Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C([O-])([O-])=O.[K+].[K+].[CH3:27][CH:28]([SH:30])[CH3:29]>O1CCOCC1>[CH:28]([S:30][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12)([CH3:29])[CH3:27]
Reactant: CC(C)S
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)Sc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.61 mmol) in dioxane (5 mL) were added K2CO3 (668 mg, 4.83 mmol) and 2-propanethiol (0.3 mL, 3.22 mmol). The reaction mixture was stirred for overnight for 70° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (320 mg, 56% yield). MS m/z: [M+1].
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)[N:3]=[CH:4][C:5]=2[C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[N:10]=1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1ncccc1Br
Product: Cc1ccc2c(-c3cccnc3C)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 3-bromo-2-methylpyridine and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[O:8]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:6][C:18]1[CH:19]=[CH:20][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][C:17]=1[OH:21]
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: Oc1cc(Oc2ccccc2)ccc1Br
Temperature: -70 °C
Reaction time: 5 h
Yield: 26.8 %

Procedure:
To a solution of t-butylamine (1.1 ml, 10.7 mmol) in 13 ml toluene, cooled to -30° C. was added bromine (0.28 ml, 5.35 mmol). The mixture was cooled to -70° C. and was treated with 3-phenoxyphenol (2.0 g, 10.7 mmol) dissolved in 2 ml CH2Cl2. The reaction was stirred to ambient temperature over 5 h, quenched with water and diluted with CH2Cl2. The organic phase was washed with water and brine and dried over Na2SO4. Column chromatography (SiO2 ; 5:95 EtOAc/Hex) afforded 380 mg (14%) of 2-bromo-5-phenoxyphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:42]1[CH2:46][CH2:45][C@@H:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:46][CH2:45][C@@H:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@@H]4CCN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3R)-(−)-1-Benzyl-3-aminopyrrolidine (89 mg) was then added thereto, and the mixture was stirred at room temperature for 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (114 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of tert-butyl 4-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I121) (81.5 mg, 0.137 mmol) in DMF (10 mL) was added to a solution of 10% Pd/C (170 mg) in DMF (7 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite, washimg with EtOAc (100 mL). The solvent was removed in vacuo to afford an oil which was purified on by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I122) (61.4 mg, 75%) as a viscous oil; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.56-7.50 (m, 3H), 7.49 (s, 1H), 7.19-7.14 (m, 2H), 7.12 (dd, J=7.7, 4.8 Hz, 1H), 4.23 (bs, 2H), 3.72 (s, 2H), 3.70 (s, 3H), 3.40-3.33 (m, 2H), 3.32-3.23 (m, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.62 (tt, J=12.1, 3.5 Hz, 1H), 1.81 (d, J=12.9 Hz, 2H), 1.65-1.55 (m, 2H), 1.48 (s, 9H). LCMS Method C: rt 6.01 min; m/z 622 [M+Na]+, 600 [M+H]+, 544 [M−tButyl+2H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: Cc1c(F)cccc1-n1nn[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(F)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-fluorophenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.47 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.5 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-fluorophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 2.19 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14](Cl)Cl.CO>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: ClCCl
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was dissolved in 1 ml of SOCl2. The solution was refluxed for 1 hour. Excess SOCl2 was removed under reduced pressure and 5 ml of CH2Cl2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. Excess MeOH and TEA were removed and the residue was purified by column chromatography with ethyl acetate/hexane (1/3) to yield the title compound as a yellow solid (316 mg). 1H NMR δ7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.67 (dd, J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[N:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=N[C@@H](C)CO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN[C@@H](C)CO)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Into a 10000 mL 4-necked, round bottomed flask was placed a solution of (S)-2-(4-methoxybenzylideneamino)propan-1-ol (693 g, 3.59 mol) in CH3OH (7000 mL). sodium borohydride (271.2 g, 7.17 mol) was added in several batches. The reaction mixture was cooled −10° C. After 2 hours at −10° C., the reaction was warmed to room temperature and concentrated under vacuum. The residual solution was diluted with 2000 mL of water and extracted three times with 3000 mL of ethyl acetate. The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica, 1:4 ethyl acetate/petroleum ether) to afford the title compound as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[N+:1]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[OH:17])([O-:4])=[O:2]
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Temperature: 60 °C
Yield: 43.4 %

Procedure:
Nitric acid (60 μL, 1.0 mmol) was added to a solution of 4-pyridin-3-yl-phenol (164 mg, 0.96 mmol) in acetic acid (2.8 mL). The mixture was heated at 60° C. for 30 min and the solution turned orange/brown in color. Upon cooling, water was added (3 mL) and 6 N NaOH (aq) was added until the solution was basic. The solution was extracted with ethyl acetate (3×) and then the aqueous phase was concentrated. The crude residue was washed with boiling methanol to afford 90 mg (43%) of 2-nitro4-pyridin-3yl-phenol as an orange solid: mp>300° C., MS (Cl) m/z 217.1 (M+1).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([NH2:29])=[N:23][NH:24]2>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([NH:29][CH:8]=[C:9]1[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]1=[O:18])=[N:23][NH:24]2
Reactant: Nc1n[nH]c2cccc(F)c12
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]c2cccc(F)c12

Procedure:
The named compound is prepared by substituting 4-fluoro-1H-indazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2186 gms. of 4-fluoro-1H-indazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH2:1]([N:8]1[CH2:30][CH2:29][CH2:28][C:10]2([O:14][CH2:13][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:30][CH2:29][CH2:28][C:10]2([O:14][CH2:13][C:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[CH:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC2(CCCN(Cc3ccccc3)C2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1=CC2(CCCN(Cc3ccccc3)C2)OC1

Procedure:
A mixture of 7-benzyl-3-tributylstannyl-1-oxa-7-azaspiro[4,5]dec-3-ene (Desc. 3; 1.68 g, 3.24 mmol), 2-bromoanisole (0.80 ml, 6.42 mmol), lithium chloride (0.94 g, 22 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in toluene (40 ml) was degassed then heated at reflux overnight (17 hours). The mixture was allowed to cool, filtered and concentrated in vacuo. The residue was dissolved in ether (100 ml) and extracted with 2M hydrochloric acid (100 ml then 25 ml). The aqueous phases were washed with more ether (100 ml), combined, basified with 4 M sodium hydroxide (70 ml) and extracted with ethyl acetate (2×50 ml). The organic phases were washed with brine (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:2 then 1:1), to give 7-benzyl-3-(2-methoxyphenyl)-1-oxa-7-azaspiro[4,5]dec-3-ene (0.67 g, 62%. This oil was dissolved in isopropanol and treated with excess ethereal hydrogen chloride. The mixture was concentrated in vacuo and recrystallised from isopropanol/diethyl ether to afford the title compound, m.p. 198°-201° C.; (Found: C, 69.61; H, 6.85; N, 3.62. C22H26ClNO2 0.4H2O requires C, 69.70; H, 7.13; N, 3.69%); δH (360MHz, D2O) 1.78-2.22 (4H, m), 2.98-3.26(3H, m), 3.58 (1H, m), 3.89 (3H, s, ArOCH3), 4.29 (1H, br d, NCHAHBPh), 4.43 (1H, d, J 13.1Hz, NCHAHBPh), 5.00 (2H, m, 2-CH2), 6.33 (1H, br, s, 4-H), 7.02 (1H, t, J 7.5Hz, ArH), 7.11 (1H, d, J 8.4Hz, ArH), 7.16 (1H, m, ArH), 7.39 (1H, m, ArH), 7.53 (5H, m, PhH); m/z (ES+) 336 ([M+H]+).
Reaction SMILES: O[CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:4]=[CH2:5].O.CC(C)=[O:14]>>[OH:14][CH:6]1[CH:2]([CH2:3][CH:4]=[CH2:5])[C:8](=[O:7])[CH:9]=[CH:10]1
Reactant: CC(C)=O
Reactant: C=CCC(O)c1ccco1
Solvent: O
Product: C=CCC1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 96 h
Yield: 43 %

Procedure:
Into 350 ml of a water-acetone (1:6 by volume) mixture, was dissolved 10 g of 2-(1-hydroxy-3-butenyl)furan. To the solution heated at 55° C. under reflux, was added dropwise 6.6 g of polyphosphoric acid. After having been stirred at 55° C. for 96 hours, the reaction mixture was freed from the acetone by distillation and the residue was extracted twice with 300 ml of ether. The extract solution was washed with an aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and freed from the solvent by distillation to obtain 8.5 g of a concentrate. The concentrate was purified by a column chromatography using 100 g of a silica gel (Wako Gel C-200) and a toluene-ether (2:1 by volume) mixture as eluent, to obtain 4.3 g (43% yield) of 4-hydroxy-5-allyl-2-cyclopentenone.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])#N.Cl.[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C1C=CC2N(O)N=[N:44][C:42]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[C:42]([CH:15]1[CH2:14][O:13][CH:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[CH:11][CH:10]=3)[C:6]([C:18]3[CH:19]=[C:20]([C:21]([NH:28][CH:29]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[N:7]2)[CH2:17][CH2:16]1)#[N:44]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(C(=O)O)c1)nn2C1CCCCO1
Reactant: On1nnc2ccccc21
Reactant: NC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1CCC(n2nc(-c3cccc(C(=O)NC4Cc5ccccc5C4)c3)c3ccccc32)OC1
Yield: 77.8 %

Procedure:
The title compound was prepared in a similar fashion to that of Example 367 A using the following amounts of reagents: 3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)benzoic acid (800 mg, 2.29 mmol), 2-aminoindan hydrochloride (652 mg, 3.84 mmol), HOBT (931 mg, 6.89 mmol), EDAC.HCl (1.32 g, 6.89 mmol) and triethylamine (535 μL, 3.85 mmol) in anhydrous THF (20.0 mL) and anhydrous DMF (7.0 mL). Precipitation from methanol and ethyl acetate with hexanes afforded the desired compound (824 mg, 78% yield) as an off-white powder 1H NMR (DMSO-d6) δ 8.87 (d, 1H), 8.7 (s, 1H), 8.39 (s, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.84 (dd, 1H), 7.62 (t, 1H), 7.3–7.1 (m, 4H), 6.02 (dd, 1H), 4.78–4.7 (m, 1H), 3.9–3.7 (m, 2H), 3.27 (dd, 2H), 2.98 (dd, 2H), 2.1–1.5 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].C[O-].[Mg+2].C[O-].Br[CH2:34]CNC(=O)OC(C)(C)C>CO.CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:34][CH2:20][NH:18][C:16](=[O:17])[C:12]3=2)[C:7]1=[O:23]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (1.00 g, 2.63 mmol; Example 1, Step 9) and magnesium methoxide in methanol (13.1 mL, 6-10% methanol solution available from Aldrich) in DMSO (26 mL) was heated at 60° C. for one hour. Methanol was exhaustively removed under vacuum over 45 minutes. The resulting DMSO solution was treated with tert-butyl (2-bromoethyl)carbamate (2.94 g, 13.13 mmol) and stirred at 60° C. under an atmosphere of nitrogen for one hour. The reaction mixture was diluted with ethyl acetate and washed successively with 10% sodium thiosulfate and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O>[N:23]([C:7]([C:3]1[CH:4]=[N:5][O:6][C:2]=1[CH3:1])=[O:9])=[N+:24]=[N-:25]
Reactant: Cc1oncc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oncc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-methylisoxazole-4-carboxylic acid (500 mg, 3.94 mmol) in a mixture of acetone (10 mL) and water (3 mL) was added triethylamine (0.83 mL, 5.91 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (640 mg, 5.91 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (410 mg, 6.30 mmol), and the mixture was stirred for another 2 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give crude material, which was carried on to the coupling without further purification.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27](F)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[O:15]
Reactant: FC1(F)CNC1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(N3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 24.6 %

Procedure:
3,3-Difluoroazetidine hydrochloride (98 mg, 0.76 mmol) was added to a suspension of 5-chloro-4-(5-chloro-6-fluoropyridin-3-yloxy)-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 150 mg, 0.38 mmol) and potassium carbonate (74 mg, 0.53 mmol) in dimethylsulfoxide (1 mL). The reaction mixture was stirred at 90° C. in the microwave for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by reverse phase preparative HPLC eluting with acetonitrile:water (from 5:95 to 95:5) to give the title compound as a colourless solid (44 mg, 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]([CH3:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]([CH3:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(CO)c(OCc2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cn1cc(C=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 81.2 %

Procedure:
A mixture of (3-benzyloxy-1-methyl-1H-pyrazol-4-yl)methanol (18.40 g), active manganese dioxide (40.00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 9 hrs. Manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-methyl-1H-pyrazole-4-carbaldehyde (14.80 g, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [H][H].[CH3:3][C@@:4]12[C@H:13]3[CH2:14][C@@H:15]([OH:29])[C@:16]4([CH3:28])[C@@H:20]([C:21]5[CH2:26][O:25][C:23](=[O:24])[CH:22]=5)[CH2:19][CH2:18][C@:17]4([OH:27])[C@@H:12]3[CH2:11][CH2:10][C@@H:9]1[CH2:8][C@@H:7]([OH:30])[CH2:6][CH2:5]2.O=O>O.CC(C)=O.[Pt]=O>[CH3:3][C@@:4]12[CH:13]3[CH2:14][C@@H:15]([OH:29])[C@:16]4([CH3:28])[C@@H:20]([C:21]5[CH2:26][O:25][C:23](=[O:24])[CH:22]=5)[CH2:19][CH2:18][C@:17]4([OH:27])[CH:12]3[CH2:11][CH2:10][C@@H:9]1[CH2:8][C:7](=[O:30])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: O=[Pt]
Agent: O=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1

Procedure:
Platinum oxide (Adams' catalyst) (500 mg.) was suspended in water (50 ml.) and a continuous stream of hydrogen passed for 1 hour. The hydrogen was displaced by nitrogen and digoxigenin (2.0 g.), in acetone (200 ml.) and water (50 ml.), added. A continuous stream of oxygen was passed through the mixture for 18 hours. The catalyst was removed by filtration, washed with acetone, the washings added to the filtrate and the filtrate concentrated in vacuo. The residue was dissolved in chloroform, washed with water and the solution dried (magnesium sulphate). Evaporation of the solvent in vacuo gave a gum which crystallised from acetone/ether. The 3-dehydrodigoxigenin melted at 251.2°C. and had [α] D25 + 39.1° (c = 0.48 in methanol).