Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:24]=[C:23]2[C:19]([C:20]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C:21]=3[N:22]2[CH3:25])=[CH:18][CH:17]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:10](=[O:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Product: CN1CCc2c(n(C)c3cc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)ccc23)C1
Product: Cl
Yield: 38.5 %

Procedure:
4-(4-Chlorophenyl)pyridin-2(1H)-one (80 mg, 0.33 mmol) and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (49 mg, 0.33 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (28 mg, 19%) as a yellow-green solid: mp 316-323° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.0 (br s, 1H), 7.83 (dd, J=6.8, 1.9 Hz, 2H), 7.76 (d, J=7.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.07 (dd, J=8.3, 1.8 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz, 1H), 4.79 (d, J=15.2 Hz, 1H), 4.44 (dd, J=15.2, 6.0 Hz, 1H), 3.74-3.68 (m, 4H), 3.48-3.38 (m, 1H), 3.10-2.99 (m, 5H); ESI MS m/z 404 [M+H]+; HPLC (Method B)>99% (AUC), tR=13.5 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][PH3+].[CH2:19]([O:21][C:22](=[O:33])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=O)[CH3:20]>C(Cl)Cl.C1COCC1.C1COCC1>[CH2:19]([O:21][C:22](=[O:33])/[C:23](/[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])[CH3:20]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Reactant: CC(C)(C)CC[PH3+]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(SC)cc1
Temperature: 25 °C

Procedure:
Add sodium bistrimethylsilylamide(4.67 mL, 2.0 M in THF, 9.35 mmol) to a solution of (3,3-Dimethyl-butyl) phosphonium bromide (4.00 g, 9.35 mmol)in CH2Cl2/THF at 0° C. Dissolve (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (prepared as described by I. T. Barnish et. al. J. Med. Chem. 1981, 24, 399-404) in THF and add the resulting solution to the reaction mixture at 78° C. Stir at room temperature over-night. Add water and extract 3 X with dichloromethane, dry over sodium sulfate and concentrate under vacuum to afford 2.79 g raw material as a yellow oil. Further purify this material via silica gel chromatography, eluting with a gradient from 100% hexane to 50:50 hexane:dichlormethan to afford a colorless oil (700 mg). MS (m/e): 293 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Fc1cc(Br)cc2cn[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(Br)cc2cnn(C3CCCCO3)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-bromo-7-fluoro-1H-indazole (9.3 g, 43.26 mmol) and DHP (4.36 g, 51.9 mmol) in dry dichloromethane (100 mL), was added PTSA (424 mg, 2.16 mmol) at room temperature. The resulting mixture was stirred overnight. Work-up: saturated aqueous NaHCO3 (30 mL) was slowly added to the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) to give 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a light yellow solid. (7.8 g). 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.64 (s, 1H), 7.22 (dd, 1H), 5.84 (dd, 1H), 4.07-4.02 (m, 1H), 3.78-3.71 (m, 1H), 2.62-2.53 (m, 1H), 2.16-2.07 (m, 2H), 1.79-1.71 (m, 2H), 1.63-1.33 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:23])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](I)[CH2:25][CH2:26][CH2:27]CC>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCOc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Reactant: CCCCCCI
Product: CCCCCCOc1c(OCCCC)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Yield: 57 %

Procedure:
In accordance with EXAMPLE 2, using 7-nitro-3-hexyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, hexyl iodide was used instead of methyl iodide, 7-nitro-4-butoxy-3-hexyloxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 3, the title compound (51) was obtained by reduction reaction of nitro group. (yield=57%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].O[CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>C(O)C.C(O)(=O)C>[CH:24]1[C:23]2[CH:22]([CH:8]([C:6](=[O:7])[C:5]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C(=O)OC)c(OC)c1
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(C(=O)OC)c(OC)c1)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 3-methoxy-4-methoxycarbonylbenzoylacetate (4.1 g, 14.6 mmol) in a mixture of ethanol (30 ml) and acetic acid (30 ml) was added portionwise 9-hydroxyxanthene (3.2 g, 16.1 mmol). After stirring for 2 weeks at room temperature, the solution was concentrated in vacuo, diluted with water and extracted with dichloromethane (2×). The combined extracts were washed with a saturated solution of sodium bicarbonate, water and dried over magnesium sulphate. Filtration and evaporation gave ethyl 2-(9H-xanthen-9-yl)-2-(3-methoxy-4-methoxycarbonyl-benzoyl)acetate as an oil.
Reaction SMILES: N[OH:2].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].[C:19]([N:26]1C=CN=C1)(N1C=CN=C1)=[O:20].O>C(O)(C)C.O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:26][C:19](=[O:20])[O:2][N:15]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cccc(COC2CCCCO2)c1
Reactant: NO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2cccc(COC3CCCCO3)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 886.2 %

Procedure:
Add 50% aqueous hydroxylamine (9.73 g, 147 mmol) dropwise to a refluxing solution of 3-(tetrahydro-pyran-2-yloxymethyl)-benzonitrile (8.00 g, 36.8 mmol) in isopropanol (0.1M). After 2 hours, cool to room temperature and concentrate under reduced pressure to give a residue. Dissolve the residue in dioxane (0.1M). Add carbonyldiimidazole (7.16 g, 44.2 mmol) and heat to 110° C. After 30 minutes, cool to room temperature and pour into water. Extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (90.10 g, 89%): 1H NMR (CDCl3) δ 1.53-1.95 (m, 6H), 3.59 (m, 1H), 3.93 (m, 1H), 4.58 (d, 1H), 4.77 (t, 1H), 4.88 (d, 1H), 7.52 (t, 1H), 7.57 (d, 1H), 7.71 (d, 1H), 7.82 (s, 1H), 11.16 (bs, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([CH:23]=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Manufacturing Example 12-1-1 in anhydrous tetrahydrofuran (250 mL) were added dropwise n-butyl lithium (2.67 M n-hexane solution, 25.6 mL, 68.4 mmol) under nitrogen atmosphere on a dry ice-ethanol bath (−78° C.), which was stirred for 30 minutes at −78° C. N,N-Dimethylformamide (6.60 mL, 85.5 mmol) was then added thereto at −78° C., and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring for 10 minutes at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:7 then 1:5) to obtain the title compound (4.87 g, 40%).
Reaction SMILES: [OH:1][C@:2]([CH3:18])([C:16]#[CH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(N(CC)CC)C>[C:19]([O:1][C@:2]([CH3:18])([C:16]#[CH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Solvent: CCN(CC)CC
Product: C#C[C@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1.23 g (5 mmol) of (S)-2-[3-hydroxy-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione ([α]D25 +11.3° CH2Cl2), 1.05 mL of triethylamine, 120 mg of 4-N,N-dimethylamino pyridine, and 0.6 mL of acetic anhydride in 8 mL of CH2CL2 was stirred at 25° C. under argon for 17 h. It was diluted with CH2CL2 (70 mL), washed with 1.0N HCl, saturated NaHCO3 solution, water and dried over MgSO4. The crude material (1.6 g) was purified by flash chromatography on silica gel (50 g; 230-400 mesh). Elution with ether:petroleum ether (3:17) gave 1.47 g of (S)-2-[3-(acetyloxy)-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione as a yellow oil, [α]D25 -21.42° (c, 0.994, CH2Cl2).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35]N)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:25][CH2:26][CH2:27][O:28][C:29]=5[CH:34]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1ccc2c(c1)OCCO2
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2
Yield: 33 %

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for Example 91 in 33% yield. MS: M=439.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C@H:13]1[CH2:17][CH2:16][NH:15][C@H:14]1[CH3:18].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([N:15]2[CH2:16][CH2:17][C@H:13]([OH:12])[C@@H:14]2[CH3:18])[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(Cl)cc1F
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)c(Cl)cc1N1CC[C@H](O)[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution (25 mL) of 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg) in dimethyl sulfoxide were added 0.9M-dimethyl sulfoxide solution (5.56 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine and lithium carbonate (370 mg), and the mixture was stirred at 100° C. for 1 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 374 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)[CH3:21]>C1COCC1.C(OCC)(=O)C.[Cu]I.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>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(C#Cc2ccc(C(=O)OC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To methyl 4-bromo-2-fluorobenzoate (1.29 g, 5.54 mmol) in THF (10 mL)-triethylamine (5 mL) solvent were added 1-ethoxy-4-ethynylbenzene (1.24 mL, 8.30 mmol), copper(I) iodide (106 mg, 0.544 mmol) and bis(triphenylphosphine)palladium(II) chloride (195 mg, 0.277 mmol), and the mixture was stirred under an argon stream at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3 to 17:3) to give the title compound (1.38 g, yield 84%) as an oil.
Reaction SMILES: [F:1][C:2]([C:9]1[N:14]=[N:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)=[N:11][C:10]=1O)([CH3:8])[C:3]([O:5]CC)=O.P(Cl)(Cl)(Cl)=O.[NH3:38].C(#[N:41])C>>[NH2:38][C:10]1[N:11]=[C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:13]=[N:14][C:9]=1[C:2]([F:1])([CH3:8])[C:3]([NH2:41])=[O:5]
Reactant: CCOC(=O)C(C)(F)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Reactant: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(F)(C(N)=O)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.522 mmol) of ethyl 2-fluoro-2-{3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}propanoate were admixed with 3 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 10 ml of dry acetonitrile and, with ice-cooling, stirred into 5 ml of concentrated aqueous ammonia solution (35% strength). Stirring was continued for 2 h at RT and for 16 h at 50° C. After cooling, the precipitate was filtered off with suction and dried in vacuo. This gave 294 mg (purity 95%, quant. yield) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Na].[CH3:16][CH:17]([C:20](=O)[CH3:21])[CH:18]=O>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:20]([CH3:21])[C:17]([CH3:18])=[CH:16][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)C(C)C=O
Agent: [Na]
Solvent: CC(=O)O
Product: Cc1cn2nc(SCc3ccccc3)nc2nc1C
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 5.0 g (24 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 5.0 g (41 mmol) of the sodium salt of 2-methyl-3-oxobutanal in 200 ml of glacial acetic acid was heated at reflux overnight. The solution was cooled to room temperature and the reaction mixture was concentrated by evaporation at reduced pressure. The residue was combined with ice and H2O to separate a tan solid. The solid was collected by filtration, dried and carefully recrystallized from ethyl acetate to yield 3.53 g (54%) of the desired product as a crystalline solid, m.p. 147°-149° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([CH3:26])=[N:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)cn1

Procedure:
The title compound, white solid (22.6 mg, 62.8%), MS (ISP) m/z=450.0 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 6-methylnicotinic acid
Reaction SMILES: C1([O:7][C:8]2C=CC=CC=2)C=CC=CC=1.C([N:18](CCCC)CCCC)CCC.[C:27]([C:29]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[CH:30]C(N=[N+]=[N-])=O)#[N:28]>C(Cl)Cl>[O:7]=[C:8]1[C:40]2[CH:39]=[CH:38][S:37][C:36]=2[C:29]([C:27]#[N:28])=[CH:30][NH:18]1
Reactant: N#CC(=CC(=O)N=[N+]=[N-])c1cccs1
Reactant: CCCCN(CCCC)CCCC
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1c[nH]c(=O)c2ccsc12
Temperature: 212.5 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of diphenyl ether (1.5 L) and trin-butylamine (0.3 L) heated to an equilibrated temperature of 215° C. was dropwise added a solution of 3-cyano-3-thiophen-2-yl-acryloyl azide 23 (85 g, 0.416 mol) in CH2Cl2 (340 mL). The temperature was maintained between 210-215° C. during this time. Following addition, the reaction was stirred a further 30 min, then allowed to cool to room temperature, during which the pure product precipitated from solution. The product was filtered and washed with copious hexane. Drying the precipitate under vacuum provided 58.4 g of 24. 1H NMR (400 MHz, d6-DMSO) δ 12.36 (s, 1H), 8.27 (s, 1H), 7.81 (d, J=5 Hz, 1H), 7.57 (d, J=5 Hz 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[CH3:38][N:27]([CH3:26])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: CN(C)c1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 14.3 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(dimethylamino)phenylacetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 33 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.15 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.35 (br s, 1H), 7.18 (m, 2H), 6.68 (d, 2H), 3.5 (s, 2H), 2.9 (s, 6H); ES-MS (m/z) 414 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=C)[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[O:26]=[O+][O-].CSC>ClCCl>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=[O:26])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)Oc2ccc(F)cc21
Solvent: CSC
Solvent: ClCCl
Product: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 2.20 g (6.28 mmol) ((6R,7S)-9-allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 120 ml dichloromethane was treated with ozone at −75° C. for 20 minutes. Methyl sulfide, 2.27 g (30.6 mmol), was added and the solution was stirred for 4.5 hours at room temperature. The solvent was distilled off under vacuum and the residue was extracted with ethylacetate/water to yield 2.05 g crude [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 353.2 (M+H+, 11), 297.3 (60), 253.2 (100).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(N)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with m-toluidine according to the procedure from Example 137C substituting m-toluidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (56 mg, 70%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 2.21 (s, 3H), 3.15-3.29 (m, 1H), 3.78 (s, 3H), 7.00 (d, J=8.82 Hz, 2H), 7.12-7.37 (m, 4H), 7.40 (d, J=8.82 Hz, 2H), 7.64 (d, J=8.46 Hz, 1H), 7.84 (d, J=11.40 Hz, 1H), 7.99 (s, 1H), 8.59 (s, 1H), 8.86 (d, J=8.46 Hz, 1H), 9.87 (s, 1H), 10.21 (s, 1H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N+:1]([CH:4]=[C:5]([NH:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: NCCSCCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCCc1ccccn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with 2-[2-(2-aminoethyl)thioethyl]pyridine according to the procedure of Example 1(a)(ii) yields the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7](C1C=CC=CN=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Li]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[PH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: c1ccc(P(c2ccccn2)c2ccccn2)nc1
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tris(pyridin-2-yl)phosphine (22.4 g, 85 mmol) was suspended in THF (400 ml). To this were added lithium granules (5.0 g, 720 mmol). The mixture was then stirred at room temperature for four hours. This gave an intense red solution. The solution was then filtered into a clean Schlenk flask to remove any un-reacted lithium metal. The solvent was then removed under vacuum and water (100 ml, degassed with nitrogen gas for 20 minutes) added. Ether (400 ml) was then added and the biphasic solution stirred for 20 minutes. The upper (organic) phase was then cannula transferred into a clean Schlenk flask and then dried under vacuum. This gave dark orange/red oil. Yield=15.1 g, 94% 31P{1H} NMR (121 MHz, CDCl3) ä: −33.8 (s, PPy2).