Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:69]=[CH:68][C:65]([CH2:66]O)=[CH:64][CH:63]=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:66][C:65]2[CH:64]=[CH:63][C:62]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][N:56]=3)=[CH:69][CH:68]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: OCc1ccc(-c2ccccn2)cc1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 139.8 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (934 mg, 1.95 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using 4-(pyridin-2-yl)benzyl alcohol (397 mg, 2.14 mmol) in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (1.76 g) (pure content 1.26 g) substantially quantitatively as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=5)[C:13]4=[O:33])[CH2:11][O:10][C:9]3=[CH:34][C:5]=2[O:4][N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:31][C:30]1[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]4([C:8]5[C:9](=[CH:34][C:5]6[O:4][N:3]=[C:2]([CH3:1])[C:6]=6[CH:7]=5)[O:10][CH2:11]4)[C:13]3=[O:33])=[CH:27][CH:26]=2)[NH:37][N:36]=1
Reactant: NN
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Solvent: O
Solvent: CCO
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(-c3cc(N)n[nH]3)cc2)c2ccccc21
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-((3-methyl-2′-oxo-6H-spiro[benzofuro[5,6-d]isoxazole-5,3′-indoline]-1′-yl)methyl)phenyl)-3-oxopropanenitrile in ethanol (20 mL) was added hydrazine hydrate (0.40 mL, 15 mmol). The solution was heated at reflux for 4 h, allowed to cool to ambient temperature and concentrated in vacuo. The resultant solid was dissolved in anhydrous methanol (10 mL) and a saturated solution of hydrogen chloride in anhydrous methanol (1.5 mL) was added, causing a precipitate to be deposited. The solid was collected by filtration to obtain 1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.14 g, 43%) as a pale yellow solid: mp 191-195° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 7.82-7.71 (m, 3H), 7.52 (d, J=8.3 Hz, 2H), 7.31-7.18 (m, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.04-6.97 (m, 2H), 6.40 (s, 1H), 5.16 (d, J=16.3 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 4.98-4.89 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 164.3, 157.8, 155.9, 145.7, 142.7, 138.0, 130.5, 129.7, 128.3, 127.5, 126.6, 124.7, 124.4, 123.8, 117.8, 109.2, 108.5, 108.4, 81.5, 56.1, 43.5, 9.8; MS (ES+) m/z 463.9 (M+1). Anal. Calcd. for C27H21N5O3.1.6HCl: C, 62.15; H, 4.37; N, 13.42. Found: C, 61.97; H, 4.52; N, 13.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([N:12]2[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:19])=O)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[N:41](CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:19][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:17]([CH3:18])[N:12]1[C:10]1[N:8]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:6][N:41]=1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)N(N)c1ccc(F)cn1
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 79.9 %

Procedure:
To an ice cold solution of Intermediate 96a (1.38 g, 5.19 mmol) in THF (50.0 mL) was added sequentially triphenylphosphine (2.72 g, 10.4 mmol), Et3N (2.89 mL, 20.8 mmol) and hexachloroethane (2.46 g, 10.4 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo then resubmitted to the reaction conditions overnight. After analogous workup the residue was concentrated in vacuo to give the title compound (1.03 g, 80%). NMR (300 MHz, CDCl3): 0.68 (6H, d, J 6.2 Hz), 1.36-1.68 (3H m), 1.74-1.90 (3H, m), 3.35 (2H, m), 7.14 (1H, ddd, J 9.8, 7.5, 2.3 Hz), 7.65 (1H, ddd, J 9.9, 4.7, 0.8 Hz), 8.02 (1H, ddd, J 3.2, 2.3, 0.8 Hz).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[N:21]([CH3:29])[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23].N(OC(C)(C)C)=O>O1CCCC1.C(#N)C.CS(C)=O.O>[C:19]([C:4]1[C:3]([N:21]([CH3:29])[S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: CN(c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N)S(=O)(=O)C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: CN(c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N)S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Yield: 55.2 %

Procedure:
To a solution of Example 20 (150 mg, 0.31 mmol) in tetrahydrofuran (5 ml) was added dropwise tert-butyl nitrite (111 μl, 0.93 mmol). The reaction mixture was then heated at 60° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with brine (20 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 10 g) eluting with dichloromethane/ethyl acetate [9:1]. The appropriate fractions were combined and concentrated to give the crude product. The crude product was dissolved in a mixture of acetonitrile, dimethyl sulphoxide and water (4:5:1, 2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [60:40 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (80 mg).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (186 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 24%).
Reaction SMILES: O[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:55])=O>C1COCC1.O1CCOCC1.O1CCOCC1>[Cl:55][CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Yield: 97.8 %

Procedure:
1-(1-Hydroxy-1 -t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidin- 2-one (646mg) was dissolved in dry THF/dioxan (1:1, 12ml) and the solution, under nitrogen, was cooled to -15°. Dry pyridine (227mg) in dioxan (1ml) was then added followed by the dropwise addition of thionyl chloride (357mg) in 1:1 tetrahydrofuran/dioxan (5ml) over 1-2 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added and the solution decanted from any solid, and evaporated to give 1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidine-2-one as an amorphous solid (650mg) after drying overnight in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2.Cl.[NH2:26]O.C([O-])(=O)C.[Na+].Cl>C(O)C.[Pd].ClCCl.C(O)C>[ClH:1].[NH2:26][CH2:17][C:14]1[CH:15]=[CH:16][N:12]([C:11]2[CH:10]=[C:9]3[C:4]([NH:5][C:6](=[O:24])[CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:8]3)=[CH:3][C:2]=2[Cl:1])[CH:13]=1
Reactant: NO
Reactant: CCOC(=O)c1nc2cc(-n3ccc(C=O)c3)c(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of the compound of Example 1 (166 mg, 480 μmol) in ethanol (5 ml) were added hydroxylamine hydrochloride (66.7 mg, 960 μmol) and successively sodium acetate (78.7 mg, 960 μmol), and the mixture was refluxed for 3 hours. After cooling, the insolubles were filtered off and solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [dichloromethane-ethanol=10:1] to obtain yellowish brown powder. After dissolved this into ethanol (10 ml), 10% palladium on carbon (containing 51.1% moisture, 50.0 mg) and successively concentrated hydrochloric acid (0.5 ml) were added and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4 Kgf/cm2) (392 KPa). Catalyst was filtered off using celite and solvent was distilled off. Acetone was added to the residue obtained and the crystals were collected by filtration. After washed with acetone, these were air-dried, thereby obtaining 61.2 mg of title compound as colorless powder. Yield 33%.
Reaction SMILES: [F:1]/[C:2](/[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[CH:3]/[F:4].[Li]C(C)(C)C.[I:19]I.O>C1COCC1>[F:1]/[C:2](/[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[C:3](/[F:4])\[I:19]
Reactant: CCCC1CCC(/C(F)=C\F)CC1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(/C(F)=C(\F)I)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.0 g (26.3 mmol) of 1-((E)-1,2-difluorovinyl)-4-propylcyclohexane are initially introduced in 150 ml of THF at −55° C., and 20.5 ml (30.2 mmol, 15% soln. in n-pentane) of t-BuLi are metered in. After 2 h at this temperature, a solution of 7.67 g (30.0 mmol) of iodine in 50 ml of THF is added dropwise. The mixture is slowly warmed to 0° C., and water is added. The batch is extracted with MTBE, and the organic phase is washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, pentane), giving 1-((Z)-1,2-difluoro-2-iodovinyl)-4-propylcyclohexane as a pale-violet oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([N:20]2[CH2:24][CH2:23][CH:22]([C:25]([O:27]C)=[O:26])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([N:20]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)N2CCC(C(=O)O)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of methyl 1-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}pyrrolidine-3-carboxylate (Example 190, 0.32 g, 0.80 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 3 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.29 g, 92%) as a white amorphous. It was crystallized from diisopropyl ether-ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(NCC)C.C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][N:6]([CH2:7][CH3:8])[CH2:5][CH3:1])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (from intermediate A3) in 1 mL of diethylamine and 2 mL of THF was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.Cl.O>CN(C=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>[F:24][C:14]1[C:13]([CH:11]([OH:12])[C:8]2[N:6]3[N:7]=[C:2]([C:30](=[O:32])[CH3:31])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(C(O)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a flask charged with Pd(PPh3)4 (67 mg, 0.058 mmol) under nitrogen was added a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(5,7-difluoroquinolin-6-yl)methanol (200 mg, 0.56 mmol) in DMF (10 mL). The system was purged with nitrogen gas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.21 mL, 0.61 mmol) was added. The temperature was increased to 100° C. and stirred overnight. Then the reaction mixture was cooled to rt, 3N HCl was added and the mixture was stirred for additional 4 h. Water was added and the product was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 132 mg (55%) of the title compound. 1H-NMR (400 MHz, CDCl3). ppm 8.98 (dd, 1H), 8.42 (d, 1H), 8.05 (dd, 1H), 8.00 (s, 1H), 7.77 (dd, 1H), 7.68 (d, 1H), 7.48 (q, 1H), 7.03 (s, 1H), 2.72 (s, 3H). LCMS (method B): [MH]+=355, tR=2.08 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH:18]=[C:13]3[C:12]([C:23]3[N:24]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[S:26][CH:27]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[OH-].[OH-].[Pd+2]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=[C:13]3[C:12]([C:23]3[N:24]=[C:25]([CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)[S:26][CH:27]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=Cc1cnc2c(c1)c(-c1csc(C3CCN(C)CC3)n1)cn2S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1cnc2c(c1)c(-c1csc(C3CCN(C)CC3)n1)cn2S(=O)(=O)c1ccccc1
Reaction time: 72 h
Yield: 91.2 %

Procedure:
To a solution of 75 (166 mg, 0.34 mmol) in MeOH (10 mL) was added 20% Pd(OH)2 on carbon (50 mg, cat.), and the reaction mixture was stirred vigorously under H2 for 72 h. The mixture was then filtered through Celite, which was then washed with MeOH (100 mL). The filtrate was concentrated to afford 76 as a foam (155 mg, 0.31 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 0.93 (d, J=6.6 Hz, 2H), 1.85-1.97 (m, 1H), 2.06-2.18 (m, 2H), 2.26-2.47 (m, 4H), 2.48 (s, 3H), 2.60 (d, J=7.3 Hz, 2H), 3.10-3.21 (m, 3H), 7.37 (s, 1H), 7.45-7.61 (m, 3H), 8.08 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 8.21-8.26 (m, 2H), 8.29 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][Br:17])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C=Cc2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(C=Cc2ccc(CBr)cc2)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 5.7 g. (0.025 m) of 4-chloro-4'-methylstilbene (m.p. 196°-197° C.) and 4.43 g. (0.025 m) of N-bromosuccinimide in 124 ml. of carbon tetrachloride was heated at reflux for eight hours. The reaction mixture was filtered hot, allowed to cool and stand overnight and again filtered to remove a small amount of amorphous material. The solvent was removed in vacuo and the residue crystallized from cyclohexane to give 4-(4-chlorostyryl)benzyl bromide, m.p. 130°-132° C. in 85% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:10]=[C:11]([CH:15]=1)[C:12](O)=[O:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.Cl.Cl.[NH2:57][C@@H:58]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C@H:59]([OH:73])[CH2:60][NH:61][C@@H:62]([CH3:72])[C:63]([NH:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1)=[O:64]>CN(C=O)C>[CH2:74]([C@H:58]([NH:57][C:12](=[O:13])[C:11]1[CH:15]=[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH:8]=[C:9]([C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:10]=1)[C@H:59]([OH:73])[CH2:60][NH:61][C@H:62]([C:63](=[O:64])[NH:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1)[CH3:72])[C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1
Reactant: C[C@H](NC[C@@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CCCCC1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN[C@@H](C)C(=O)NC2CCCCC2)cc(N2CCCC2=O)c1
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To a solution of 5-(2-oxo-pyrrolidin-1-yl)-N,N-dipropyl-isophthalamic acid (A80) (66 mg, 0.2 mmol, 1 equiv) in DMF (5 ml) at room temperature was added EDAC.HCl (46 mg, 0.24 mmol, 1.2 equiv), HOBT (37 mg, 0.24 mmol, 1.2 equiv), 4-ethylmorpholine (153μ, 1.2 mmol, 6 equiv) and (S)-2-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butylamino)-N-cyclohexyl-propionamide di-hydrochloride (C6) (82 mg, 0.2 mmol, 1 equiv). The resulting mixture was stirred for 3 h then concentrated in vacuo. The residue was diluted in CH2Cl2 and the organic phases washed with a saturated NaHCO3 aqueous solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by preparative LC/MS gave N-[(1S,2R)-1-benzyl-3-((S)-1-cyclohexylcarbamoylethylamino)-2-hydroxypropyl]-5-(2-oxopyrrolidin-1-yl)-N′,N′-dipropylisophthalamide (E1) (78 mg, 60%) as a white foam. [M+H]+=648.3 RT=2.70.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([O:17][C@H:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Cl>O.O1CCCC1>[C:3]([C:7]1[CH:8]=[C:9]([O:17][C@H:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:10]=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:12]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](C)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 2.0 g (36 mmol) of potassium hydroxide in water (100 mL) and tetrahydrofuran (100 mL) was added 11.48 g (36 mmol) of methyl (2R)-2-(3,5-di-t-butylphenyloxy)propanate (13). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and the resulting solution was extracted with diethyl ether (3×200 mL). The combined extracts were washed with an aqueous saturated sodium chloride solution (1×300 mL) and dried (MgSO4). Filtration and concentration resulted in a yellowish sludge. The crude product was purified by precipitation from hexane at -78° C. to afford 8.2 g (75%) of (2R)-2-(3,5-di-t-butylphenyloxy)propanoic acid (14) as an off-white crystalline material: 1H NMR (CDCl3) δ1.29 (s, 18 H), 1.64-1.66 (d, 3 H), 4.56-4.82 (q, 1 H), 6.75 (s, 2 H), 7.06 (s, 1 H); 13C NMR (CDCl3) δ177.7, 156.8, 152.5, 116.2, 109.7, 72.3, 35.0, 31.4, 18.4.