Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [OH-].[Li+].C([O:10][C:11](=[O:33])[CH2:12][O:13][C:14]1[C:19]([I:20])=[CH:18][C:17]([C:21](=[O:31])[C:22]2[CH:27]=[C:26]([I:28])[C:25]([OH:29])=[C:24]([I:30])[CH:23]=2)=[CH:16][C:15]=1[I:32])C1C=CC=CC=1.Cl>C1COCC1>[OH:29][C:25]1[C:24]([I:30])=[CH:23][C:22]([C:21]([C:17]2[CH:16]=[C:15]([I:32])[C:14]([O:13][CH2:12][C:11]([OH:33])=[O:10])=[C:19]([I:20])[CH:18]=2)=[O:31])=[CH:27][C:26]=1[I:28]
Reactant: O=C(COc1c(I)cc(C(=O)c2cc(I)c(O)c(I)c2)cc1I)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1c(I)cc(C(=O)c2cc(I)c(O)c(I)c2)cc1I
Reaction time: 6 h
Yield: 125.9 %

Procedure:
A 1.2 M solution of lithium hydroxide (100pL, 0.12 mmol) was added to a solution of [4-(4-hydroxy-3,5-diiodobenzoyl)-2,6-diiodo-phenoxy]-acetic acid benzyl ester (prepared according to Example 10, 50 mg, 0.043 mmol) in 1 mL THF. The biphasic solution was stirred for 6 hours, after which time 1 M HCl was added. The resulting white precipitate was isolated by filtration, rinsed with water, and dried in vacuo, yielding the title compound as a white powder (42 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 13.18 (br. s, 1H), 10.57 (br. s, 1H), 8.06 (s, 2H), 8.03 (s, 2H), 4.55 (s, 2H). HPLC (40-90), 12.41 min. LRMS (EI−) calc'd for [C15H8I4O5—H] 744.6, found 744.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a mixture of (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (100 mg, 0.31 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added K2CO3 (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (143 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: c1ccc(CCC2CCNCC2)cc1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(CCc3ccccc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-(2-phenylethyl)piperidine. MS (+ESI) m/z 381 (MH+).
Reaction SMILES: CN(C)[N:3]=[CH:4][C:5](=[CH2:7])[CH3:6].[C:9]1([C:15]2[C:16](=[O:29])[NH:17][C:18]3[C:23]([CH:24]=2)=[C:22]([O:25]C)[CH:21]=[CH:20][C:19]=3[O:27]C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH3:6][C:5]1[CH:7]=[C:21]2[C:20](=[N:3][CH:4]=1)[C:19](=[O:27])[C:18]1[NH:17][C:16](=[O:29])[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:24][C:23]=1[C:22]2=[O:25]
Reactant: C=C(C)C=NN(C)C
Reactant: COc1ccc(OC)c2[nH]c(=O)c(-c3ccccc3)cc12
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(c1)C(=O)c1cc(-c3ccccc3)c(=O)[nH]c1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
Methacrolein dimethylhydrazone (90 mg, 0.75 mmol) in one portion was added to a solution of 3-phenyl-5,8-dimethoxy-2-(1H)-quinolinone (190 mg, 0.71 mmol) in chloroform (50 ml.) The solution was agitated at room temperature for 3 hours and was evaporated. The residue was chromatographed over silica gel, eluting with ethyl acetate to give 120 mg (50%) of 6-methyl-3-phenyl-1H-1,8-diazaanthracen-2,9,10-trione (I-j). m.p. 275° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][C@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (1R,2S)-ethyl 2-aminocyclohexanecarboxylate hydrochloride (9.08 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=531.7 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.13 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.8 Hz, 0.4H), 1.32-1.41 (m, 3H), 1.41-1.54 (m, 2H), 1.46 (d, J=7.1 Hz, 2.6H), 1.55-1.66 (m, 2H), 1.67-1.84 (m, 6H), 1.98-2.11 (m, 3H), 2.22-2.32 (m, 1H), 2.45-2.55 (m, 3H), 2.62-2.68 (m, 1H), 3.06-3.18 (m, 4H), 3.35-3.47 (m, 1H), 3.49-3.60 (m, 1H), 3.73-3.85 (m, 1H), 3.92-4.01 (m, 2H), 4.02-4.11 (m, 1H), 6.19 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.60-7.67 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1)[CH2:3][CH2:4][N:5]([CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[CH3:1][N:2]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=1)[CH2:3][CH2:4][N:5]([CH3:25])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(CN(C)CCN(C)Cc2ccc(Oc3ccc(-c4ncco4)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCN(C)Cc1ccc(C(=O)O)cc1)Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Yield: 34.8 %

Procedure:
Methyl 4-[[methyl[2-[methyl[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]amino]-ethyl]amino]methyl]benzoate (120 mg 0.25 mmol) was stirred with aqueous sodium hydroxide solution (1.25 mL, 2 M) in methanol (3 mL) overnight at ambient temperature, and then concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Flash chromatography gave 41 mg of 4-[[methyl[2-[methyl[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]amino]ethyl]amino]methyl]benzoic acid; 1H NMR (300 MHz, CD3OD) δ 7.98 (d, 2H), 7.96 (d, 2H), 7.95 (d, 1H), 7.41 (d, 2H), 7.38 (d, 2H), 7.26 (d, 1H), 7.06 (d, 4H), 3.80 (s, 2H), 3.78 (s, 2H), 2.86 (m, 4H), 2.40 (s, 3H), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: OB(O)c1ccc2cnccc2c1
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2cnccc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using isoquinolin-6-ylboronic acid and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 2.34 (s, 3 H), 7.67 (d, J=8.30 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H), 7.90 (d, J=5.86 Hz, 1 H), 7.94 (s, 1 H), 8.28 (t, J=8.30 Hz, 2 H), 8.50 (d, J=5.86 Hz, 1H), 9.35 (s, 1 H); ESI-MS m/z [M+H]+ 330.4.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13].[OH:28][CH:29]([P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[CH3:30]>>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12]([O:28][CH:29]([P:31](=[O:38])([O:32][CH2:33][CH3:34])[O:35][CH2:36][CH3:37])[CH3:30])=[O:13]
Reactant: CCOP(=O)(OCC)C(C)O
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Product: CCOP(=O)(OCC)C(C)OC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
by using 2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyl chloride and diethyl 1-hydroxyethylphosphonate there is obtained diethyl 1-[2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyloxy]-ethylphosphonate, 1H-NMR (CDCl3, 400 MHz) 7.93 ppm and 7.92 ppm (2d, 1H), 7.79 ppm (d, 1H), 7.51-7.55 ppm (m, 1H), 7.23 ppm and 7.19 ppm (2d, 1H), 6.68 ppm and 6.58 ppm (2d, 1H), 6.53 ppm and 6.46 ppm (2q, 1H), 5.31 ppm and 5.29 ppm (2q, 1H), 4.88 and 4.85 ppm (2q, 1H), 4.21-4.05 ppm (m, 4H), 1.73 ppm and 1.72 ppm (2d, 3H), 1.45 ppm and 1.42 ppm (2q, 3H), 1.36-1.26 ppm (m, 6H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[C:16]([N+:28]([O-:30])=[O:29])[C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7])(=O)C.C1COCC1.[Li+].[OH-].C(O)(=O)C>CO>[SH:4][CH2:5][CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[C:16]([N+:28]([O-:30])=[O:29])[C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)SCC(C)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(CS)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
The thioacetate prepared in Example 9A (65 mg, 0.15 mmol) was dissolved in 2 mL methanol and 1 mL THF with 0.3 mL of 1N LiOH. After stirring for 1 hour, 0.1 mL of acetic acid was added. The solution was extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The product was dissolved into 1.0 ml acetic acid, heated to about 50° C. and concentrated in vacuo to give a light yellow solid (30 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1OC(=O)N(C2C=CC(I)=C([F:48])C=2)C1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([Sn:22]([CH3:23])([CH3:24])[CH3:25])=[C:20]([F:48])[CH:21]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1

Procedure:
Using essentially the same procedure as described for (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-2-one, but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (1.97 g, 4.37 mM) gave the title compound as a white solid after chromatography using hexanes then 20% ethyl acetate/hexanes (1.75 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C12(O)CC3CC(CC(O)(C3)C1)C2.C(OC=C)(=O)C.[CH:25]([O:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][C:30]([O:38]C=C)([CH2:31]3)[CH2:29]1)[CH2:35]2)=[CH2:26]>C1(C)C=CC=CC=1>[CH:25]([O:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][C:30]([OH:38])([CH2:31]3)[CH2:29]1)[CH2:35]2)=[CH2:26]
Reactant: C=COC12CC3CC(C1)CC(OC=C)(C3)C2
Agent: O=C([O-])[O-]
Agent: OC12CC3CC(C1)CC(O)(C3)C2
Agent: [Na+]
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COC12CC3CC(CC(O)(C3)C1)C2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and sodium carbonate (64 mg, 0.6 mmol) in toluene (1.0 ml), 1,3-adamantanediol (1 mmol) and vinyl acetate (6 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 5 hours. The reaction mixture was analyzed by gas chromatography to find that 1,3-bis(vinyloxy)adamantane and 3-vinyloxy-1-adamantanol were produced in yields of 41% and 16%, respectively, with a conversion from 1,3-adamantanediol of 97%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.Cl>ClCCl.O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCC(=O)O)c4ccc(OC(F)F)cc34)nc12
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: NCCN
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCC(=O)O)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
In a round-bottomed flask, 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid (80 mg, 0.13 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.40 ml, 5.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.53 ml, 7.85 mmol) was added. The reaction was stirred at room temperature for 1 h then diluted with water and acidified with 1 M HCl then conc. HCl to pH=˜4. The resulting suspension was filtered and washed with hot water and ethyl acetate and the product was dried under high vacuum to provide 27 mg (41%) of 4-[3-(7-tert-butylcarbamoyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-difluoromethoxy-indazol-1-yl]-butyric acid as a brown powder. MS: (M+Na)+=509; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.09 (s, 1H), 8.39 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.86-7.92 (m, 2H), 7.42 (dd, J=9.1, 2.3 Hz, 1H), 7.21 (t, J=74.3 Hz, 1H), 4.59 (t, J=6.8 Hz, 2H), 2.26-2.33 (m, 2H), 2.08-2.19 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Reactant: Nc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.38 g, 1.37 mmol) and 2-chloroaniline (0.23 mL, 2.2 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Recrystalized from ethylacetate and hexanes, 203 mg (41%) of 3-(2-chloroanilino)-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione was obtained. LCMS(H+) 360.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](C(OC(C)(C)C)=O)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[O:10][N:9]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].Cl>ClCCl.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)on1
Yield: 47.9 %

Procedure:
To a solution of tert-butyl 3-[2-(acetoxy)ethoxy]-5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-isoxazolecarboxylate (Preparation 2) (3.16 g) in dichloromethane (40 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was heated to reflux for 3 hours. After which time the reaction mixture was basified to pH8 using sodium hydrogen carbonate solution and then re-acidified to pH2 using aqueous hydrochloric acid (1.0 M). This aqueous layer was extracted into ethyl acetate (2×250 mL) and the organics combined, dried over magnesium sulfate and the solvent removed in vacuo to yield the crude material (2.6 g). This was dissolved up in toluene and refluxed for 2 hours. The solvent was removed in vacuo to yield the crude material as a light brown solid (2.3 g). The crude material was purified using the Biotage Flash 40i system (silica, 90 g) and eluted with hexane:ethyl acetate (5:2) to yield the product as a white solid (1.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[OH:26])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH4+].[Cl-].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[CH:4]=2)(=[O:11])=[O:10])[CH2:18][CH2:17]1
Reactant: N#Cc1cccc(S(=O)(=O)N[C@H]2CC[C@@H](c3ccc(O)cc3O)CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1)c1cccc(-c2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of Example 9 (20 mg, 54 μmol) in DMF (2 ml) was treated with NH4Cl (17 mg, 323 μmol ) and NaN3 (21 mg, 323 μmol). The mixture was heated under reflux for 6 hr, then stirred for 18 hr at 20° C., before being partitioned between EtOAc (30 ml) and H2O (5 ml). The aqueous phase was extracted with EtOAc (3×15 ml) and the combined organic extracts were washed with brine (30 ml) and dried (MgSO4). Filtration, solvent evaporation under reduced pressure, and FCC (EtOH-EtOAc, 1:3) afforded the title compound (16 mg, 72%) as a pale yellow solid. δH ((CD3)2CO) 1.30-1.88 (m, 8H), 2.60-2.71 (m, 1H), 3.62-3.69 (m, 1H), 4.23-4.30 (m, 1H), 6.20 (dd, 1H), 6.44 (d, 1H), 6.50 (d, 1H), 6.87 (d, 1H), 7.55 (t, 1H), 7.63-7.68 (m, 1H), 7.72-7.76 (m, 1H), 7.80 (d, 1H), 8.30 (d, 1H), 8.73 (s, 1H); m/z (ES−) 414 [M−H]−.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:17](Cl)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCOCc1ccccc1
Reactant: C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -78 °C

Procedure:
The carboxylic esters (621A; 3.75 g) were dissolved in anhydrous diethyl ether (50 ml) and cooled to −78° C., under an atmosphere of nitrogen. KHMDS (69 ml of a 0.5M solution in toluene) was added dropwise and the resulting mixture was stirred for a further 15 min., before the addition of BOMCl (1.7 eq.) and the reaction flask was removed from the cooling vessel and allowed to warm slowly to room temperature. Water (approx. 10 ml) was added and the mixture was partitioned between EtOAc and 10% aq. HCl. The organic phase was separated, washed with sat. aq. sodium bicarbonate, water, dried (MgSO4), and the volatiles removed under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc:Hexanes (1:20) as eluent, providing the intermediate benzyl ether (3.01 g), a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:27]C(=O)C)=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 49.3 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]morpholine (0.045 g, 0.101 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.020 g, 0.0498 mmol, 49%).