[O:12])[CH3:5])[CH:9]=[CH:10][C:5]=1[C:2]([CH3:3])=[CH2:1])(=[O:11])[CH3:7]
Reactant: CC(C)(O)c1ccc(O)cc1O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)c1ccc(OC(C)=O)cc1OC(C)=O
Reaction time: 0.5 h
Yield: 142299.41 %

Procedure:
Compound (23) (1.7 g, 0.012 mmol) was dissolved in acetic anhydride (3.3 ml), and the solution was stirred for 30 minutes, and refluxed for four hours. The reaction solution was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=6/1), to obtain 2 g (85%) of pure compound (24).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:19]1
Reactant: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
H2O2 (70%, 1.4 mL, ca. 28 mmol) was added dropwise to a stirred solution of TFAA (4.0 mL, 28 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 34 (890 mg, 2.8 mmol) and TFA (1.1 mL, 14 mmol) in DCM (35 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 35 (390 mg, 42%) as a red solid: mp 152° C. (dec.); 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.30 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.67-3.72 (m, 2H, CH2N), 3.54 (dt, J=5.9, 5.5 Hz, 2H, CH2N), 3.25 (s, 3H, OCH3), 3.11 (dt, J=7.4, 0.9 Hz, 2H, H-6), 3.06 (dt, J=7.4, 1.1 Hz, 2H, H-8), 2.95-2.99 (m, 2H, CH2N), 2.78 (t, J=5.9 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.8, 115.8, 111.6, 69.9, 61.5 (2), 58.0, 56.0, 39.5, 33.4, 32.4, 25.6; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C16H21N5O3.0.15CH2Cl2: C, 56.4; H, 6.2; N, 20.4. Found: C, 56.2; H, 6.1; N, 20.4%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[O:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1)#[N:2]
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Oc2ccc(B(O)O)cc2)ccc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[C:7]1=[O:19])[CH3:4].[C:20]1([N:26]2[C:30]3([CH2:35]CNC[CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:17][CH3:18])[C:7](=[O:19])[CH:6]([CH2:5][N:3]1[CH2:4][CH2:35][C:30]3([N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][NH:28][C:29]3=[O:36])[CH2:31][CH2:2]1)[CH2:14]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CN(C)C)C2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Yield: 90.2 %

Procedure:
2-[(Dimethylamino)methyl]-5,6-dimethoxy-1-indanone, hydrochloride (1:1) (2.0 g) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1.94 g) are stirred for 20 hours in 20 ml of absolute ethanol while a slow stream of nitrogen is bubbled through. The resultant precipitate is filtered off and dried to yield 2.75 g of the title compound, melting point 174°-177° C.
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH:13]2[C:25](=[O:26])[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH3:27])[C:16]=3[CH2:15][CH2:14]2)[N:8]=[CH:7]1)(=O)=O>Cl.C(O)C>[CH3:27][N:17]1[C:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:9]3[N:8]=[CH:7][NH:6][C:10]=3[CH3:11])[C:25](=[O:26])[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Agent: Cl
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 89.1 %

Procedure:
A solution of N,N,5-trimethyl-4-[(2,3,4,9-tetrahydro-9-methyl-4-oxo-1H-carbazol-3-yl)methyl]-1H-imidazole-1-sulphonamide (400 mg) in 2N hydrochloric acid (30 ml) and absolute ethanol (5 ml) was heated at 100°-110° for 8 h. Work up and FCC as described in Example 32 gave the title compound (261 mg) as a solid. The 1H-n.m.r. and t.l.c. of this material were consistent with those obtained for the product of Example 8.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (5.5 g, 45 mmol) was added dropwise to a solution of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (15.00 g, 40.67 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (200 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.01 g) was added. The stirring was continued, and over the course of five hours, a total of 13 g of ethoxyacetyl chloride was added. The work-up procedure described in Part A of Example 19 was followed to provide N-[2-chloro-4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)quinolin-3-yl]-2-ethoxyacetamide as an orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@@H:7]2[C@H:3]1[CH2:4][C:5](=[O:8])[CH2:6]2.[C:10](OCC)(=[O:13])[CH2:11][CH3:12]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1([CH3:9])[CH:7]2[CH:3]1[CH2:4][C:5](=[O:8])[CH:6]2[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CC1(C)[C@@H]2CC(=O)C[C@@H]21
Reactant: CCOC(=O)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCC(=O)C1C(=O)CC2C1C2(C)C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of (1S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (2.0 g, 16.1 mmol, step f above) in THF (20 mL) is treated with K. tert.-butylate (1.99 g, 17.7 mmol). The dark brown solution is stirred at rt for 30 min before ethyl propionate (18.5 mL, 161 mmol) is added. Stirring is continued at rt for 1 h. The mixture is diluted with 10% aq. citric acid and extracted with diethyl ether. The organic extract is washed with brine, dried over NaSO4 and the solvent is evaporated to leave rac-(1S,5R)-6,6-dimethyl-2-propionyl-bicyclo[3.1.0]hexan-3-one (2.35 g) as a brown oil. LC-MS: tR=0.99 min, [M+1]+=181.29, 1H NMR (CDCl3): δ 2.64 (dd, J=7.6, 20.0 Hz, 1H), 2.36-2.22 (m, 3H), 1.75 (d, J=7.6 Hz, 1H), 1.30-1.22 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 1.10 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)=O)[CH2:3][CH2:2]1.CSC.B>C1COCC1>[N+:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=1)[CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
In a round bottomed flask morpholino(3-nitro-5-(trifluoromethyl)phenyl)methanone (1.60 g, 5.25 mmol) was dissolved in 8 mL of anhydrous THF and cooled to 0 C. To this solution, a 2 M solution of Borane-dimethyl sulfide (10.5 mL, 21 mmol) in THF was added dropwise. The reaction was stirred overnight while warming to room temperature. The solution was then concentrated to an oil. This was partitioned between dichloromethane and water, then basified with 1 M sodium hydroxide solution, and extracted twice. The extracts were combined, washed with water and brine. They were then dried over magnesium sulfate, filtered and concentrated and purified by silica gel chromatography (using a 0-50% ethyl acetate/hexane gradient) to afford 4-(3-nitro-5-trifluoromethyl-benzyl)-morpholine (409 mg, 27% yield). 1H NMR (DMSO-d6) δ 8.46 (s, 1H), 8.4 (s, 1H), 8.15 (s, 1H), 3.7 (s, 2H), 3.6 (m, 4H), 2.4 (s, 4H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][C:36]=1[CH3:44]>C1COCC1>[Br:1][CH2:42][C:41]([C:38]1[CH:39]=[CH:40][C:35]([Br:34])=[C:36]([CH3:44])[CH:37]=1)=[O:43]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CBr)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
Trimethyl phenylammonium tribromide (13 g, 0.036 mol) was added to a solution of 1-(4-bromo-3-methyl-phenyl)-ethanone (6.3 g, 0.030 mol) in THF (30 mL) and the reaction mixture was stirred at RT for 12 h, filtered, and concentrated to provide the title intermediate (8.6 g, 100% yield). 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.82 (m, 1H), 7.66 (m, 2H), 4.38 (s, 2H), 2.56 (s, 3H)
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:12][N:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1.CCOCC.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([S:52]([O:8][CH2:9][C@H:10]2[CH2:12][N:11]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])(=[O:54])=[O:53])=[CH:50][CH:51]=1)([O-:45])=[O:44]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]1COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of tert-butyl (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)aziridine-1-carboxylate (prepared following literature procedures: Travins, J. M.; Etzkorn, F. A. Tetrahedron Lett. 1998, 39, 9389-9392) in THF/Et2O (1/1) (0.17 M) was cooled in an ice bath and treated dropwise over 20 min with 1 M TBAF in THF (1.05 eq). The resulting solution was stirred in the ice bath for 30 min, before being quenched by the addition of sat. aq. NaHCO3 and extracted into Et2O/PE (4/1). The organic layers were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was taken up in dry DCM (0.17 M) and TEA (1.3 eq) introduced prior to cooling to 0° C. DMAP (0.1 eq) and 4-nitrobenzenesulfonyl chloride (1.1 eq) were added and the resulting mixture left to stir at RT overnight. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3, water and brine before drying over Na2SO4, filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 80:20) to afford the title compound as an off-white solid (57%). (ES+) m/z 359 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH:8]=[C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:24])[O:3]1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])=[CH:8][C:7]=2[C:2]([CH3:25])([CH3:1])[O:3][C:4]1=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)OC(C)(C)c2cc(OS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a stirred solution of (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate (0.50 g, 1.24 mmol) in dimethylformamide (DMF) (6 mL) with potassium carbonate (0.51 g, 3.72 mmol) was added methyl iodide (0.1 mL, 1.60 mmol). After stirring overnight at room temperature, the solution was then quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave (1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (0.30 g, 59%). 1H NMR (DMSO-d6): δ 8.14 (dd, J=8.1, 1.5 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.12 (s, 2H), 7.00 (m, 1H), 3.25 (s, 3H), 1.49 (s, 6H). MS (ESI) m/z 416/418/420 ([M+H]+); Anal. calcd for C17H15Cl2NO5S: C, 49.05; H, 3.63; N, 3.36. Found: C, 49.01; H, 3.44; N, 3.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:15]=1C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:21]3[CH:22]=[C:14]([OH:13])[CH:15]=[CH:19][C:20]=3[OH:23])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: Oc1ccc(O)c(-c2nc3ccc(O)cc3o2)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 2,5-dimethoxybenzoic acid and was obtained as a tan solid, m.p. 278–280° C.; MS m/e 244 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:21](CC)CC>CN(C=O)C.Cl[Hg]Cl>[C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:21])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.2 %

Procedure:
To a solution of 205 (340 mg, 1.6 mmol), N,N'-bis-tert-butoxycarbonylthiourea (442 mg, 1.6 mmol, prepared according to literature procedure: Synthetic Commun.1993, 23, 1443.), and Et3N (292 mL, 3.36 mmol) in DMF (4 mL) at 0° C. was added HgCl2 (478 mg, 1.76 mmol) and the mixture was allowed to warm to rt overnight, stirring a total of 20 h. The crude product was isolated in the same manner as described in Example 201 and the was chromatographed on silica gel (5% ethyl acetate/dichloromethane) to afford bis-Boc-guanidine 206 (229 mg, 31%) as a pale orange solid: 1H NMR (300 MHz, CDCl3) d 1.49 (s, 9H), 1.54 and 1.56 (2s, 18H), 4.48 (br s, 2H, NOE observed for C-4 NH2 and C-3 H), 6.73 (d, 1H, J=8.4), 7.68 (dd, 1H, J=1.6, 8.4), 7.86 (s, 1H), 9.96 (s, 1H), 11.64 (s, 1H).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=O.C(O)C.[CH3:16][NH:17][CH3:18]>>[CH3:16][N:17]([CH3:18])[C:4]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:12])=[O:3]
Reactant: CNC
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCO
Product: CN(C)C(=O)C1CCCCC1=O
Temperature: 0 °C

Procedure:
0.313 mol (50 ml) of ethyl cyclohexanone-2-carboxylate and 140 ml 33% dimethylamine in ethanol (about 0.78 mol dimethylamine) were stirred in a pressure reactor for 12 hours at 110° C. After cooling the reaction mixture was concentrated on a rotary evaporator, the residue was dissolved in 500 ml ethyl acetate and the organic phase was washed with 200 ml of 1 M NaOH and 3×50 ml water. The organic phase was then evaporated on a rotary evaporator to dryness. 46 g of the crude product was dissolved in 100 ml tert-butyl methyl ether and cooled to 0° C. Precipitated product was filtered off and dried, 3.6 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][CH:11]([C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[CH2:10][C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][N:5]2[C:20]=1[CH3:21].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:19][CH:9]1[C:8]2[CH:7]=[CH:6][N:5]3[C:20]([CH3:21])=[C:2]([CH3:1])[N:3]=[C:4]3[C:13]=2[NH:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH2:10]1
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)CC(c1ccsc1)N3
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)C(O)CC(c1ccsc1)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
1 g of 2,3-dimethyl-9-(3-thienyl)-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, suspended in 10 ml of methanol, is treated with 500 mg of sodium borohydride, the solvent is stripped off in vacuo after stirring at room temperature for 1 hour, the yellowish residue is treated with saturated aqueous ammonium chloride solution (100 ml) and the mixture is extracted three times with methylene chloride. The combined organic phases are washed with a little water, dried over sodium sulfate and the solvent is stripped off in vacuo. The remaining solid residue is stirred with a little (15 ml) diethyl ether and then filtered off. 0.88 g of the title compound of m.p. 192–94° C. (diethyl ether) is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:45]1([CH2:51][CH2:52][CH2:53]Br)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:34][CH2:35][N:36]([CH2:53][CH2:52][CH2:51][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:37][CH2:38]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.