Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.FC1C=CC(C=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Yield: 99.1 %

Procedure:
A mixture of 4-amino-3-nitrophenol (1.54 g; 10.0 mmol), 4-fluorobenzaldehyde (1.05 mL; 10.0 mmol) and Cs2CO3 (3.91 g; 12.0 mmol) in anhydrous dimethylsulfoxide (10 mL) was heated at 80 degrees Centigrade, under nitrogen. An additional portion of 4-fluorobenzaldehyde (0.050 mL; 0.50 mmol) was added after 1 hour and heating was continued. After 2 hours the mixture was cooled, poured into water and extracted three times with ethyl acetate. Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexanes), affording 2.56 g of 4-[(4-Amino-3-nitrophenyl)oxy]benzaldehyde as an orange solid. 1H NMR (400 MHz, CDCl3) delta ppm 6.11 (br. s, 2H), 6.90 (d, J=9.1 Hz, 1H), 7.04 (m, 2H), 7.20 (dd, J=9.0, 2.8 Hz, 1H), 7.86 (m, 2H), 7.89 (d, J=2.7 Hz, 1H), 9.93 (s, 1H) ppm. (M+H) 259, 2.33 min (LC/MS method A).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[OH:29][CH:30]([C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32]>>[OH:29][CH:30]([C:35]1[CH:36]=[CH:37][C:38]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)=[CH:39][CH:40]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: COC(=O)C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 75.4 %

Procedure:
Compound 3a (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with methyl 2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (666 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 9c (300 mg, 72% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H29N5O4: 524.2 (M+H). Found 524.2.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.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.C(O)C>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=[C:26]([C:21]3[CH:22]=[C:23]([C:12]4[C:11]5[C:6]([C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=6[CH:13]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:24]=[C:19]([Br:18])[CH:20]=3)[N:27]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a stream of argon, 0.71 g (3.21 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.0 mg (0.0321 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 60° C. and maintained at that temperature for 12 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (2:1) mixed solvent as an eluent to give 0.54 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3-bromophenyl]-1,3,5-triazine as a white solid (yield: 30%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:28]N(Cl)C(OCC)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.Cl>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[C:18]([Cl:28])=[C:17]([C:21]([F:23])([F:22])[F:24])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Reactant: CCOC(=O)N(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Reaction time: 0.25 h
Yield: 130.7 %

Procedure:
A stirred solution of 0.84 gram (2.1 mmole) of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (prepared as described in Example 2) in 20 mL of acetic acid had 0.16 gram (1.0 mmole) of N,N-dichlorourethane added via syringe. Upon completion of the addition the clear reaction mixture was stirred for 15 minutes, then one drop of concentrated hydrochloric acid was added, and the reaction mixture was stirred at ambient temperature for 72 hours. After this time the reaction mixture was poured into 100 mL of water, and 10 grams of sodium carbonate were added. The mixture was extracted with three 50 mL portions of methylene chloride. The organic extracts were combined and washed with one 50 mL portion of an aqueous 5% sodium carbonate solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrate under reduced pressure, yielding a pale yellow oil which was subjected to column chromatography on silica gel. Elution was accomplished with 9:1 heptane:ethyl acetate, followed by 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.57 gram of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 83°-86° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:16][CH3:17].O.C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([O:16][CH3:17])[CH:6]=2)[CH2:15][CH2:14]1)=[O:28]
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 185.2 %

Procedure:
To a 3 L flask equipped with a mechanical stirrer was added 1-(4-chloro-3-methoxyphenyl)piperazine dihydrochloride (220 g, 0.73 mol, 1 equiv), CH2Cl2 (1000 mL), and water (1000 mL). The biphasic mixture was cooled to 5° C. with an ice-water bath. K2CO3 (506 g, 5 equiv) was added to the vigorously stirring solution in portions to minimize foaming. A solution of chloroacetyl chloride (124.4 g, 1.5 equiv) in CH2Cl2 (100 mL) was added dropwise from an addition funnel, while maintaining an internal temperature below 8° C. After 1 h, the cooling bath was removed, and the reaction warmed to room temperature. After an additional 1 h, the layers were partitioned. The aqueous phase was extracted with CH2Cl2 (2×300 mL), and the combined organic layers dried over 3:1 Na2SO4/K2CO3 (addition of K2CO3 helps the solution phase to become clear). After filtration, the filtrate was concentrated in vacuo, and the residue was dried for 16 h under vacuum to afford the product as an off-white solid (410 g, 92% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH:32]C(=O)OC(C)(C)C)[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH2:32])[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Yield: 36.1 %

Procedure:
4×0.1 cm3 of trifluoroacetic acid (containing 10% of anisole) are added to a mixture of 127 mg of 1,1-dimethylethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate in 5 cm3 of dichloromethane stirred at 20° C., this addition taking place over 7 h, until the starting product has disappeared. The reaction mixture is then concentrated under reduced pressure, so as to recover 186.5 mg of yellow powder which is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 μm), elution being carried out with a gradient of dichloromethane then dichloromethane/methanol: 99.5/0.5, 99/1, 98.5/1.5, 98/2, 97.5/2.5, 97/3. 36.6 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([F:17])[CH:5]=[CH:4][C:3]=1[NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20].I[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[F:1][C:2]1[C:3]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:20])=[O:21])=[CH:4][CH:5]=[C:6]([F:17])[C:7]=1[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1F
Temperature: 80 °C

Procedure:
A mixture of crude Intermediate N-(2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (854 mg), Intermediate (S)-methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (350 mg, 90% pure), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2 M aqueous sodium carbonate solution (6 ml), toluene (50 ml), and ethanol (6 ml) was heated at 80° C. for 16 h. The cooled mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (70:1 to 40:1 DCM/methanol eluant) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH:8]=[O:9].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH2:8][OH:9]
Reactant: Cn1cnc(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1cnc(CO)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a 0° C. solution of 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde (475 mg, 3.3 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (190 mg, 5.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. Water (25 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (20 mL). The mixture was extracted with water (5 mL). The organic extract was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (5-chloro-1-methyl-1H-imidazol-4-yl)methanol (397 mg, 82% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8](Br)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].O.O.O.O.O.O.O.O.[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1>CC(C)=O>[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1.[C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)(=[O:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(=O)OCC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 70.3 %

Procedure:
A solution of 36.3 g (0.2 mol) of crude 4-acetoxy-1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 50 ml of acetone was added dropwise, at the boil, to a suspension of 21 g (0.3 mol) of 1,2,4-triazole and 30g (0.2 mol) of potassium carbonate in 200 ml of acetone. After heating for 15 hours under reflux, the mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water at a time, dried over sodium sulphate and concentrated. The residue was dissolved in 100 ml of acetone and 36 g (0.1 mol) of 1,5-naphthalenedisulphonic acid octahydrate in 100 ml of acetone were added. The crystalline precipitate which resulted was filtered off and dried. 45 g (45% of theory) of 4-acetoxy-1-(4-chloro-phenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one 1,5-naphthalenedisulphonate of melting point 155°-160° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](O)=[O:31])=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH3:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:33]([O:40][CH2:41][CH2:42][N:43]([CH3:44])[C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]=1)=[O:31])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35]
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 48.1 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-02) (2 g, 48.09%) was synthesized as a yellow liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (7-02) (3 g, 6.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) (1.39 g, 7.399 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:14][CH2:13][CH2:12]1)[C:8]2=[N:21][S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCC2
Agent: [Ti+4]
Agent: CC[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC2
Temperature: 25 °C
Yield: 135.3 %

Procedure:
6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-one (Intermediate 38, 1.1 g, 4.38 mmol), 2-methylpropane-2-sulfinamide (0.96 g, 7.88 mmol), and titanium ethoxide (1.805 mL, 8.76 mmol) were dissolved in methyl THF (20 mL), and heated to reflux overnight. The reaction was allowed to cool to r.t., then it was diluted with EtOAc (150 mL). Water (22 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were evaporated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetate 8:1) to afford the title compound (2.1 g, 77% yield), used as such in the next step: MS (ES+) m/z 354 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].O1CCCC1>CN(C)C=O>[CH2:18]([O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
11 g of sodium hydride was added to a mixture of 39.63 g of 2-chloro-3-nitropyridine, 31.23 g of ethyl glycolate, 250 ml of tetrahydrofuran and 20 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 48.3 g of 2-(ethoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C)C=O>[CH3:9][C:4]([O:3][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])([CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C)(C)O
Reactant: C=CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCCOC(C)(C)C(=O)OC
Yield: 30.4 %

Procedure:
To 500 ml of dry N,N-dimethylformamide, 17 g of 60% sodium hydride was added, and 48 g of methyl 2-hydroxyisobutyrate was added dropwise with stirring under ice-cooling, and stirred for 10 minutes. Then, 100 g of 9-bromo-1-nonene (purity: 63.4%) was added, and the mixture was stirred for 15 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 29.9 g of the objective compound as yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](=[NH:31])OCC>C(O)C>[ClH:18].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1c(F)cccc1F
Yield: 2.2 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave art oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (0.18 g), m.p. 127°-135° C.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]#[N:10].OO.Cl>O.C(O)C>[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]([NH2:10])=[O:1]
Reactant: CCCCCC(O)CCCN(C#N)CCCCCC(C)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCC(C)C(=O)O)C(N)=O

Procedure:
To a solution of sodium hydroxide (0.4 g., excess) in water (50 ml.) and ethanol (50 ml.) is added 7-[N-(4-hydroxynonyl)-cyanamido]-2-methylheptanoic acid (1.5 g., 0.005 mole). The clear solution that is obtained is treated with 30% hydrogen peroxide (1.25 ml., excess). After two hours the reaction is poured into water (125 ml.), acidified with 5% hydrochloric acid and extracted with ethyl acetate (3 × 75 ml.). The organic phase is washed with brine, then dried over sodium sulfate. Evaporation of the solvent yields 7-[1-(4-hydroxynonyl)ureido]-2-methyl-heptanoic acid as a viscous oil.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O)c2ccccc2)c1
Yield: 98.9 %

Procedure:
A solution of 2-bromo-2-phenylacetic acid (0.5 g, 2.28 mmol) and 3-methoxyaniline (0.54 mL, 4.56 mmol) in THF (12 mL) is refluxed for 4 hours. Solvent is removed under vacuum, the residue is taken up with 1M HCl and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=98/2 to 9/1) to obtain intermeaditae I116 as a white solid (0.58 g, 99% yield).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].O.[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([CH:12]=[O:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=[Se]=O
Reactant: Cc1ncccc1NS(C)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cccnc1C=O
Yield: 83.6 %

Procedure:
To a solution of 3-methylsulfonamido-2-methylpyridine (310 mg, 1.66 mmol) in dioxane (8 mL) was added water (0.8 mL) and selenium(IV) oxide (241 mg, 2.17 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 1:1) to afford the title compound (278 mg, 83%). 1H NMR (CDCl3) □ 3.14 (s, 3H), 7.53 (dd, 1H, J=9, 6 Hz), 8.16 (dd, 1H, J=9, 3 Hz), 8.53 (dd, 1H, J=6, 3 Hz), 10.09 (s, 1H), 10.41 (br s, 1H, NH).