Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH2:55][O:56][CH3:57])=[N:52][N:51]([CH:58]4[CH2:60][CH2:59]4)[C:50]=3[C:49](=[O:61])[N:48]2[C:62]2[CH:67]=[C:66]([CH3:68])[C:65](=[O:69])[N:64]([CH3:70])[CH:63]=2)=[CH:43][CH:42]=1>CCCCCCC.CC(O)C>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH2:55][O:56][CH3:57])=[N:52][N:51]([CH:58]4[CH2:60][CH2:59]4)[C:50]=3[C:49](=[O:61])[N:48]2[C:62]2[CH:67]=[C:66]([CH3:68])[C:65](=[O:69])[N:64]([CH3:70])[CH:63]=2)=[CH:43][CH:42]=1
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COCc1nn(C2CC2)c2c1[C@@H](c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound (32 mg, 42% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralcel OD-H 5 μm, 20×250 mm; mobile phase: heptane/iPrOH 80:20; flow: 10 mL/min; detection UV: 210 nm) of the racemic mixture of 4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 132).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])=[CH:3][C:4]=2[C:17]([F:20])([F:19])[F:18])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1C(F)(F)F
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(C(F)(F)F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[S:14][CH:15]=1)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[CH2:38][CH2:39][O:40][CH:41]=[O:42]>ClCCl>[CH2:39]([O:40][C:41]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[S:14][CH:15]=1)[CH:6]=[CH:5]2)=[O:42])[CH3:38]
Reactant: O=COCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(N)ccc43)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc2c(ccn2-c2csc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
To a stirred solution of tert-butyl 4-((4-(5-amino-1H-indol-1-yl)thiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate-35) (0.100 g, 0.214 mmol) in dichloromethane (4 mL), triethylamine (0.036 g, 0.362 mmol), and chloroethylformate (0.026 g, 0.214 mmol) were added at 0° C. and stirred at room temperature for 10 minutes. The reaction was quenched with water and the mixture was extracted with dichloromethane. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give tert-butyl 4-((4-(5-((ethoxycarbonyl)amino)-1H-indol-1-yl)thiazol-2-yl)oxy)piperidine-1-carboxylate (0.010 g, 8.5%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].BrCCOC.BrCC(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:37]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=1[CH2:50][CH3:51])(=[O:39])[CH3:38]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].[C:37]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](=[O:46])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:14])=[CH:43][C:42]=1[CH2:50][CH3:51])(=[O:39])[CH3:38]
Reactant: CCc1cc(C(=O)O)ccc1NC(C)=O
Agent: COCCBr
Agent: COCCOc1ccccc1C(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)CBr
Solvent: C1CCOC1
Product: CCc1cc(C(=O)CC(=O)c2ccccc2OCCOC)ccc1NC(C)=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A separated flask was charged with 1-(2-(2-methoxyethoxy)phenyl)ethanone (11.2 g, 57 mmol). (1-(2-(2-Methoxyethoxy)phenyl)ethanone was prepared by a procedure analogous to Example 1, in which commercially 1-bromo-2-methoxyethane was substituted for 1-bromo-2-methyl propane). The 1-bromo-2-methoxyethane was added to anhydrous THF (50 mL) and cooled to −78° C. To this solution was added commercially available lithium hexamethyl-silylamide (1M in hexanes, 172 mL, 172 mmol, Aldrich) over a 3 hour period at −78° C. The mixture was stirred for an additional 2 hours at −78° C. To the resulting mixture were added dropwise a solution of CDI and 4-acetamido-3-ethylbenzoic acid (above) at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 min and subsequently allowed to warm up to room temperature over 12 h. The reaction was quenched with 1 N HCl and extracted with EtOAc and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give 1-(4-acetamido-3-ethylphenyl)-3-(2-(2-methoxyethoxy)phenyl)propane-1,3-dione as a white solid (11 g, 60%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:10][CH2:9][CH2:8][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCNC1CCCCC1
Reaction time: 48 h
Yield: 45.2 %

Procedure:
To a solution of cyclohexanone (6.260 g, 63.8 mmol), ethylenediamine (42.640 mL, 637.8 mmol), acetic acid (36.515 mL, 637.8 mmol), and 4 {acute over (Å)} molecular sieves (25 g) in anhydrous methanol (250 mL) was added sodium cyanoborohydride (8.017 g, 127.6 mmol). The mixture was stirred for 48 hrs, filtered to remove the solids, and concentrated in vacuo. The residue was dissolved in 3 N aqueous sodium hydroxide (150 mL) and extracted with methylene chloride (3×300 mL). The combined organic layers were washed with basic saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give the crude product. The material was vacuum distilled to give the desired product as a clear liquid (4.1 g, 45%). 1H NMR (300 MHz, CDCl3) δ 2.80-2.76 (td, 2H, J=0.9, 6.0 Hz), 2.68-2.64 (td, 2H, J=0.9, 6.0 Hz), 2.43-2.34 (m, 1H), 1.89-1.83 (m, 2H), 1.74-1.70 (m, 2H), 1.62-1.57 (m, 1H), 1.32-0.98 (m, 8H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=C[CH:20]=[C:19](Br)[CH:18]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cccc(Br)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a mixture containing piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (80 mg, 0.28 mmol) and sodium t-butoxide (400 mg, 4 mmol) in toluene (20 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (250 mg, 37% yield for two steps) as TFA salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH2:29]([S:31]SCC)[CH3:30]>O1CCCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([S:31][CH2:29][CH3:30])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: CCSSCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a solution 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 3.3 g, 10.5 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6M, 10 mL, 16 mmol) dropwise. After stirring for 20 min at −78° C., ethyl disulfide (1.96 g, 16 mmol) was added. The resulting mixture was stirred for 1 h, quenched with a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (2×100 mL), dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by flash column chromatography (Qingdao silica gel, 300 mesh, 10% dichloromethane/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.2 g, 71%): LC/MS m/e calcd for C15H26N2SSi [M+H]+ 295.54.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[OH:31])=[CH:26][CH:25]=1>>[CH3:14][NH:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[O:31][CH2:5][C:19]([F:22])([F:21])[F:20])=[CH:26][CH:25]=2)[N:7]=1)=[O:12]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Product: CCOP(=O)(OCC)C(OCC(F)(F)F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 36.2 %

Procedure:
The title compound was prepared using the procedure for Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol). The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 13.8 mg of the desired product (yield: 18%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.6 Hz, 3 H), 1.31 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.91-4.08 (m, 4 H), 4.12-4.18 (m, 2 H), 4.95 (d, J=14.8 Hz, 1 H), 7.18 (t, J=7.2 Hz, 1 H), 7.36 (d, J=8.4 Hz, 2 H), 7.49 (dt, J=2.4, 7.6 Hz, 1 H), 7.64 (dd, J=1.6, 7.6 Hz, 1 H), 7.68 (d, J=7.6 Hz, 2 H), 8.35 (s, 1 H), 8.43 (m, 1 H). MS (ES+): m/z 636.14 [MH+]. HPLC: tR=1.59 min (UPLC TOF, polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH2:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH:25][C:32]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[O:33])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CN)c3)cnc21
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CCOCC4)c3)cnc21
Reaction time: 16 h

Procedure:
6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), tetrahydro-pyran-4-carboxylic acid (57 mg, 0.44 mmol) and triethyl amine (0.12 mL, 0.88 mmol) are mixed in acetonitrile (3.0 mL). Then TBTU (113 mg, 0.35 mmol) is added and the mixture is stirred for 16 hrs. All the solvent is removed in vacuo and to the residue are added saturated NaHCO3 aqueous solution (5 mL), water (15 mL) and EtOAc (20 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×15 mL). The organic layers are combined and concentrated to give the crude 6-(5-{[(Tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester which is used in the next step directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:21][CH:20]=[CH2:19])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCI
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (3,5-dichloro-phenyl)-carbamic acid-tert-butyl ester (6 g, 22.89 mmol) in DMF (130 mL) at 0° C. under Ar was added NaH (60% dispersion in mineral oil, 1.725 g, 45 mmol, 2 eq). The mixture was stirred at 0° C. for 30 min and then allyl iodide (13.32 mL, 110 mmol, 5 eq) was added over 5 min. The mixture was warmed to room temperature and stirred for 2 h. The mixture was then diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (200 mL). The aqueous phase was washed with EtOAc (3×60 mL) and the combined organic extracts were washed with saturated aqueous NaCl (200 mL), dried over Na2SO4, filtered and concentrated to give a brown oil which was purified by flash column chromatography eluting with 2% EtOAc/hexanes to give allyl(3,5-dichloro-phenyl)-carbamic acid-tert-butyl ester as a clear oil (4.632 g, 15.33 mmol, 67%).). 1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.24 (m, 2H), 6.00 (m, 1H), 5.30 (m, 2H), 4.30 (m, 2H), 1.59 (s, 9H).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[C:1]([C:5](=[N:15][OH:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CC
Yield: 69.4 %

Procedure:
Ethyl propionylacetate (14.4 g.) was added to acetic acid (19 ml.) and stirred at 5° to 10° C. To the solution was added dropwise over 40 minutes about 2/3 volume of an aqueous solution (30 ml.) of sodium nitrite (15 g.), and further water (50 ml.) was added to the solution and stirred at 25° C. for 1.5 hrs. The remaining aqueous solution of sodium nitrite was added dropwise over 10 minutes to the solution and stirred at room temperature for 2 hrs. The reaction mixture was extracted with diethyl ether (50 ml.) twice, and the extract was washed with saturated aqueous sodium bicarbonate (30 ml.) three times and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give ethyl 2-propionyl-2-hydroxyiminoacetate (12 g.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C@@H:10]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[C:18]([NH2:26])[C:17]=4[N:27]=[C:14]3[CH2:13][O:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](CCl)COC1
Reactant: CN1CCNCC1
Product: CN1CCN(C[C@H]2COCc3nc4c(N)nc5ccccc5c4n32)CC1
Temperature: 150 °C
Yield: 16.5 %

Procedure:
Methyl piperazine (0.3 mL, 2.5 mmol) was added to a vial containing (11R)-11-(chloromethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (90 mg, 0.31 mmol). The vial was placed in a stainless-steel, high-pressure vessel and heated to 150° C. for 18 hours. The reaction mixture was cooled to ambient temperature. The resulting light brown oil was purified by chromatography (SiO2, 0-30% CMA/CHCl3). The resulting oil was slurried in acetonitrile to produce a solid which was isolated by filtration to give 18 mg of the desired product as a tan solid, mp 187-190° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>O.CS(C)=O.CCOCC>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])[CH3:12]
Reactant: Oc1ccccc1Br
Reactant: CCOC(CBr)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(COc1ccccc1Br)OCC
Temperature: 100 °C

Procedure:
A solution of KOH pellets (85%, 0.68 g, 10.3 mmol) in water (1.5 mL) was added to 2-bromophenol (1 mL, 8.6 mmol). The mixture was diluted with DMSO (20 mL) and bromoacetaldehyde diethyl acetal (1.43 mL, 9.5 mmol) was added. The mixture was heated at 100° C. for 6 h, cooled to rt, diluted with ether (175 mL), washed with water (3×40 mL) and 5% aq NaOH (40 mL), and dried over MgSO4. Removal of the solvent left 1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, quant) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[N+](C1C=CC(N)=CC=1)([O-])=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1
Reactant: O=c1n(-c2ccc([N+](=O)[O-])cc2)cnn1-c1ccc(OC(F)(F)F)cc1
Agent: Nc1ccc([N+](=O)[O-])cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: Nc1ccc(-n2cnn(-c3ccc(OC(F)(F)F)cc3)c2=O)cc1

Procedure:
4-(4-Nitrophenyl)-2-(4-trifluoromethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one. The title compound was prepared according to the procedure in Henbach, DE 2724891 A1, 1978, with modifications to three steps: In the addition of the aniline, 4-nitroaniline was used instead of 3,5-dichloroaniline and dry THF was used as solvent instead of toluene. In the formation of the triazolinone ring, triphosgene (0.65 equiv) was used instead of phosgene: mp 136-140° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J=9.3 Hz, 2H), 7.32 (d, J=9.3 Hz, 2H); ESIMS m/z 367 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([NH2:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28]C[O-].[Na+].CI>C(O)C>[CH2:24]([O:23][C:21]([C:10]1([CH3:28])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([NH2:27])[N:8]=[C:9]1[NH2:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(N)C(C)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 37.5 g of 2,6-diamino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol was treated with 15 g of methyl iodide at the boil. After a further 60 minutes under reflux, the mixture was concentrated by distillation. The residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water, and the organic phase is concentrated. Recrystallization of the residue from ethanol gave 2.6-diamino-3-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 142° C (18 g, 41.5% of theory).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:23]=[CH:22][C:16]2[N:17]=[C:18]([CH2:20][OH:21])[S:19][C:15]=2[CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C.O>O1CCCC1>[N+:10]([C:13]1[CH:23]=[CH:22][C:16]2[N:17]=[C:18]([CH2:20][O:21][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:19][C:15]=2[CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc2nc(CO)sc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 ml of benzoyl chloride was added dropwise to a solution of 15 g of the 6-nitro-2-hydroxymethylbenzothiazole obtained in the Preparation Example 2 and 11 ml of triethylamine in tetrahydrofuran at 10° C. The reaction mixture was stirred at room temperature for 1 h and water was added thereto. After extraction with ethyl acetate, the extract was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: dichloromethanol/methanol) to give 10 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([Si:19]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole (7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure yielding a brown oil that was purified by high vacuum distillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of the title compound. 1H NMR (400 MHz, CDCl3): δ0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]1[NH:27][CH2:26][CH2:25][NH:24]1>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:24]2[CH2:25][CH2:26][NH:27][C:23]2=[N:22][C:16]2[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[O:11])=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Clc1cccc(Cl)c1N=C1NCCN1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=O)N2CCNC2=Nc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
4.40 g (22 mmoles) of p-methylsulfonylbenzoic acid are dissolved in 70 ml of anhydrous tetrahydrofuran, 3.56 g (22 mmoles) of N,N'-carbonyldiimidazole are added and stirred at room temperature for one hour. A solution of 4.60 g (20 mmoles) of 2-(2,6-dichlorophenylimino)-imidazolidine in 50 ml of anhydrous tetrahydrofuran is added dropwise while stirring further and the mixture is allowed to stand at room temperature for 20 hours. The residue from evaporation is triturated with water, separated off, washed with water, dried and recrystallized from dimethylformamide/water (1:1). 5.15 g (62.5% of theory) of 1-(p-methylsulfonylbenzoyl)-2-(2,6-dichlorophenylimino)-imidazolidine of melting point 240°-244° C. are obtained.