Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH2:10](Br)[CH:11]=[CH2:12].[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:12][CH:11]=[CH2:10])=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium turnings (9.6 g) in anhydrous ether (50 ml) was added dropwise to a solution of p-chlorobromobenzene (76.6 g) in anhydrous ether (500 ml) at such a rate as to maintain reflux. After refluxing for a further 20 minutes, the solution was cooled to 5o and a solution of allyl bromide (48.4 g) in anhydrous ether (100 ml) was added over 15 minutes. After 30 minutes the solution was allowed to warm to room temperature, and then saturated ammonium chloride was added dropwise, cautiously to avoid excessive frothing. The organic layer was separated and the aqueous phase was extracted with ether. After washing the ether extracts with water and drying, evaporation of the solvent gave a pale yellow oil which was purified by fractional distillation to give 3-(4-chlorophenyl)prop-1-ene as a colourless oil, b.p. 72°-74°/4 mm Hg. (532 Pa).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:22](Br)[CH3:23].Cl>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:14][CH2:23][CH2:22][O:13][C:12]=12)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: CC(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCCO2
Reaction time: 24 h

Procedure:
Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.5 g, 2.5 mmol) and potassium carbonate (1.74 g, 12.65 mmol) in acetone (25 mL). Add dibromoethane (2.37 g, 12.65 mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueous hydrochloric acid solution (35 mL), add water (25 mL), and extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry over-MgSO4, filter, and concentrate in vacuo to give methyl 3-methoxy-4,5-ethylenedioxybenzoate.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C=O)C>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([O:16][CH2:27][C:28]#[N:29])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCCl
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2

Procedure:
A stirred mixture of 2-cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone (2.9 g., 0.1 mole), potassium carbonate (15.2 g., 0.11 mole) and chloroacetonitrile (7.5 g., 0.10 mole) in DMF (100 ml.) is heated at 55°-60° C. for two hours and poured into water. The 2-cyclopentyl-6-cyanomethoxy-7,8-dichloro-1-tetralone that separates is collected and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:14]2[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[CH:16][C:15]=2[O:24][CH3:25])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:14]2[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[CH:16][C:15]=2[O:24][CH3:25])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COCOc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)OC

Procedure:
A solution of Example 32A (10.0 g) and 10% Pd/C (1.0 g) in methanol (200 mL) at room temperature was hydrogenated at 4 atm for 1 hour, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product. MS (ESI(−)Q1MS) m/z 316 (M−H)−.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.N1CCCCC1>C(O)C>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=Cc1cccs1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cccs2)S1
Yield: 66.5 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 16.0 ml (171 mmol) of 2-thiophenecarboxaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 24.03 g of the desired compound (66.6% yield, pale yellow crystals).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[CH3:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nccs2)cc1OCc1ccccc1
Yield: 58 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (70 mg, 0.34 mmol) and K2CO3 (52 mg, 0.32 mmol) in acetone (4.4 mL) was treated with benzyl bromide (58 mg, 0.34 mmol) at RT. Reaction control by TLC showed full conversion after 2 h 30 min. Subsequent benzyl bromide (20 microliter) and K2CO3 (20 mg) were added and stirred over night The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 58% yield (58 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.[CH3:21][C:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:25]([C:22]4([CH3:21])[CH2:24][CH2:23]4)=[O:26])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CC[C@@H](Cc3n[nH]c(=O)n3-c3ccc(Br)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Into a 5 mL microwave vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.473 mmol), 1-methylcyclopropanecarboxylic acid (0.499 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.200 mmol), 1-hydroxybenzotriazole (1.208 mmol), N,N-diisopropylethylamine (1.431 mmol), and N,N-dimethylformamide (2 mL). The vial was capped and the contents were stirred at room temperature for 4 h. Purification of the crude material by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA) followed by collection and concentration of the desired fractions provided the title compound (166 mg, 87%). MS(ES)+ m/e 405.0, 407.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:52])[CH3:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 19b (3 g, 4.15 mmol) in dry tetrahydrofuran (50 mL) was added methylmagnesium bromide (2 mL, 6.22 mmol, 3M in ethyl ether) dropwise at 0° C. The mixture warmed up to room temperature and stirred for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2) and then saturated aqueous sodium chloride (50 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 19c as yellow oil (2.16 g, 70.4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][S:3]1.[CH2:6]([NH:10][C:11]#[N:12])[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:6]([N:10]1[CH2:4][C:2]([CH3:1])([CH3:5])[S:3][C:11]1=[NH:12])[CH2:7][CH2:8][CH3:9]
Reactant: CC1(C)CS1
Reactant: CCCCNC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCN1CC(C)(C)SC1=N
Temperature: 80 °C
Yield: 66.6 %

Procedure:
A mixture of 2,2-dimethyl-thiirane (TCI, 1.5 g, 17 mmol), N-butyl-cyanamide (1.7 g, 17 mmol) (prepared as described in Ross J. Med. Chem. 1979, 22; 412) and potassium carbonate (2.4 g, 17 mmol) in 2-butanone (15 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted twice with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford 2.11 g of the title compound.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH2:19])([CH3:18])[CH3:17]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH:19][CH2:2][CH2:1][C:3](=[O:4])[CH3:5])([CH3:17])[CH3:18]
Reactant: CC(C)(N)C(=O)Nc1cc(Cl)ccc1Cl
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCNC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Yield: 97.4 %

Procedure:
Methyl vinyl ketone (1.02 g) was added to a solution of N-(2,5-dichlorophenyl)-2-aminoisobutyramide (2.4 g) in tetrahydrofuran (10 mL) and the mixture was heated at reflux 30 hours. After distilling off the solvent under reduced pressure, 3 g of N-(2,5-dichlorophenyl)-2-(3-oxobutylamino)isobutyramide was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)CCc3ccc(C(F)(F)F)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-[4-(trifluoromethyl)phenyl]propionic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16].[OH:18]O>C(O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13](=[O:18])[C:14]=2[CH:1]=1)([OH:17])=[O:16]
Reactant: OO
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1O2
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1O2
Reaction time: 17 h

Procedure:
Phenoxathiin-2-carboxylic acid (0.61g) was dissolved in refluxing absolute ethanol (40 ml) and 30% w/v hydrogen peroxide solution (1.50 ml) added. Reflux was maintained for 2 hours, more 30% w/v hydrogen peroxide solution (1.00 ml.) added, and reflux continued for 17 hours. The solution was evaporated to low volume, and the product crystallised out. The solid was filtered, washed and dried to give 2-carboxyphenoxathiin-10-oxide m.p. 223° C. Recrystallisation from absolute ethanol raised the melting point to 237° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1[C:36](=O)[CH3:37])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:36](/[CH3:37])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.44 mL, 1.75 mmol) and 1-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 65, 184 mg, 0.58 mmol) were reacted to give the title compound as a pink oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[S:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1f from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Yield: 39.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) was treated with sodium hydride (8.8 g, 220 mmol) and bromononane (59 g, 54.4 ml, 285 mmol) in DMF (700 ml) as per the procedure of Example 2 (the diamino compound in DMF was cooled in an ice bath during the addition of NaH) to yield 83 g of crude product. 50 g of crude product was purified by silica gel chromatography. Fraction containing 2'-O-nonyl and 3'-O-nonyl product were combined to give a 77:23 mixture (29 g) of the 2' and 3' product. Pure 2'-O-nonyl product is obtained by chromatography. 1H NMR (DMSO-d6) δ 0.95 (t, 3, CH3); 1.17 [m, 12, O--CH2 --CH2 --(CH2)6 ]; 1.42 [m, 2, O--CH2CH2 (CH2)6 ]; 3.27-3.70 (m, 2, H-5'); 3.50-3.70 [m, 2, O--CH2 (CH2)7 ]; 3.95 (m, 1, H-4'), 4.24 (m, 1, H-3'); 4.40 (m, 1, H-2'); 5.10 (d, 1, 3'-OH, J=5 Hz); 5.50 (t, 1, 5'-OH, J=6 Hz); 5.76 (s, 2, 2-NH2); 5.83 (d, 1, H-1', J=6.0 Hz); 6.81 (s, 2, 6-NH2); and 7.96 (s, 1, 8-H).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][NH2:15].[OH-].[K+].Cl>C(O)C>[C:2]1([C:1]2[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:15][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: NN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC(c2ccccc2)=NN1

Procedure:
A mixture of 10.0 g of 3-benzoylacrylic acid, 1.8 g of hydrazine, and 3.7 g of potassium hydroxide in 30 ml. of aqueous ethanol (1:1) is stirred and heated at reflux for 2 hours. The cooled solution is treated with 5 ml of concentrated hydrochloric acid to pH 4.0 to precipitate 7.1 g of solid, melting point 180°-182° C. This material is dissolved in 40 ml of warm dimethylformamide and treated with 140 ml of methanol to crystallize 3.9 g of the title compound, melting point 199°-201° C.
Reaction SMILES: [BrH:1].Br.CC(O)=O.C1(C)C=CC(S([N:16]2[CH2:29][CH2:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:23][C:22]3[N:50]=[C:18]([CH:19]=[CH:20][CH:21]=3)[CH2:17]2)(=O)=O)=CC=1>CC(O)=O>[BrH:1].[C:18]12[CH:19]=[CH:20][CH:21]=[C:22]([N:50]=1)[CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:16][CH2:17]2
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)Cc3cccc(n3)CN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1cc2nc(c1)CNCCNCCNC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A solution of HBr and AcOH was prepared by mixing 48% HBr and glacial AcOH in a 64:35 ratio. To 112 mL of the HBr/AcOH mixture was added 5.5 g (8.2 mmol) of 3,6,9-tris(ρ-tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (prepared by the procedure of Example B) and the reaction mixture was heated at mild reflux with constant stirring for 72 hrs. The reaction mixture was then cooled to room temperature and concentrated to approximately 1/10 of the original volume. The remaining solution was stirred vigorously and 15-20 mL of diethyl ether was added. A off-white solid formed which was filtered, washed with diethyl ether, and dried in vacuo. The dry tetrahydrobromide salt was then dissolved in 10 mL of water, adjusted to pH 9.5 with NaOH (50% w/w) and continuously extracted with chloroform for 4 hrs. After drying over anhydrous sodium sulfate, the chloroform was evaporated to give a Light-tan oil which gradually crystallized upon standing at room temperature to yield 1.2 g (71%) of the title product, mp 86°-88° C. and further characterized by:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24](OC)=[O:25]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:15]([N:18]2[C:24](=[O:25])[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:29][CH:28]=3)[NH:30][C:31]2=[O:32])(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(S(N)(=O)=O)c1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: Nc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 49 %

Procedure:
From 3.5 g (12.9 mmol) of 3-t-butoxycarbonylaminobenzenesulfonamide and 3.9 g (12.8 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a similar manner to Preparation Example 7, 2.2 g (yield 49%: 4 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 5.72 (2H, s), 6.87 (1H, d), 7.12 (1H, s), 7.23-7.27 (2H, m), 7.33 (1H, s), 7.86 (1H, d), 11.61 (1H, s).
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([F:43])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:37][C@@H:38]([OH:42])[C:39]([OH:41])=[O:40])[NH:22][C:23]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH:26]=3)=[O:24])=[CH:16][CH:15]=2)[CH:13]=1.CCN(CC)CC.CC(C)=O>>[C:1]([O:4][CH2:5][O:41][C:39](=[O:40])[C@H:38]([OH:42])[CH2:37][N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]=2[F:43])=[CH:15][CH:16]=1)[NH:22][C:23]([C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH:26]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
Bromomethyl acetate (11.9 mL, 121 μmol) was added to a mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (40.0 mg, 76 μmol) and Et3N (21.1 mL, 152 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and the residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC. The desired fractions were frozen and lyophilized to yield the title compound (8.5 mg, purity 98.5%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H24ClF2N3O7, 600.13. found 600.1.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:17])=[O:9]
Reactant: O=C(O)CCCOc1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCOc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 4-(2-chloro-phenoxy)-butyric acid (250 mg, 1.165 mmol) was added portion wise thionyl chloride (1.69 mL), and the reaction mixture was stirred for 3 hours at 90° C. After such time the excess of thionyl chloride was removed in vacuo to yield the crude title compound which was used in the next step without any further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([N:15]([CH3:17])[CH3:16])[CH:10]([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:16][N:15]([CH3:17])[CH:11]1[CH:10]([CH3:18])[CH2:9][NH:8][CH2:13][CH:12]1[CH3:14]
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC(C)C1N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)C1N(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and Mixtures A+B of 1-benzyl-4-dimethylamino-3,5-dimethylpiperidine (2.7 g, 10.1 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford Mixtures A+B of 4-dimethylamino-3,5-dimethylpiperidine. Yield 0.9 g (52.6%), C9H20N2, m/z 157 (M+1).