Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>O1CCOCC1>[F:1][C:2]1[C:3](=[S:11])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1COCCO1
Product: O=c1[nH]cc(F)c(=S)[nH]1
Yield: 144.8 %

Procedure:
A mixture of 5-fluorouracil (26 g, 0.12 mole) and phosphorus pentasulfide (45 g, 0.2 mole) in 500 mL dioxane was heated under reflux for 3 hr. The hot reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 650 mL water, heated with 5 g charcoal and filtered. The solid which crystallized on cooling was collected by filtration to yield 25.4 g (88%) of 5-fluoro-4-thiouracil, m.p. 269°-272° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:26]=[C:27](C(F)(F)F)[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O.[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)[C:5]1[CH:26]=[CH:27][CH:28]=[CH:3][CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
(rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (3.0 g, 9.0 mmol, synthesis described in example 156) was dissolved in dry tetrahydrofuran (50 mL) and triphenylphosphin (3.1 g, 11.7 mmol), methanol (0.374 g, 11.7 mmol) and diethylazodicarboxylate (5.35 mL, 40% in toluene, 11.7 mmol) were added sequentially and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol/triethyl amine 98:1:1) to yield the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (2.57 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: O=Cc1cc(Br)cs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1csc(C=O)c1
Yield: 100 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (3.0 g, 16 mmol) in N,N-dimethylformamide (30 ml) were added successively (trimethylsilyl)acetylene (11 ml, 79 mmol), triethylamine (13 ml, 94 mmol), and dichlorobis(triphenylphosphine)palladium (1.1 g, 1.6 mmol) under a nitrogen atmosphere with stirring, and the resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. After stirring, the reaction mixture was diluted with ethyl acetate, poured into a saturated aqueous solution of ammonium chloride (250 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:19) as the eluent to afford the title compound (3.3 g) in a yield of 100% as a brown oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C(N(CC)CC)C.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][O:42][CH3:43])=[CH:37][N:36]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:35]3[N:40]=[CH:39][C:38]([CH2:41][O:42][CH3:43])=[CH:37][N:36]=3)[CH2:18][CH2:19]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: COCc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N(C)C)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,5-difluoro-4-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}phenyl-)-N,N-dimethylacetamide (40.0 mg, 0.109 mmol) in 1 ml anhydrous DMF at RT was added triethylamine (0.046 ml, 0.33 mmol) and 2-chloro-5-(methoxymethyl)pyrimidine (20.8 mg, 0.131 mmol). The mixture was stirred at RT for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD Sum 19×100 mm column; 35-65% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. LC/MS (m/z): 489.5 (M+H)+. Human EC50: 1.6 nM
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([F:37])[C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([F:37])[C:31]=1[O:32][C:33]([F:35])([F:34])[F:36])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1OC(F)(F)F
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2cc(F)c(OC(F)(F)F)c(F)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 33.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3,5-difluoro-4-(trifluoromethoxy)phenoxy)piperidine (297 mg, 1.0 mmol) as crude materials, 87 mg title compound was generated and yield was 33%.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:20][S@](C(C)(C)C)=O)[C:11]1[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1)(C(C)(C)C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[ClH:27].[NH2:20][C@@H:10]([C:11]1[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:9][OH:8]
Reactant: COc1ncc(F)cc1[C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ncc(F)cc1[C@H](N)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (S)-N-((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) was added 4N HCl/dioxane (8.65 mL, 34.6 mmol). The solution was stirred at ambient temperature for 16 hours, then concentrated and dried under vacuum to afford (S)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride as a yellow oil which was used without purification, assuming 100% yield. MS (apci) m/z=186.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:46])[C:35]([O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)([CH3:37])[CH3:36])[CH3:32].N#N>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:46])[C:35]([CH3:37])([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:41][CH:40]=1)[CH3:36])[CH3:32]
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCCn1c(CCOc2ccc(OC(C)(C)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.194 g, 1.51 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.088 g, 0.392 mmol) and CS2CO3 (0.156 g, 0.478 mmol) in DMF (15 mL) was heated at 55° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (2 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a gradient of 4:1 to 1:1 hexanes:acetone to afford 0.036 g (19%) 2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:18][CH3:19])C(=O)OC(C)(C)C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:18][CH3:19])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCNc1cc(Br)cn(C)c1=O
Temperature: 30 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate (99.0 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30° C. The reaction mixture was stirred for 30 min at 30° C. Then the mixture was filtered and the filter cake collected. The filtrate was adjusted to pH=9 with saturated aqueous NaHCO3, extracted with EA (20 mL), dried over Na2SO4, filtered and concentrated to give a light green solid which is combined with the filter cake to give the title compound (46.0 mg) which was carried forward without purification. 1H NMR (CDCl3 400 MHz): δ 6.72 (d, J=2.4 Hz, 1H), 6.20 (d, J=1.6 Hz, 1H), 3.51 (s, 3H), 3.09 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 231.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[CH3:27][O:28][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C2CCc3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: COc1cccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1

Procedure:
2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-methoxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.32 (t, 1H, J 15.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 8.4 Hz), 7.01 (s, 1H), 7.00 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.92 (d, 1H, J 8.7 Hz), 6.90 (dd, 1H, J 8.4, 2.6 Hz), 5.12 (dd, 1H, J 10.0, 2.3 Hz), 3.77 (s, 3H), 2.93-2.97 (m, 1H), 2.71-2.77 (m, 1H), 2.15-2.20 (m, 1H), 1.99-2.05 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(OO)(=[O:14])C>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1cccc(Br)n1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Reaction time: 19 h
Yield: 83 %

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C for 2 hours and at 55° C for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (1M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: Cl[C:2]1[C:3]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CCO>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:3]3[S:11][C:10]4[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)c2sc3c(c2n1)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2nc(N)nc3c4c(sc23)CCCC4)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 44.5 %

Procedure:
To a solution of 4-chloro-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine (0.09 mg, 0.37 mmol) in EtOH (3.7 mL) was added K2CO3 (0.12 g, 0.84 mmol) followed by N-methylpiperazine (0.05 mL, 0.44 mmol). After stirring at rt for 22 h, EtOH was removed under reduced pressure and the mixture was dissolved in CH2Cl2 (5 mL) and poured over H2O (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, such as with a satd. aq. NaCl, (30 mL), dried, for example with Na2SO4, and concentrated to afford the title compound (0.05 g) as a pale yellow solid. MS: 304.2. 1H NMR (400 MHz, CD3OD) δ ppm 3.93-3.88 (m, 4H), 2.80 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.1 Hz, 2H), 2.56-2.52 (m, 4H), 2.33 (s, 3H), 1.96-1.81 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
4-Chloro-3-nitro-benzenesulphonyl chloride (2.56 g, 10 mmol) was added in small portions to a solution of N-methyl piperazine (1.33 ml, 12 mmol) in DCM (25 ml) at 0° C. To this solution was added triethylamine (2.08 ml, 15 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 2 h and then reduced in vacuo. The residue was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried (MgSO4) and reduced in vacuo. Purification with column chromatography eluting with 0-20% methanol in ethyl acetate gave 1-(4-chloro-3-nitro-benzenesulphonyl)-4-methyl-piperazine as an off-white solid (1.84 g, 58%). (LC/MS: Rt 1.84, [M+H]+ 319.97).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][NH:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][N:26]([CH2:40][CH2:39][O:38][CH3:37])[CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CNCCO1
Reactant: COCCBr
Product: COCCN1CCO[C@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-4-(2-methoxyethyl)morpholin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-morpholin-2-ylmethyl]1,3-thiazolidine-2,4-dione (Example 183) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
2-Amino-N-(3-imidazol-1-ylpropyl)benzamide (32.9 g) was dissolved in pyradine (165 ml) and 4-chlorobenzenesulphonyl chloride (41.2 g) was added in portions. The temperature of the reaction mixture rose to 52° C. The solution was stirred at room temperature for 4 hours and poured into water (1.5 l) to precipitate an oil which slowly solidified on standing. The solid was collected, washed with water and recrystallised from ethanol to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)-benzamide (24.4 g), in the form of a white solid, m.p. 175°-177° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[C:24](=[C:26]([CH2:33][CH3:34])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:16][N:15]=1)C.[CH3:46][CH:47]([CH3:50])[CH2:48][OH:49]>>[CH2:48]([O:49][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[C:24](=[C:26]([CH2:33][CH3:34])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)(=[O:37])=[O:38])=[CH:16][N:15]=1)[CH:47]([CH3:50])[CH3:46]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: CC(C)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)cnc3OCC(C)C)[nH]c(=O)c2nn1CCOC

Procedure:
Potassium bis(trimethylsilyl)amide (306 mg, 1.54 mmol) was added to a solution of the title compound of example 2 (155 mg, 0.31 mmol) in 2-methyl-n-propanol (10 ml) and the reaction stirred under reflux for 24 hours. The cooled mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 95:5) to afford the title compound, 88 mg, as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:17])=[O:18])=[O:21])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1cccs1
Reactant: COc1nc(C)nc(N)n1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccs2)n1
Reaction time: 6 h

Procedure:
To a suspension of 14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml. of acetonitrile was added, dropwise, 19 g of thiophene-2-sulfonyl isocyanate. After stirring for six hours, the mixture was filtered to yield the desired solid product melting at 182°-184° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine (1.0 g, 9.16 mmol) in DMF (5 ml) at room temperature was added potassium carbonate (2.53 g, 18.32 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 15 min. Then, 4-chloro-3-nitropyridine (1.45 g, 9.16 mmol) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated. 4-(6-Methylpyridin-3-yloxy)-3-nitropyridine (2.1 g, 100%) was obtained as an orange oil, which precipitated on standing, mp 87-90° C., and was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH:13]3[NH:17][C:16](=[O:18])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.CI.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][N:17]1[CH:13]([CH:10]2[CH2:9][CH2:8][C:7]3([O:3][CH2:4][CH2:5][O:6]3)[CH2:12][CH2:11]2)[CH2:14][CH2:15][C:16]1=[O:18]
Reactant: O=C([O-])O
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCC1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (27 mg, 1.07 mmol, 95%) in THF under argon was added 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one (135 mg, 0.60 mmol, prepared in the Example 12 Step E). After stirring 1 hour at room temperature, Methyl iodide (0.07 mL, 1.12 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was poured onto saturated NaHCO3 and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/DCM).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[O-]CC.[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](OCC)=[O:16]>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:16])[CH2:1][C:2](=[O:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8.71 g (150 mmol) of dry acetone in 100 ml of absolute tetrahydrofuran is added under argon to a solution of 20.42 g (300 mmol) of sodium ethoxide in 300 ml of absolute tetrahydrofuran. A solution of 22.68 g (150 mmol) of ethyl pyridine-2-carboxylate in 100 ml of absolute tetrahydrofuran is subsequently added dropwise over the course of 20 minutes. The mixture is stirred for 15 hours at room temperature and for 4 hours at the boiling point. The mixture is evaporated on a rotary evaporator, admixed with 150 ml of water and rendered neutral with glacial acetic acid. It is extracted twice with diethyl ether, the organic extracts are combined and dried (sodium sulfate), evaporated on a rotary evaporator, and 1-pyridin-2-ylbutane-1,3-dione is obtained as an orange oil. 1H-NMR (360 MHz, CDCl3) for enol tautomer: 15.8-15.5 (br s, OH); 8.60-8.55 (dm, 1H); 8.20-7.95 (dm, 1H); 7.79-7.71 (tm, 1H); 7.35-7.29 (m, 1H); 6.74 (s, 1H); 2.15 (s, 3H). Keto tautomer: CH2 group at 4.20 ppm (ratio of enol/keto form=87:13).