Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]([CH3:17])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:18][CH2:19][CH3:20])[C:9]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:19]([N:18]1[C:10]2[C:9]([CH3:21])=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=[C:15]([CH3:17])[C:11]=2[C:12](=[O:14])[O:13][C:32]1=[O:34])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1c(=O)oc(=O)c2c(C)cc(C(=O)OC(C)(C)C)c(C)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 253.3 %

Procedure:
4-(tert-Butoxycarbonyl)-2-(ethylamino)-3,6-dimethylbenzoic acid (115 mg, 0.392 mmol) was dissolved in tetrahydrofuran (1 mL) and then cooled in an ice bath. N,N-Diisopropylethylamine (0.07 mL, 0.403 mmol) and triphosgene (40 mg, 0.135 mmol) were added, and the mixture was stirred at ambient temperature for 0.5 h. The mixture was quenched with water and extracted with dichloromethane (2×). The combined organic portion was dried over sodium sulfate, then filtered and concentrated to provide tert-butyl 1-ethyl-5,8-dimethyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (109 mg, 0.342 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 4.06 (q, 2H), 2.70 (s, 3H), 2.46 (s, 3H), 1.62 (s, 9H), 1.28 (t, 3H); MS (EI) for C17H21NO5: 320 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-morpholine following General Procedure C.
Reaction SMILES: C(OC([N:7]1[CH2:11][CH:10]([F:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([C:16]1[CH2:22][C@H:21]2[N:18]([C:19](=[O:26])[C@@H:20]2[C@H:23]([OH:25])[CH3:24])[C:17]=1[C:27]([O:29]CC=C)=[O:28])[CH3:15])=O)C=C.N1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][CH:10]1[CH2:11][NH:7][C@H:8]([CH:13]=[C:14]([C:16]2[CH2:22][C@H:21]3[N:18]([C:19](=[O:26])[C@@H:20]3[C@H:23]([OH:25])[CH3:24])[C:17]=2[C:27]([OH:29])=[O:28])[CH3:15])[CH2:9]1
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2CC(F)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1COCCN1
Product: CC(=C[C@@H]1CC(F)CN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Yield: 20.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S)-1-allyloxycarbonyl-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.7 g), morpholine (694 μl), and triphenylphosphine (199 mg) in tetrahydrofuran (30 ml) and ethanol (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (263 mg) at room temperature. After stirring for an hour, the precipitate was filtered, washed in turn with dichloromethane (3 times) and acetone (twice), and dried under reduced pressure to give (5R,6S)-3-[2-{(2S)-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (248 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:13]([N:21]=[C:22]=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([NH:21][C:22]([N:7]1[CH:8]=[C:3]([C:2]([F:11])([F:1])[F:12])[C:4](=[O:10])[NH:5][C:6]1=[O:9])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN=C=O
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Product: CCCCCCCCNC(=O)n1cc(C(F)(F)F)c(=O)[nH]c1=O
Yield: 22 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from 5-(trifluoromethyl) uracil (0.10 g, 0.55 mmol); 3.0 equivalents of octyl isocyanate were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (gradient from cyclohexane:EtOAc 70:30 to cyclohexane:EtOAc 60:40) and then washed with n-heptane to afford the title compound (0.04 g, 22%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J=6.8 Hz, 3H), 1.18-1.44 (m, 10H), 1.53-1.70 (m, 2H), 3.41 (td, J=7.1, 5.5 Hz, 2H), 8.90-8.97 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 14.20, 22.75, 26.92, 29.20, 29.26, 31.89, 41.80, 121.16 (q, J=268.7 Hz), 139.73, 148.25, 150.83, 156.86, MS (ESI) m/z 334 [M-H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:11][C@@H:12]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)[CH3:13].[Cl:30][C:31]1[N:36]=[C:35](S(C)(=O)=O)[C:34]2[N:41]([CH:44]([F:46])[F:45])[CH:42]=[N:43][C:33]=2[CH:32]=1>CN(C=O)C>[Cl:30][C:31]1[N:36]=[C:35]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:34]2[N:41]([CH:44]([F:45])[F:46])[CH:42]=[N:43][C:33]=2[CH:32]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: CS(=O)(=O)c1nc(Cl)cc2ncn(C(F)F)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C(F)F)c34)CC2=O)cc1
Reaction time: 0.17 h

Procedure:
Under Ar, NaHMDS (1.0 M in THF, 0.96 mL, 0.96 mmol) was added over 30 s to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (255 mg, 0.968 mmol) in DMF (3 mL). After stirring 10 min, the resulting mixture was added over ca. 45 s to a cooled (−20° C.) solution of 6-chloro-3-(difluoromethyl)-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine (215 mg, 0.763 mmol) in DMF (3 mL). After stifling 15 min, the reaction was quenched with saturated NH4Cl (3 mL) and was diluted with EtOAc (20 mL) and water (20 mL). The phases were separated, and the organic layer was washed with water (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (20-45% acetone in hexanes) to provide (R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H24ClF2N4O3: 465.2; found: 464.9.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[S:31]1(=[O:39])(=[O:38])[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH:34]4[CH2:35][CH2:36][S:31](=[O:39])(=[O:38])[CH2:32][CH2:33]4)[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: NC1CCC(Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Reactant: O=C1CCS(=O)(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)CCC(N[C@H]2CC[C@H](Nc3cc(-c4nc(NCC5CCOCC5)ccc4Cl)c(Cl)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound N2′-(4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (0.100 g, 0.222 mmol) (synthesized in the same manner as in Example 1b), 2,3,5,6-tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.036 g, 0.244 mmol), and triethylamine (0.251 ml, 0.182 g, 1.798 mmol) were dissolved in anhydrous CH2Cl2 (1.0 ml) and placed under argon. This solution was then treated with sodium triacetoxyborohydride (0.094 g, 0.444 mmol). The reaction was then stirred at room temperature for 18 hours. At this time a LC-MS was run. The reaction was about 25% complete. Additional 2,3,5,6-tetrahydro-4H-thiopyran-4-one 1,1-dioxide (˜4 equivalents) and sodium triacetoxy borohydride (˜8 equivalents) were added and the reaction continued for additional 27 hours. The reaction was about 60% complete as indicated by LC/MS. The reaction was quenched with sat NaHCO3 (15 ml). This was extracted with EtOAc (3×15 ml). The combined extracts were washed with brine (1×15 ml), dried (Na2SO4), filtered and the solvent removed in vacuo. The material was purified using the HPLC and lyophilized to give 19.7 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 582/584 (MH+), retention time=0.58 min.
Reaction SMILES: C(OC(=O)/[CH:5]=[C:6]1/[C:7]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]/1=2)C.[OH-].[Li+].C(O)(=O)C.[Br:29]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.C(O)(C)C>[Br:29]/[CH:5]=[C:6]1/[C:7]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]/1=2
Reactant: CCOC(=O)/C=C1\c2ccccc2COc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc2c(c1)OCc1ccccc1/C2=C\Br
Temperature: 80 °C
Yield: 97.4 %

Procedure:
To a clean, dry 100-gallon reactor with stirring under nitrogen, charge isopropanol (125 L), (E)-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidene)-acetic acid ethyl ester (13.857 kg, 46.42 mol), and a solution of lithium hydroxide (3.896 kg, 92.84 mol) in water (54 L). Heat the reaction mixture to 80° C. and stir for 2 h. Cool the reaction mixture to 40° C. and add acetic acid (5.575 kg, 92.84 mol) over 20 min between 40° C. and 45° C. Add N-bromosuccinimide (48.74 mol, 8.676 kg) portion-wise over 30 min at <45° C. Cool the reaction to room temperature and stir for a minimum of 12 h. Add an aqueous solution of sodium bisulfite (−37.7 L) and stir 15 min. Add an aqueous solution of sodium bicarbonate (−37.7 L) and stir 15 min. Add water (129 L) and stir 30 min. Filter to collect the resulting solids, washing with isopropanol:water (1:1, 2×20 L). Dry the solids under vacuum at 32° C. to a constant weight to obtain the title compound (13.8 kg, 97%).
Reaction SMILES: [OH:1][C:2]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][OH:28])=[CH:21][C:20]=2[Cl:29])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:1][C:2]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH:27]=[O:28])=[CH:21][C:20]=2[Cl:29])=[O:17])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1C=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of trans-4-((3-(2-chloro-4-(hydroxymethyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 42; 0.4 g, 0.68 mmol) in chloroform (8.1 mL) was added in portions manganese (IV) oxide (0.62 mg, 7.2 mmol). The heterogeneous mixture was stirred at 45° C. for 3 hours. The mixture was filtered and the solvent was removed under reduced pressure to give the title compound as a yellow solid (88%), which was used in the next step without further purification.
Reaction SMILES: [Li+].[OH-].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>O.CCOCC.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NNc1ccc(Cl)cc1)c1cccs1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of LiOH (2.4 g) in 50 mL water was added to a suspension of 1-(4-chloro-phenyl)hydrazine HCl salt (17.9 g, 100 mmol) in Et2O (300 mL), and the resulting mixture was stirred for 30 minutes. After the mixture became homogenous, the organic layer was separated, and triethylamine (1 eq.) followed by thiophene-2-carbonyl chloride (14.6 g, 100 mmol) were added slowly dropwise at a constant temperature of 0° C. The mixture was stirred for additional 1 hour at room temperature, and then the organic layer was diluted with ethyl acetate (100 mL), washed with brine, and dried over Na2SO4. The crude N′-(4-chlorophenyl)thiophene-2-carbohydrazide (24 g) obtained after the removal of the solvent was used in the next step without further purification.
Reaction SMILES: [Br-].[CH2:2]([O:9]CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1C=CC=C[CH:4]=1.[H-].[Na+].[CH2:34]1[CH2:44][C:42](=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1.O>O1CCCC1>[OH:9][CH2:2][CH2:3][CH2:4][CH:42]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:44]1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphoniumbromide (1.00 g) was dissolved in tetrahydrofuran (10 ml), sodium hydride (162 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. α-Tetralone (1.36 ml) was added to the reaction mixture, and the mixture was stirred at 75° C. for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethyl acetate (10 ml) was added 10% palladium carbon (200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the object product (140 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[C:27]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[ClH:35]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4cccnc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and nicotinic acid chloride hydrochloride (70 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a hydrochloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:14]1[CH2:18][CH2:17][CH:16]([S:19][CH2:20][CH2:21][NH2:22])[CH2:15]1.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:14]1[CH2:18][CH2:17][CH:16]([S:19][CH2:20][CH2:21][NH:22][S:41]([C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)(=[O:43])=[O:42])[CH2:15]1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: COc1ccc2nccc(N3CCC(SCCN)C3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(N3CCC(SCCNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
To the solution of HCl salt of [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]amine (from Example 7b) (420 mg, 1.23 mmol) in DCM/MeOH (15 mL, 1:1) with triethylamine (0.86 mL, 6.1 mmol) was added 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (388 mg, 1.48 mmol). After stirring at 25° C. for 12 h, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH) to afford the title compound as a white solid (400 mg, 61%): LC/MS m/z 532 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 9.05. (br, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.45 (d, J=5.9 Hz, 1H), 6.2 (br, 1H), 4.38-4.43 (m, 1H), 3.93-4.18 (m, 6H), 3.52-3.61 (m, 1H), 3.47 (s, 2H), 3.22-3.28 (m, 2H), 2.82-02.87 (m, 2H), 2.4-2.47 (m, 1H), 1.99-2.08 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(C2CCCC2)=O)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:31]1([C:29]([NH:28][C:24]2[CH:23]=[C:22]([N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:36])=[O:3])=[CH:8][N:9]=3)[CH:27]=[CH:26][CH:25]=2)=[O:30])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(=O)C3CCCC3)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: Nc1cccc(NC(=O)C2CCCC2)c1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(=O)C3CCCC3)c2)s1

Procedure:
The title compound was prepared via (2-{3-[3-(cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentanecarboxylic acid (3-amino-phenyl)-amide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][CH3:5].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C:12](=[CH:14][CH:15]=[O:16])[CH3:13])[CH3:8].[NH4+].[Cl-]>O1CCCC1>[CH3:13][C:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:6])[CH3:8])=[CH:14][CH:15]([OH:16])[CH:3]=[CH:4][CH3:5]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C=C(C)CCC=C(C)C
Reaction time: 8 h

Procedure:
12 g. of magnesium turnings were suspended under nitrogen in 250 ml. of dry tetrahydrofuran. Between 60° and 65°, 60 g. of 1-bromopropene dissolved in 50 ml. of tetrahydrofuran were added dropwise. During the addition, to prevent escaping of 1-bromopropene, the reflux condenser fitted on the reaction flask was cooled to -40°/-50°. When all Mg had reacted, the mixture was cooled to 20° and 76 g. of citral was added dropwise with cooling. After standing overnight, the mixture was poured into 1.5 liter of concentrated aqueous NH4Cl at 0°. The mixture was extracted 3 times with ether and the combined ether extracts treated as usual. After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene, b.p. 70°/0.1 Torr was obtained as a liquid with following constants: nD20 = 1.4950; d420 = 0.9145.
Reaction SMILES: [OH-].[K+:2].Br[CH:4]([CH:8](Br)[C:9]([OH:11])=[O:10])[C:5]([OH:7])=[O:6]>CO>[K+:2].[K+:2].[C:8]([C:9]([O-:11])=[O:10])#[C:4][C:5]([O-:7])=[O:6]
Reactant: O=C(O)C(Br)C(Br)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C#CC(=O)[O-]
Yield: 233.8 %

Procedure:
To a mixture of potassium hydroxide (44.8 g) and methanol (200 ml) was added 2,3-dibromosuccinic acid (55.2 g), and the whole was heated under reflux for 5 hours over a water bath. After cooling, white crystals were filtered and washed with methanol to afford a mixture (89 g) of acetylenedicarboxylic acid di-potassium salt and potassium bromide. The mixture was dissolved in water (as little water as possible was used) and 6N sulfuric acid (36 ml) was carefully added. White crystals formed were filtered to give 12.8 g of acetylenedicarboxylic acid mono-potassium salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].Cl[O-].[Na+].C([O-])(=O)C.[Na+].[Cl:14][C:15]1[C:24]([CH:25]=[N:26][OH:27])=[C:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[Cl:14][C:15]1[C:24]([C:25]2[CH2:4][C:3]([O:2][CH3:1])([CH3:5])[O:27][N:26]=2)=[C:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: C=C(C)OC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)(OC)C2)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (102 mmol) of 2-methoxy-1-propene, 28 ml of sodium hypochlorite solution (12.5% strength) and a spatula-tip of sodium acetate were added successively to 10.0 g (34 mmol) of methyl 2-chloro-3-(hydroxyiminomethyl)-4-methylsulfonylbenzoate in 200 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, the solvent was removed and the residue was taken up in ethyl acetate, washed with water, dried and concentrated. The residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=3:2). This gave 5.8 g (47% of theory) of methyl 2-chloro-3-(5-methoxy-5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[I-:18].[K+]>O.CCOC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:3]=1[I:18]
Reactant: [I-]
Reactant: CS(=O)(=O)c1ccc(F)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(F)c(I)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-5-(methylsulfonyl)aniline (Intermediate 57; 500 mg; 2.64 mmol) was treated with a 5 N solution of hydrochloric acid in water (8.98 ml; 44.92 mmol) and the solution cooled to 0° C. The solution was treated with sodium nitrite (219 mg; 3.17 mmol) and stirred at 0° C. for 30 minutes, then treated with a solution of potassium iodide (4.39 g; 26.43 mmol) in water (8 mL) and stirred at RT for 1 hour. EtOAc was added, the phases were separated and the organic phase was washed with a saturated sodium thiosulfate solution twice, then with brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.