Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41](O)[CH2:42]C>>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH2:41][CH3:42])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and 7.0 ml of n-propanol was stirred under reflux for 2 hours. After cooling to room temperature, the solvent was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography to give propyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-14).
Reaction SMILES: C(C(CCCC(OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)N.[C:29]([CH:32]([CH2:44][CH2:45][CH2:46][C:47]([OH:54])([CH3:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])(=[O:31])[NH2:30]>>[C:29]([CH:32]([CH2:44][CH2:45][CH2:46][C:47]([OH:54])([CH3:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])(=[O:31])[NH2:30]
Reactant: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(N)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1, Step F, except that the ethyl 8-carbamoyl-12-acetoxyheptadecanoate is replaced by an equimolar amount of ethyl 8-carbamoyl-12-hydroxy-12-methylheptadecanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(I)c2ccc(Cl)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Temperature: -16 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-3-iodo-1-methyl-1H-indazole (108 mg, 0.35 mmol) was dissolved in THF (2 ml) and the solution was cooled to −16° C. using a NaCl/ice bath. Isopropylmagnesium chloride (2.0M in THF, 0.20 ml, 0.40 mmol) was added dropwise and the reaction mixture was stirred at −16° C. for 15 min. Tributylchlorostannane (0.11 ml, 0.40 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 6-chloro-1-methyl-3-tributylstannanyl-1H-indazole as a brown oil which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C:24](=[O:26])[NH:23][S:22]3(=[O:28])=[O:27])=[C:17]([OH:29])[CH:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[OH:29][C:17]1[CH:16]=[C:15]([CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[N:21]1[S:22](=[O:28])(=[O:27])[NH:23][C:24](=[O:26])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1CN(c2ccc(CC3CCCNC3)cc2O)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-[3-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-piperidine-1-carboxylic acid tert-butyl ester (24 mg, 0.052 mmol) in ether (1.5 mL) is added 2 mL of HCl in dioxane (4 M) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure to give the hydrochloride salt of the title compound: (M−1)−=324.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(O)cc1
Yield: 85.4 %

Procedure:
109 g (1 mole) of 4-amino-phenol and 101 g of triethylamine were dissolved in 700 ml of tetrahydrofuran. 120.5 g (1 mole) of pivalyl chloride were added dropwise at 10°-15° C., with stirring. The mixture was subsequently stirred at room temperature for 2 hours and then poured into 3 liters of water. The crystals precipitated were filtered off with suction and dried in air. 165 g (85.5% of theory) of 4-pivaloylamino-phenol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[N:20][CH:21]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cn1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
1 g of methyl 6-chloronicotinate was reacted via Procedure O to yield methyl 6-(methylsulfonyl)nicotinate. 1 g of methyl 6-(methylsulfonyl)nicotinate was hydrolyzed via Procedure M to give 6-(methylsulfonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(methylsulfonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]([SH:39])[NH:29][C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:22][CH:21]=1>S(=O)(=O)(O)O.O.CN(C)C=O>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]2[N:29]=[C:28]([S:39][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=3)[NH:27][C:26]=2[C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:32][CH:33]=1
Reactant: Nc1cccc(F)c1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3cccc(F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.1 %

Procedure:
5.49 g of 3-fluoroaniline is dissolved in 6.0 g of concentrated sulfuric acid and 120 ml of water and, after the addition of 10 g of ice, diazotized at 0° with a solution of 3.6 g of sodium nitrite in 10 ml of water. The diazonium salt solution is then neutralized with sodium acetate and introduced at 5° under thorough agitation into a solution of 17.2 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in 700 ml of dimethylformamide. The mixture is agitated for another 20 minutes, poured into 2.5 l of water, extracted with ethyl acetate, the organic solution washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 500 g of neutral aluminum oxide (activity stage II). Elution with ethyl acetate/hexane produces 7.24 g of 4,5-bis(4-methoxyphenyl)-2-(3-fluorophenylthio)imidazole, mp 147°-149° after recrystallization from ether/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.CO.C[N+]1([O-])CCOCC1>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Agent: [Pd]
Agent: C[N+]1([O-])CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The aromatic enone 46 (321 mg, 1.20 mmol) was dissolved in anhydrous THF (6 mL) and anhydrous MeOH (6 ml). Added 2 small scoops of Pd 10% on activated C, placed under an atmosphere of hydrogen and allowed to stir for 2 hours at room temperature. Purged with nitrogen, filtered through Celite and removed solvent by evaporation under vacuum. The benzylic alcohol is reoxidized to the ketone by the following procedure. The crude was taken back in anhydrous CH2Cl2 (10 mL), with 3 Å molecular sieves, TPAP (1 scoop) was added followed by NMO (212 mg, 1.8 mmol). Stirred at room temperature for 30 minutes and filtered through a plug of silica gel. Solvent was evaporated under vacuum and purified by column chromatography using 10% EtOAc/Hexane.
Reaction SMILES: [OH:1][C@H:2]1[C:7](=[O:8])[CH2:6][CH2:5][O:4][C@@H:3]1[CH2:9][OH:10].[C:11](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:20]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=1)[C:12]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=1>N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[CH:18][CH:19]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:9][C@@H:3]2[C@@H:2]([OH:1])[C:7](=[O:8])[CH2:6][CH2:5][O:4]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1CCO[C@H](CO)[C@H]1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OCCC(=O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Dissolve (2R,3R)-3-hydroxy-2-(hydroxymethyl)dihydro-2H-pyran-4(3H)-one (662 mg, 4.53 mmol) and DMTCl (1.688 g, 4.98 mmol) in pyridine (5 mL). The reaction was stirred overnight and a TLC was taken in 30% EtOAc/Hexane. The crude reaction mixture was partitioned with 1M CuSO4 (10 mL) and the aqueous layer extracted with DCM (3×30 mL). The combined organic fractions were washed once with water (20 mL) and dried over Na2SO4. The crude product was chromatographed using a gradient from 10%-30% EtOAc/Hexane to yield 1.51 g (74%). 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.4, 1.2 Hz, 2H), 7.40-7.35 (m, 4H), 7.29 (t, J=4.3, 2H), 7.20 (t, J=7.3 Hz, 1H), 6.86-6.80 (m, 4H), 4.39 (ddd, J=11.3, 7.5, 1.0 Hz, 1H), 4.26 (ddd, J=9.5, 3.8, 1.4 Hz, 1H), 3.79 (s, 6H), 3.70-3.61 (m, 1H), 3.47 (dd, J=5.8, 2.8 Hz, 2H), 3.43-3.34 (m, 2H), 2.90-2.78 (m, 1H), 2.60-2.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 208.13, 158.91, 145.38, 136.50, 130.62, 129.60, 128.70, 128.25, 127.20, 113.56, 86.57, 84.09, 74.84, 67.87, 64.25, 55.67, 41.45; IR (neat film) 3458, 2938, 1720, 1509, 1250, 1178, 1110; LRMS for C27H28O6 (M+Na) 471.02.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:29]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:31])=[O:30])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[Cl:37][C:34]1[S:33][C:32]([S:29]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:30])=[O:31])=[CH:36][CH:35]=1
Reactant: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled, ice/water bath, solution of 1,1-dimethylethyl 3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 9) (4.17 g, 6.68 mmol) in DCM (20 mL) was added TFA (10.29 mL, 134 mmol) and the solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL) and water (50 mL). The organic phase was passed through an hydrophobic frit and the solvent was removed in vacuo to give the product (3.78 g) as a white solid. This was dried in vacuo at 45° C. for 2 days to give the title compound (3.55 g, 100%) as a white solid. LCMS (System A) RT=1.33 min, ES+ve m/z 524/526/528 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.[S:10](Cl)([CH3:13])(=[O:12])=[O:11].C1(=O)NC(=O)C=C1>N1C=CC=CC=1>[S:10]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12)([CH3:13])(=[O:12])=[O:11]
Reactant: Oc1cccc2c1CC2
Reactant: CS(=O)(=O)Cl
Agent: O=C1C=CC(=O)N1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1cccc2c1CC2

Procedure:
4-Mesyloxybenzocyclobutene is prepared by reaction between 4-hydroxybenzocyclobutene and mesyl chloride (methanesulfonyl chloride) in pyridine, using excess pyridine as solvent. The mesyloxy compound is reacted with maleimide, otherwise as in paragraph (a), to produce 4-(N-maleimidyl)benzocyclobutene, which is hydrolyzed with hydrazine hydrate to 4-aminobenzocyclobutene, otherwise as in paragraph (b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]2[CH:11]=[N:10]1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]2[CH:11]=[N:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1cccc(F)c1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)cccc1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 74A (1.19 g, 3.24 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g, 13.86 mmol), potassium acetate (1.36 g, 13.86 mmol), and anhydrous DMSO (12.5 mL). The reaction mixture was purged with argon and treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol). The reaction mixture was heated to 85° C. for 1 h, then at 105° C. for 1 h to give conversion to the desired product. LC/MS (Condition B): ret. T=2.7 min, (M+H)+ 276.01.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide (106 mg, 0.192 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 66 mg (82%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder. MS: (M+H)+=422; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.91 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 7.15-7.21 (m, 1H), 5.47-5.61 (m, 1H), 4.18 (s, 3H), 1.66 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:7]=1.[CH3:26][C:27](O)=O>[Fe]>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:6]2=[N:7][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:10]=[C:11]2[N:12]=[C:26]1[CH3:27]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc(Cl)c1Cl
Agent: [Fe]
Product: Cc1nc2ccc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 30 %

Procedure:
To a refluxed solution of N-(2,3-dichlorobenzyl)-6-morpholino-3-nitropyridin-2-amine (1.15 g, 3 mmol) in CH3COOH (100 mL) was added iron powder (504 mg, 9 mmol) in portions. The mixture was then refluxed for 16 h and cooled to room temperature. It was filtered and the filtrate was concentrated in vacuo. The residue was then purified by chromatography on silica gel eluting with EtOAc/Pet ether=1/1 to afford the desired product as a pale solid (352 mg, 30%). LC/MS: MS (ES+) m/e 377 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 3.36 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.8 Hz, 4H), 5.46 (s, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:31]4[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=4)[CH:27]=[CH:28][C:29]=3[OH:30])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:31]4[CH:38]=[CH:37][C:34]([CH:35]=[C:43]5[S:39][C:40](=[O:45])[NH:41][C:42]5=[O:44])=[CH:33][CH:32]=4)[CH:27]=[CH:28][C:29]=3[OH:30])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: O=Cc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)cc2)S1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of toluene (180 mL), piperidine (0.60 mL), acetic acid (0.63 mL), 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzaldehyde (6.08 g, 18.30 mmol) and 2,4-thiazolidinedione (2.14 g, 18.30 mmol) was heated at reflux for 12 hours under an argon atmosphere. The resulting suspension was filtered hot and the solid was stirred at room temperature in 210 mL of H2O/EtOH (6:1). After 30 minutes the solid was filtered and dried under high vacuum to afford 5.6 g (71%) of 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzylidene-2,4-thiazolidinedione, mp 307–308.5° C. 1H NMR (300 MHz; DMSO-d6): δ 1.75 (brs, 6H), 2.05–2.13 (m, 9H), 6.88 (dd, J1=1.8 Hz, J2=8.7 Hz, 1H), 7.40–7.42 (m, 2H), 7.61–7.64 (m, 2H), 7.73–7.79 (m, 3H), 9.62 (s, 1H), 12.57 (brs, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](/[O:20][CH3:21])\[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O.O1CC[CH2:42][CH2:41]1>C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](/[O:20][CH3:21])\[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:41][CH3:42])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(/OC)C(=O)OC)cc2OCCCC)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(/OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.33 g (0.65 mmol) of methyl (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 8 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 6 hours. After cooling, the reaction is worked up by addition of 2 mL (2 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 and then 50/50 heptane/ethyl acetate mixture. The product obtained is then recrystallized from isopropyl ether to give 0.25 g (90%) of (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a white solid with a melting point of 89° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)cc(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Temperature: 0 °C
Yield: 94.8 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,5-trifluorophenyl)-naphthalen-1-yl]-methanone (2.85 g, 5.34 mmol) in 50 mL methylene chloride and cool to 0° C. Add boron tribromide (3.0 mL, 31.7 mmol) and allow to come to room temperature. Pour into a two phase system of saturated sodium bicarbonate and 3/1 chloroform/isopropanol. Wash the organic layer with brine and dry over 3 Å molecular sieves. Concentrate to give 2.63 g (95%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:21]([CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)([OH:23])=[O:22]
Reactant: CCOC(=O)CCCCl
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1ccc2sc3ccccc3c(=O)c2c1

Procedure:
2-Hydroxy-thioxanthone (4.56 g) was mixed with dimethylformamide (125 ml), ethyl 4-chlorobutyrate (6.02 g), potassium carbonate (2.80 g) and potassium iodide (0.50 g) and the mixture was stirred under reflux for four hours. The resulting mixture was poured carefully with stirring into cold distilled water. The yellow solid which precipitated, which is the ethyl ester of 2-(3-carboxypropoxy)thioxanthone, was collected by filtration and recrystallised from ethanol. The ethyl ester of 2-(3-carboxy-propoxy)thioxanthone (4.2 g) was dissolved in triethanolamine (50 ml) and a solution of potassium hydroxide (5.0 g) in distilled water (5 ml) and ethanol (20 ml) was slowly added with stirring. The resulting mixture was stirred under reflux for two hours, cooled, poured into a large excess of distilled water, and then acidified with hydrochloric acid. The resulting yellow precipitate was filtered off and recrystallised from ethanol to give 2-(3-carboxy-propoxy)thioxanthone.