Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.O[CH2:37][CH2:38][N:39]([CH:69]1[CH2:72][O:71][CH2:70]1)[C:40]([C:42]1[C:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:46]([OH:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:62][CH2:61][CH2:60][CH2:59]2)[N:43]=1)=[O:41]>>[CH2:49]([O:48][C:47]1[C:46](=[O:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:59][CH2:60][CH2:61][CH2:62]2)[N:43]2[CH2:37][CH2:38][N:39]([CH:69]3[CH2:70][O:71][CH2:72]3)[C:40](=[O:41])[C:42]=12)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1COC1
Yield: 80.9 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (297) (150 mg, 0.28 mmol). The product was obtained as off-white solid (110 mg, 80.65%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[C:11]([CH3:31])=[N:12][C:13]([NH:16][N:17]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[C:11]([CH3:31])=[N:12][C:13]([NH:16][NH2:17])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1nc(NN=C(c2ccccc2)c2ccccc2)ccc1Oc1ccnc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(NN)ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
Concentrated HCl (21.31 mL, 256 mmol) was added to a solution of Example A2 (4.2 g, 10.1 mmol) in toluene (80 mL) and the reaction mixture was stirred at 110° C. for 1.5 h. The organic solvent was removed in vacuo and the remaining aqueous solution was diluted with water (50 mL), washed with toluene (2×20 mL), cooled in an ice bath, and adjusted to pH ˜12 with 50% NaOH (aq). The suspension was saturated with solid NaCl and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-((2-chloropyridin-4-yl)oxy)-6-hydrazinyl-2-methylpyridine (2.1 g, 83%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=5.7 Hz, 1H), 7.50 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.85-6.84 (m, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 2.09 (s, 3H); MS (ESI) m/z: 251.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:19]([O:21]CC)=[O:20])=[CH:7][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:9](=[O:11])[CH:10]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1cn(CCOCCOC)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOCCn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 99 %

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a cream solid (99%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.00 (v br s, 1H), 9.72 (br s, 1H), 8.41 (s, 1H), 7.75 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.3, 1.9, 0.8 Hz, 1H), 7.32 (t, J=8.5 Hz, 1H), 5.47 (d, 1.2 Hz, 1H), 4.05 (t, J=5.2 Hz, 2H), 3.60 (t, J=5.2 Hz, 2H), 3.53-3.50 (m, 2H), 3.42-3.38 (m, 2H), 3.21 (s, 3H). HRMS (EI+) calcd C17H18FIN2O5 (M+) 476.0245, found 476.0236.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([CH:9]([CH3:22])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)O)([O-:8])=[O:7].[C:23]1([O:29][CH2:30][CH3:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:26]2[CH:27]=[CH:28][C:23]([O:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)[CH:9]([N+:6]([O-:8])=[O:7])[CH3:22])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOc1ccccc1
Reactant: CC(C(O)c1ccc(C(C)(C)C)cc1)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Product: CCOc1ccc(C(c2ccc(C(C)(C)C)cc2)C(C)[N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
A 1.0 kg portion of 80% sulfuric acid was added dropwise to a solution of 237g of Example 2 in 732g of phenetole and the mixture was heated to 50° C for 2 hr. The acid layer was removed and the organic phase was diluted with ether. The ethereal solution was washed with water and with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude residue which weighed 322g was triturated with 30/60 pet ether and recrystallized from isopropyl alcohol to afford a pure, white solid: mp 79°-82° C; ir (KBr) 3.4 (m), 6.5 (s), 6.6 (m), 8.0 (s), 9.5 (m), 12.2 (m) microns; nmr (CDCl3) 7.4 to 6.7 (8H, m), 5.3 (1H, doublet of quartets), 4.3 (1H, d), 3.97 (2H, q), 1.45 (3H, d), 1.29 (3H, t), 1.22 (9H, s) ppm; ms (molecular ion) 341.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[F:25].[OH-].[Na+]>CO.O1CCCC1.O>[F:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1F
Yield: 88.4 %

Procedure:
A solution of 2-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.425 g of purified 2-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 155°-156° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again degassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a little chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5-191.0°; [α]25D -16.40 (c 0.5, CHCl3). The following characteristics are noted for a racemic sample, mp 179-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201, 172, 73 and 42. ##STR3##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[CH2:15][C@H:9]1[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[CH2:15][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 50.0 g (190 mmol) of 6 in 600 mL of tetrahydrofuran was added 15.0 g (690 mmol) of lithium borohydride in one portion. The mixture was stirred at 0° C. for 1 h followed by 15 h at room temperature. The solution was cooled to 0° C. with stirring and 255 mL of water and 100 mL of 1:1 water:concentrated hydrochloric acid were added carefully. The solution was warmed until an organic phase separated. The organic phase was withdrawn and the aqueous layer was extracted with three 150 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL each of 2 N sodium hydroxide, 2 N hydrochloric acid, and brine. The organic layers were dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil was kept at 0.05 mm for 24 h and then used without further purification. The yield of 7 was 33.9 g (81%). 1H NMR (CDCl3) δ1.1-2.0 (m), 1.48 (s, 9H), 3.3-4.2 (m), 4.4 (s). 13C NMR (CDCl3) δ28.4, 37.2, 54.9, 55.4, 57.7, 58.4, 63.5, 65.9, 68.6, 80.2, 154.8, 156.5; IR (neat) 3400, 1670, 1420 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 116, step 8), 3-fluoro-4-methoxycarbonyl-phenylboronic acid (320 mg, [CAS Reg. No. 505083-04-5]) and dichloro(1,1′-bis(diphenyl-phosphino)ferrocene)palladium(II)dichloromethane adduct (39 mg) were dissolved in dioxane (9 mL) and water (5 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.81 mL). The mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (440 mg, 76%). MS (m/e)=555.2 [(M+NH4+)+], MS (m/e)=506.1 [(M-CH3O−)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH:17]([C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38])[CH2:18][NH:19][C:20](=[O:36])[CH2:21][NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24]>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH2:21][C:20]([NH:19][CH2:18][CH:17]([C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38])[NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])(=[O:25])=[O:24]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NC(CNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCC(NC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)-acetamide to give 2-(2-naphthalenesulphonamido)-N-{2-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 41% yield, m.p. 200-202° C.;
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([F:18])([F:19])[F:20])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/C(F)(F)F)cc1F

Procedure:
A solution of (E)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate (500 mg, 0.002 mol) in CH2Cl2 (10 mL) and TFA (1.0 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a white solid. LC-MS: 2.99 min, 233.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1

Procedure:
Bis(4-methoxyphenyl)methanol (30 g) was treated with thionyl chloride (40 mL). The resulting mixture was refluxed for 2.5 hours and concentrated to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5](O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-:12].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C=O)cc1Br

Procedure:
5-Bromosalicylaldehyde (25 g, 124 mmol) was dissolved in acetone (300 ml) and anhydrous potassium carbonate (17.2 g, 124 mmol) was added. The mixture was heated and dimethyl sulfate (15.7 g, 124 mmol) was dropwise added over 45 min with gentle reflux. After the dropwise addition, the mixture was refluxed for 1 hr and cooled. Acetone was evaporated under reduced pressure. Toluene and water were added to the residue and the toluene layer was separated. The aqueous layer was extracted with toluene. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (27.3 g, quantitative) as colorless crystals.
Reaction SMILES: [N+:1]([C:4](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[C:5]([O:7][CH3:8])=[O:6])([O-:3])=[O:2].C(O)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N+:1]([C:4](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[C:5]([O:7][CH2:8][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([O-:3])=[O:2]
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: OCC=Cc1ccccc1
Product: O=C(OCC=Cc1ccccc1)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
2 was prepared as a yellow solid, m.p.: 115°-116°, from 1A and cinnamyl alcohol by the procedures described in Example 1.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1
Reactant: NCc1ccc(B(O)O)cc1
Product: NCc1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)cc1
Yield: 64 %

Procedure:
The 1-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)pyrrolidin-2-one was also coupled to (4-(aminomethyl)phenyl)boronic acid using the Suzuki coupling conditions described in example 5.6.19 to obtain the titled product in 64% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.94-2.09 (m, 4H) 2.33-2.43 (m, 2H) 3.36-3.53 (m, 6H) 4.16 (s, 2H) 6.74 (d, J=9.60 Hz, 1H) 7.57 (m, J=8.34 Hz, 2H) 7.65 (d, J=9.60 Hz, 1H) 7.81 (s, 1H) 8.25 (m, J=8.34 Hz, 2H); LRMS (ESI) m/e 365.0 [(M+H)+, calcd for C20H24N6O 364.0].
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].Br[C:14]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])[CH:17]=[CH:16][CH:15]=1.C(OCC)C>CN(C)C=O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:18]2[N:19]=[C:14]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])[CH:15]=[CH:16][CH:17]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Reactant: O=C(O)c1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Sc3cccc(C(=O)O)c3)n2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.1 %

Procedure:
To a solution of 3-mercaptobenzoic acid (361 mg, 2.35 mmol) in dimethylformamide (15 mL) add sodium hydride (23 mg, 9.38 mmol) at 0° C., stir 10 min. Add 1-[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (854 mg, 2.35 mmol), heat to 100° C. for 6 hours. Cool to ambient temperature and add diethyl ether, collect the resulting red precipitate by filtration (290 mg). Purify by the residue by preparative LC (inject 110 mg) to yield the title compound as a white solid (50 mg, 0.12 mmol): 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.50 (q, 2H), 2.55 (s, 3H), 2.61 (m, 2H), 5.25 (s, 2H), 6.65 (d, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 7.62 (t, 1H), 7.76 (m, 1H), 7.83 (m, 1H), 8.02 (m, 1H), 8.07 (m, 1H), 12.85 (s, 1H), 13.25 (br s, 1H); MS (m/z): 436 (M−1).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:29]>C1(C)C=CC=CC=1>[Ti+4:29].[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O-:5])[CH3:2]
Reactant: CCP(=O)(O)CCO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)([O-])CCO
Yield: 91.3 %

Procedure:
138 g (1 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 7) and 85 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 136 g (91% of theory) of ethyl(2-hydroxyethyl)phosphinic acid titanium salt.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O>[CH2:1]([O:8][C@@H:9]([C@@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](C=O)OCc3ccccc3)O[C@@H]2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]([C@@H](C=O)OCc3ccccc3)O[C@@H]2S1
Yield: 81.3 %

Procedure:
A solution of 98 (1.5 g, 2.7 mmol) (Prepared according to the synthesis of Example 149 and 150), step 6) was treated with NaBH4 (504 mg, 13 mmol) for 1 hour at 0° C. The resulting solution was diluted with H2O (60 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by silica gel column, eluted with 20%-50% ethyl acetate in petroleum ether to give 102 as brown syrup (1.2 g, 80%); (ES, m/z): [M+H]+ 549.1; 1H NMR (300 MHz, CDCl3) δ 7.22-7.45 (m, 15H), 6.35 (d, J=6.9 Hz, 1H), 4.61-4.80 (m, 4H), 4.47-4.53 (m, 2H), 4.25-4.36 (m, 1H), 4.08-4.12 (m, 1H), 3.89-3.92 (m, 1H), 3.46-3.78 (m, 4H), 3.01 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.CC[N:16]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([NH2:16])=[O:13]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)n1ncc(C(=O)O)c1Br
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(C(N)=O)c1Br
Yield: 60.3 %

Procedure:
A solution of the compound (10.29 g, 41.64 mmol) obtained in step 3, WSC (9.58 g, 49.97 mmol), HOBt (6.75 g, 49.97 mmol), TEA (6.97 ml, 49.97 mmol) and ammonium chloride (2.67 g, 49.97 mmol) in DMF (100 mL) was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give 5-bromo-1-tert-butyl-1H-pyrazole-4-carboxamide (6.18 g, 25.1 mmol, 60%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([F:31])=[CH:24][C:23]=2[O:32][CH3:33])[N:9](CC2C=CC(OC)=CC=2)[C:8]1=[O:43]>C(O)(C(F)(F)F)=O>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=1)[CH2:6][N:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=2[C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([F:31])=[CH:24][C:23]=2[O:32][CH3:33])[NH:9][C:8]1=[O:43]
Reactant: COc1ccc(CN2C(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)N1
Reaction time: 0.02 h

Procedure:
A solution of 15 mg of 1-[3,5-bis(trifluoromethyl)benzyl]-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one in 0.5 mL of TFA was stirred overnight at r.t. The reaction mixture was concentrated and then purified by reverse-phase HPLC [Waters XTerra C8 19×25 mm column, eluting at 20 mL/min with 90% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min, then back to 90% water over 0.5 min] to provide the title compound. Mass spectrum (ESI) 623.4 (M+1).