Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O.N1CCCCC1>CN(C=O)C>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:30]([C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[F:27])=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1ccccc1F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3ccccc3F)n(Cc3csc4ccccc34)nc21
Temperature: 85 °C

Procedure:
A solution of 100 mg (0.47 mmol) of 6-hydrazino-1-isobutyl-3-methyl-2,4(1H,3H)-pyrimidinedione (Example 1d) and 76.4 mg (0.47 mmol) of 1-benzothiophene-3-carbaldehyde in 5 mL DMF was stirred at ambient temperature for 3 h. Added via syringe was 100 μL (0.95 mmol) of 2-fluorobenzaldehyde and 48 μL (0.48 mmol) of piperidine. The mixture was heated at 85° C. for 20 h. Solvent was removed, and the residue was purified by HPLC (60% CH3CN-water with 0.1% TFA) to afford the title product as a white solid.
Reaction SMILES: N1([C:6]([CH2:11][CH3:12])=[CH:7][C:8]([O-:10])=[O:9])CCCC1.[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=O.[CH2:19](N(CC)CC)[CH3:20].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:17]([C:16]1[C:7]([C:8]([O:10][CH2:19][CH3:20])=[O:9])=[C:6]([CH2:11][CH3:12])[O:15][N:13]=1)[CH3:18]
Reactant: CCC[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: CCC(=CC(=O)[O-])N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CC)noc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a 0° C. solution of 3-(pyrrolidin-1-yl)pent-2-enoate (3.4 g, 17.2 mmol), 1-nitropropane (2.0 mL, 22.2 mmol), and triethylamine (7.5 mL, 53.4 mmol) in anhydrous chloroform (20 mL) was added a solution of phosphoryl trichloride (4.0 mL, 42.9 mmol) in anhydrous chloroform (6 mL) via syringe pump (1 hour). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then stirred at reflux for 1 hour. After cooling to room temperature, the mixture was extracted with water (3×20 mL), 2 N HCl (2×20 mL), and brine (1×20 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-15% ethyl acetate/hexane), affording ethyl 3,5-diethyl-1,2-oxazole-4-carboxylate (830 mg, 25%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Br[CH2:39][CH2:40][CH2:41][OH:42]>CN(C=O)C>[OH:42][CH2:41][CH2:40][CH2:39][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Methyl (1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.14 g, 0.29 mmol) in dry DMF (1 ml) was added to NaH (9 mg, 0.38 mmol) in a small volume of dry DMF. The mixture was stirred at ambient temperature for 20 min. then 3-bromopropan-1-ol (37 μl, 0.41 mmol) was added. After stirring for 1 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water then brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide methyl (1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 65%)(1 H-NMR indicated some epimerization had occurred at C-2). This material was used without further purification. Methyl(1RS,2RS,3RS) -3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and aqueous potassium hydroxide added (2M, 0.22 ml, 0.44 mmol). The mixture was stirred under reflux overnight then cooled, diluted with water, acidified with 3M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil. The product was purified by chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was converted to its dicyclohexylamine salt. m.p. 110°-112° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C(O)CC>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: CCCCO
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: CCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-butanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extract is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:15]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:14]2[N:19]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:17]=[C:16]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:11][CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)Nc1ccc(O)cc1
Solvent: CCO
Product: O=C(CCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 45.7 g (0.16 mol) of 6-bromo-N-(4-hydroxyphenyl)hexanamide, 26.0 g (0.16 mol) of 1-phenylpiperazine and 22.4 ml (16.3 g, 0.16 mol) of triethylaminwe in 400 ml of ethanol was heated under reflux overnight and then concentrated under vacuum. The residue was mixed with sodium bicarbonate solution and trichloromethane. The resulting suspension was filtered. The solid was recrystallized from ethanol-water and then from acetonitrile to give the end product as tan crystals, mp 157°-159°.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.CN1CCCC1=O.N1C=CC=CC=1.[C:38]1(=[O:52])[N:42]([CH2:43][C:44](Cl)=[O:45])[C:41](=[O:47])[C:40]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:39]12>CN(C)C1C=CN=CC=1.O>[Cl:24][C:5]1[C:4]([NH:3][C:44](=[O:45])[CH2:43][N:42]2[C:41](=[O:47])[C:40]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:39]3[C:38]2=[O:52])=[CH:22][CH:21]=[C:20]([Cl:23])[C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline dihydrochloride (4.06 g), 4-dimethylaminopyridine (120 mg), N-methylpyrrolidone (30 ml) and pyridine (10 ml) was added phthalimidoacetyl chloride (3.35 g) at ambient temperature. The mixture was stirred at 50° C. for 1.5 hours and cooled in an ice-water bath. Water (40 ml) was added therein and the mixture was stirred for 30 minutes in an ice water bath. The precipitate was collected by vacuum filtration and washed with water and ethyl acetate to give 8-[2,6-dichloro-3(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.45 g) as a yellowish powder.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([C:32](Cl)=[O:33])[CH:26]=[CH:25]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O1CCOCC1.N1C=CC=CC=1>O>[C:1]([NH:9][NH:10][C:32]([C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=2)[CH:28]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCC(=O)NN
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCOc1ccc2cc(C(=O)NNC(=O)CCCCCC)ccc2c1
Temperature: 85 °C
Yield: 96 %

Procedure:
In a 50 ml-three-necked flask, 0.40 g (2.77 mM) of heptanohydrazide, 1.05 g (3.03 mM) of 6-decyloxy-2-naphthoyl chloride and 20 ml of dioxane were placed and heated to about 85° C. under stirring. To the mixture, 1.05 ml (13.0 mM) of pyridine was added, followed by heating to 90°-92° C. and stirring for 40 minutes at 90°-92° C. After the reaction, the reaction mixture was cooled and poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and further washing with acetone to obtain 1.21 g of N-heptanoyl-N'-(6-decyloxy-2-naphthoyl)hydrazine (Yield: 96.0%). ##STR28##
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][C:3]=1[F:15].[CH:16]1([NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[C:22]=2C)[CH2:18][CH2:17]1.[C:38](=O)([O-])O.[Na+]>CC(O)C.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>[CH:16]1([NH:19][C:20]([C:21]2[CH:22]=[C:23]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][C:3]=3[F:15])[C:24]([CH3:38])=[CH:25][CH:26]=2)=[O:37])[CH2:17][CH2:18]1
Reactant: O=C(NCC1CC1)c1ccc(Br)c(F)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)NC1CC1
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1F

Procedure:
4-Bromo-N-cyclopropylmethyl-3-fluorobenzamide (Intermediate 15, 60 mg), N-cyclopropyl-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg), tetrakis(triphenylphosphine)palladium (2.5 mg) and aqueous sodiumhydrogen carbonate (1M, 1 ml) were heated in propan-2-ol (2 ml) at 85° C. for 18 hours. The reaction was concentrated under vacuum and the residue applied to a SPE (Si, 2 g) and eluted with 1:3 and 3:1 ethyl acetate/cyclohexane. The solvent was evaporated from the latter fraction under vacuum and the residue triturated with ether to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-2′-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: C(OC(OCC)C1C=C(C2C(C3C=CC=CC=3)C(=O)C3C(C(OC)=O)=CC=CC=3N2)C=CC=1)C.[CH2:35]([O:37][CH:38]([O:67][CH2:68][CH3:69])[C:39]1[CH:40]=[C:41]([CH:45]2[CH:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:53](=O)[C:52]3[C:51]([C:62]([O:64]CC)=O)=[CH:50][CH:49]=[CH:48][C:47]=3[NH:46]2)[CH:42]=[CH:43][CH:44]=1)[CH3:36].O.[NH2:71][NH2:72]>CO>[CH2:68]([O:67][CH:38]([O:37][CH2:35][CH3:36])[C:39]1[CH:40]=[C:41]([CH:45]2[NH:46][C:47]3[C:52]4[C:53](=[N:71][NH:72][C:62](=[O:64])[C:51]=4[CH:50]=[CH:49][CH:48]=3)[CH:54]2[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:42]=[CH:43][CH:44]=1)[CH3:69]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1cccc(C(OCC)OCC)c1)N2
Agent: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccccc2)c1
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of methyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (160 mg, 0.36 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3 mL) was stirred at 25° C. for overnight. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the 8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 58%) as a yellow solid. LC-MS (ESI) m/z: 442 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(O)C.O>[OH:1][CH2:2][C:3]1[N:32]([CH2:29][CH2:30][CH3:31])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CCCN
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cn(CCC)c(CO)cc1=O

Procedure:
A mixture of 20.0 g (51 mMole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone and 30 mL of a 40% solution of propylamine in ethanol is heated in an autoclave at 100°-110° C. for 5 hours. After cooling, the crystallizate formed is taken up in water, stirred, filtered off, dried and recrystallized from ethyl acetate, colorless crystals thereby being obtained; m.p 120°-121° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[C:47]1[C:53]([N:54]2[C:61]3[N:57]([N:58]=[C:59]([C:62]4[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=4)[CH:60]=3)[CH:56]=[CH:55]2)=[C:52]([CH3:68])[CH:51]=[CH:50][C:48]=1N.[CH3:69][N:70]([CH:72]=[O:73])C>>[CH3:48][C:50]1[CH:51]=[C:52]([CH3:68])[C:53]([N:54]2[C:61]3[N:57]([N:58]=[C:59]([C:62]4[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=4)[CH:60]=3)[CH:56]=[CH:55]2)=[CH:47][C:69]=1[NH:70][C:72](=[O:73])[C:9]1[CH:13]=[C:14]([S:16]([F:21])([F:17])([F:19])([F:18])[F:20])[CH:15]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=1
Reactant: COCCOCc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: CN(C)C=O
Reactant: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COCCOCc1cc(C(=O)Nc2cc(-n3ccn4nc(-c5cccnc5)cc34)c(C)cc2C)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
58 mg (0.173 mmol) of the compound of Example 98A and 75 mg (0.198 mmol) of HATU were dissolved in 1 ml of DMF, and 24 mg (0.198 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added slowly. 50 mg (0.165 mmol) of the compound of Example 11A were then added. The reaction mixture was stirred at RT for about 16 h and then separated into its components by preparative HPLC (Method 36). Pooling of the product fractions, evaporation and drying of the residue under high vacuum gave 76 mg (75% of theory) of the title compound.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(Cl)Cl>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)(=[O:16])=[O:17])[CH2:36][C@@H:37]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:38])[CH:1]=[O:3]
Reactant: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cc2)CC1)NO)c1ccccc1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C#Cc1ccc(N2CCN(S(=O)(=O)CC(C[C@H](C)c3ccccc3)N(O)C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To formic acid (3.75 mL, 98 mmol) at 0° C. was added acetic anhydride (750 μL, 7.8 mmol) and the mixture was stirred at 0° C. for 10 minutes. This was added to a solution of 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(trimethylsilylethynyl)phenyl]piperazine (720 mg, 94 wt %, 1.35 mmol) in CH2Cl2 (5 mL) cooled to 0° C. The reaction was brought quickly to RT and stirred for 20 minutes. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (3×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for two hours. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 40–85% EtOAc in iHexane) and evaporated in vacuo. The solid was dissolved in ether/CH2Cl2 and the insoluble contaminant removed by filtration to give the title compound as a pink foam (90 mg, 0.171 mmol, 15%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].C(Cl)Cl.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1.[O:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[N:40]=[CH:41][C:42]3[CH2:48][CH2:47][NH:46][CH2:45][C:43]=3[N:44]=2)[CH2:34][CH2:33]1>O.C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[NH:11][C:25]([N:46]2[CH2:47][CH2:48][C:42]3[CH:41]=[N:40][C:39]([NH:38][CH:35]4[CH2:34][CH2:33][O:32][CH2:37][CH2:36]4)=[N:44][C:43]=3[CH2:45]2)=[O:26])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NC(c1ccc(Cl)c(Cl)c1)c1cnco1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A solution of (3,4-dichlorophenyl)(oxazol-5-yl)methanamine hydrochloride (22, 183 mg, 0.779 mmol), TEA (326 μL, 2.34 mmol) and DCM (5 mL) was stirred at RT for 10 min. CDI (158 mg, 0.974 mmol) was added and the reaction was stirred at RT for 1 h. A solution of 28 (211 mg, 0.779 mmol), TEA (326 μL, 2.34 mmol) and THF (2 mL) was stirred for 10 min then added to the solution and the resulting mixture stirred for 2 h at RT. The reaction was poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (2-5% MeOH/DCM). The recovered product was further purified by reverse phase column chromatography (SP4, 0-55% MeCN:water) to afford 82 mg (20.9%) of N-((3,4-dichlorophenyl)(oxazol-5-yl)methyl)-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (30): 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.86 (s, 1H), 7.43 (m, 2H), 7.17 (dd, 1H). 6.93 (s, 1H), 6.30 (d, 1H), 5.09 (d, 1H), 4.88 (d, 1H), 4.37 (s, 2H), 4.05-3.95 (m, 3H), 3.68 (m, 2H), 3.54 (t, 2H), 2.70 (t, 2H), 2.01 (d, 2H), 1.59-1.46 (m, 2H); LCMS (ACPI-pos) m/z 505.5 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C([O-])(=O)C>CN(C)C=O>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(I)cc1
Reactant: Oc1ccccc1S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCc1ccc(Sc2ccccc2O)cc1

Procedure:
A solution of 4-(4-iodophenyl)butyric acid (0.86M) and dimethylformamide was treated with 2 eq of potassium carbonate, 1.5 eq of 2-hydroxythiophenol and a catalytic amount of cuperic acetate (0.01 eq). The reaction mixture was refluxed for 18 hr, cooled to 25 C., acidified with aqueous acid and extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane as eluant to give 4-(4-(2-hydroxyphenyl)thiophenyl)butyric acid.