Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:31]O)[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:38][P:39]([CH2:44]P(OCC)(OCC)=O)(=[O:43])[O:40][CH2:41][CH3:42])[CH3:37].[H-].[Na+].C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>ClCCl.C1COCC1.[O-2].[O-2].[Mn+4]>[CH2:36]([O:38][P:39](/[CH:44]=[CH:31]\[C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])=[NH:9])[S:11][C:12]=2[S:33][CH3:34])(=[O:16])=[O:17])[CH:19]=1)(=[O:43])[O:40][CH2:41][CH3:42])[CH3:37]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Agent: [Mn+4]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(/C=C\c1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1)OCC
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
Manganese dioxide (0.041 g, 0.470 mmol) was added to a solution of ({[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.047 mmol) [example 213, step b] in dichloromethane [5 mL] and refluxed for 3 hours. The reaction was filtered through Celite and evaporated. The crude residue was dissolved in anhydrous THF [2 mL] and added to a solution of (diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester (0.011 g, 0.061 mmol) and sodium hydride (0.003 g, 0.056 mmol) in THF [2 mL] at room temperature and stirred for 0.5 hours. A solution of 1N NaOH/MeOH (1/1) [10 mL] was added and the crude product was extracted with ether, dried with magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.019 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C30H37N2O7PS3: 664.15; found: 664.8.
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C=C(O)C=CC=1C(C1C=CC=CC=1O)=O.OC1C=C(O)C=CC=1C(C1C=CC(O)=CC=1O)=O.OC1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O>>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: COc1ccc(C(=O)c2ccccc2O)c(O)c1
Agent: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: O=C(c1ccccc1)c1ccc(O)cc1O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
For example, 2-hydroxybenzophenone, 2,4-dihydroxybenzophenone, 2,2′,4-trihydroxybenzophenone, 2,2′,4,4′-tetrahydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, or the like may be used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.CO.C(Cl)(Cl)Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:28][CH:29]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(4-methoxyphenyl)-3-[N-(4-hydroxyphenyl)acetamido]-6-methoxy-benzo[b]thiophene (1.31 g, 3.13 mmol) and Cs2CO3 (4.10 g, 12.50 mmol) in 15 mL of anhydrous DMF was added 2-chlorethylpiperidine hydrochloride (1.15 g, 6.26 mmol). The resulting mixture was stirred vigorously at room temperature for 5 h. The reaction mixture was diluted with 200 mL of H2O, and then extracted several times with EtOAc. The combined organic was then washed with H2O several times and then dried (Na2SO4), Concentration in vacuo provided an oil. Chromatography (1% CH3OH/CHCl3, SiO2) provided 1.49 g (90%) of 2-(4-methoxyphenyl-3-[N-[4-[2-(1-piperidinyl)ethoxy]phenyl]acetamido]-6-methoxybenzo[b]thiophene as an amber oil. 1H NMR (DMSO-d6) δ (doubling due to amide rotamers) 7.66-6.70 (m, 11 H), 3.93 (m, 2H) 3.78 and 3.58 (s, 6H), 2.8-2.30 (m, 6H), 2.01 and 1.78 (s, 3H), 1.52-1.11 (m, 6H). FD mass spec: 530. Anal. Calcd. for C31H34N2O4S: C, 70.16; H, 6.46; N, 5.28. Found: C, 70.33; H, 6.34; N, 5.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:57][CH2:58][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:32])=[CH:13][CH:12]=2)[NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=2)=[O:18])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCCN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 mmol), EDC (45.8 μL, 259 μmol) and HOBt hydrate (39.6 mg, 259 μmol) in DCM (0.5 mL, 8 mmol) was stirred at room temperature for 10 minutes. 4-Morpholineethanol (41.8 μL, 345 μmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (14.1 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C22H39ClFN4O2, 577.18. found 577.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([N:22]([CH2:31][CH3:32])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:31]([N:22]([CH2:20][CH3:21])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:32]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCN(CC)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-diethylaminobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-diethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11].[C-]#[C-].[Na+].[Na+].N.S(=O)(=O)(O)[O-].[PH4+].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:27]=1.S(=O)(=O)(O)O.[PH4+]>>[CH3:12][C:10]([OH:11])([CH:9]=[CH:8][CH:7]=[C:6]([CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:14])[CH3:1])[CH:26]=[CH2:27]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Product: C=CC(C)(O)C=CC=C(C)CCC=C(C)C

Procedure:
3,7,11-Trimethyl-dodeca-1,4,6,10-tetraen-3-ol is prepared, as described in German Pat. No. 1,115,238, from pseudo-ionone by a reaction with sodium acetylide in liquid ammonia followed by hydrogenation of the triple bond. Using the conventional method described in German Pat. No. 1,068,710, the product is then converted to the phosphonium bisulfate by means of triphenylphosphine and sulfuric acid. This phosphonium salt is reacted with β-formylcrotyl acetate by the method described in German Pat. No. 1,068,710 to give 1-acetoxy-3,7,11,15-tetramethyl-hexadecy-2,4,6,8,10,14-hexaene. This ester is reacted with triphenylphosphine and sulfuric acid as described in German Pat. No. 1,068,709 to give crystalline 3,7,11,15-tetramethyl-hexadeca-2,4,6,8,10,14-hexaen-1-yl-triphenylphosphonium bisulfate. Melting point 150°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][NH2:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][CH3:19])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CN
Product: CNC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-[(2-chloro-4-iodophenyl)amino]-N-methylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.43 mmol of monomethylamine LC/MS [9.23 min; 389 (M+1)]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])C(O)=O)=[CH:12][CH:11]=1)([O-:3])=[O:2].[N+](C1C=CC=CC=1C1C=CC=CC=1)([O-])=[O:22].C(Cl)(=O)C>>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH:12]=1)(=[O:22])[CH3:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
The 2-(2'-nitro-4-biphenylyl)propionic acid is readily prepared in the following manner: 2-nitrobiphenyl is acylated with acetyl chloride, giving 4-acetyl-2'-nitrobiphenyl. This is converted with chloroacetonitrile under alkaline conditions to the intermediate isomeric 2-methyl-2-[4-(2'-nitrophenyl)]glycidonitriles which, when treated with lithium perchlorate and then base, is isomerized to methyl 2-(2'-nitro-4-biphenylyl)propionate. Saponificiation of the latter gives the desired 2-(2'-nitro-4-biphenylyl)-propionic acid. The esters are readily converted to the acid and the acid to the esters by conventional means.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:27])([CH3:26])[CH3:25].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH:33]([NH:40][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[N:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2nccn3c(-c4cccc(NC(CCNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 130 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 39 supra) (0.56 g, 1.5 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (0.45 g, 1.8 mmol), Pd2(dba)3 (90 mg), Davephos (120 mg), K2CO3 (0.25 g, 1.8 mmol) in dioxane (60 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified first by chromatography (CH2Cl2:CH3OH, 100:1) then by preparative-HPLC to give (3-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 44 mg, 5.4%). LC-MS: [M+H]+ 543.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH:18]C)[S:16][CH:17]=2)=[CH:9][CH:8]=1.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(OCC)(=O)C.CC(CC(C)C)=O>[C:20]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]4[N:14]=[C:15]([NH2:18])[S:16][CH:17]=4)=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: CNc1nc(-c2ccc(CCCCCl)cc2)cs1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4cccc5ccccc45)CC3)cc2)cs1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 2.61 g (7.5 mmol) of 4-(4-(4-chlorobutyl)phenyl)-2-methylaminothiazole hydrobromide, 1.59 g (7.5 mmol) of N-(1-naphthyl)piperazine, 1.31 ml (7.5 mmol) of diisopropyethylamine, 1.59 g (15 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutylketone. The reaction was heated at reflux for 4.5 days, cooled, and the precipitate filtered, and the filtrate evaporated. The residue was taken up in methylene chloride and chromatographed on silica gel using methylene chloride/ethyl acetate as eluent to give an oil. The oil was taken up in ethyl acetate, precipitated by addition of ethyl acetate saturated with hydrochloride, and the precipitate filtered, washed with ethyl acetate, and dried to give a white solid, m.p. 242°-245° C., 1.67 g (43%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Into a 500-mL 4-necked round-bottom flask, was placed a solution of sodium hydride (4.05 g, 168.75 mmol, 1.70 equiv) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14 g, 99.22 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 0° C. over 20 min. The resulting solution was stirred for 2 hr at room temperature. Cu2Cl2 (9.83 g, 100.31 mmol, 1.01 equiv) was added and a solution of 2,6-difluorophenol (15.5 g, 119.15 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath, diluted with 500 mL of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was placed on a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 20 g (80%) of 1,3-difluoro-2-(4-nitrophenoxy)benzene as a brown oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OC[C@H]1CCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To (R)-(tetrahydrofuran-2-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (3 mL) and pyridine (3 mL) at ambient temperature was added 4-methylbenzene-1-sulfonyl chloride (2.0 g, 10.3 mmol) portion-wise over 5 minutes. This mixture was stirred for 16 hours at ambient temperature then was quenched with 10 mL of 5% aqueous HCl and was extracted with 3×5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 75% hexanes in ethyl acetate) to give the title compound (1.7 g, 6.8 mmol, 69% yield). MS (DCI/NH3) m/z 257 (M+H)+ and 274 (M+NH4)+.
Reaction SMILES: [Na].C(O)(=[S:4])C.Br[CH:7]([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][CH3:24])[C:8]([OH:10])=[O:9].[OH-].[Na+].Cl>CO>[SH:4][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CC(O)=S
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Under inert atmosphere 2.0 gr of sodium metal suspension (40% in mineral oil) were slowly added to 100 ml of dry methanol at 0° C. At the end of the addition reaction mixture was stirred for 10 min at RT and 1.75 ml (21.58 mmole) of thioacetic acid were added. After additional 10 min of stirring, 30 ml degassed methanolic solution of 6.1 gr (18.19 mmole) of 16 bromohexadecanoic acid were added. The resulted mixture was refluxed for 15 hrs, after which, allowed to cool to RT and 50 ml of degassed 1.0 M NaOH aqueous solution were injected. Additional refluxing for 3 hrs required for reaction completion. Resulted reaction mixture was cooled with ice bath and poured, with stirring, into a vessel containing 200 ml of ice water. This mixture was titrated to pH=7 by 1.0 M HCl and extracted with 300 ml of ether. The organic layer was separated, washed with 3×150 ml of water, 150 ml of saturated NaCl aqueous solution and dried over sodium sulfate. After removal of ether material was purified by recrystalization from n-hexane, filtering out and drying over high vacuum. 5.1 gr (97% yield) of the desired product was obtained.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: NCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cccnc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
To a stirred suspension of 2-chloro-nicotinonitrile (Aldrich, 3.30 g, 23.82 mmol) in 2-propanol (30 ml) was added 4-fluoro-benzylamine (3.00 ml, 26.25 mmol) and N,N-diisopropylethylamine (8.30 ml, 47.65 mmol). The reaction mixture was heated to 80° C. for 24 hours. More 4-fluoro-benzylamine (0.55 ml, 4.81 mmol) was added and stirring was continued at 80° C. for another 24 hours. The reaction mixture was cooled to room temperature and the precipitated material was isolated by filtration and washed with 2-propanol. Residual 2-propanol was removed in vacuo affording the title compound (3.04 g) as a white crystalline material. 1H-NMR (DMSO-d6) δ 8.23-8.25 (m, 1H), 7.91 (dd, 1H), 7.73 (t, 1H), 7.34-7.38 (m, 2H), 7.08-7.14 (m, 2H), 6.63-6.67 (m, 1H), 4.57 (d, 2H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCC(C([O-])=[O:17])CC.CCCCC(C([O-])=O)CC.[Sn+2]>>[OH:17][CH:2]([CH2:3][CH2:4][CH2:5][CH:6]=[O:7])[CH:1]=[O:8]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: O=C1CCCCCO1
Agent: [Sn+2]
Product: O=CCCCC(O)C=O

Procedure:
2-Hydroxyadipaldehyde (Aldrich) was reacted with amino terminated PEG to form the Schiff base which was hydrogenated with NaBH4 to form the corresponding amine. The di-PEG derivative was reacted with lactide or caprolactone in the presence of stannous octoate to form the PLA or PCL-PEG2 diblock copolymer.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11](=[O:27])/[CH:12]=[CH:13]/[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[Cl-].[NH4+]>CS(C)=O>[CH3:9][O:10][C:11]([C@@H:12]1[CH2:2][C@H:13]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]1)=[O:27]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of trimethylsulfoxonium iodide (1.16 g, 5.25 mmol) in dimethylsulfoxide (10 ml) was added sodium hydride (60% dispersion in oil, 210 mg, 5.25 mmol) under 0° C., and the solution was stirred at room temperature for 10 minutes. To the resulting mixture was added a solution of 3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acrylic acid methyl ester (1.37 g, 5.09 mmol) was added dropwise under 0° C., and it was stirred for 1 hour at room temperature and for 2 hours at 50° C. After cooling to 0° C., saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with diethyl ether 50 ml×2), and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography (n-hexane/ethyl acetate=7/1) to give 2-(1-tert-butoxycarbonyl-4-piperidyl)-(1R*,2S*)-cyclopropane-1-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:23]([O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[C:31]([Cl:37])[CH:30]=1)([CH3:26])([CH3:25])[CH3:24]>CC(C)=O.O>[C:23]([O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)=[C:31]([Cl:37])[CH:30]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
An amount of 1.00 g (4.22 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) and 2.07 g (6.37 mmol) of caesium carbonate were suspended in 15 ml of acetone and admixed with 1.69 g (5.52 mmol) of tert-butyl-4-(bromomethyl)-3-chlorobenzoate (preparation as per WO 2003/000692, Example 4b). The mixture was stirred at 50° C. for 18 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 9:1→3:2) gave 1.41 g (53% of theory) of the target compound in a purity of 74%.