Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:29][CH:28]=3)[S:31][C:32]=2[CH3:38])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid as light yellow amorphous solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=1.[Cl:17][C:18]1[CH:23]=[C:22](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:20][N:19]=1.Cl.C(OCC)C>C1COCC1.CO>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:7]3[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Cl)c1)c1cccc(F)c1C#N
Reactant: Cc1cc(Br)cc(C(F)F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2(c3ccnc(Cl)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-Butyllithium (1.174 mL, 2.94 mmol) was added to 4-bromo-2-(difluoromethyl)-6-methylpyridine (543 mg, 2.45 mmol) in THF (15 mL) at −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min before (E)-N-((2-chloropyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (890 mg, 2.45 mmol) in THF (5 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. MeOH (15 mL) was added followed by hydrochloric acid in diethylether (7.34 mL, 7.34 mmol) and the reaction was stirred for 1 hour. NaHCO3(sat) was added and the mixture was extracted with EtOAc (×2). The combined organic phases were dried and concentrated to give 0.5 g (51%) of the title compound, which was used without further purification. MS (ES+) m/z 403 [M+1]+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[N:10]=2)=[O:8])[CH2:4][O:3]1.C(Cl)Cl.CO.Cl.O>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:11]3[N:10]=[C:9]([C:7](=[O:8])[C@H:5]([OH:6])[CH2:4][OH:3])[CH:14]=[CH:13][CH:12]=3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OC[C@H](C(=O)c2cccc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(c1cccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)[C@H](O)CO
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)(6-(4-(4-fluorophenoxyl)phenyl)pyridin-2-yl)methanone (0.621, g, 1.58, mmol) in an 85:15, mixture of DCM/MeOH (10, mL) was added 4M HCl in dioxane (2, mL, 8, mmol). After stirring overnight 0.5, mL, water was added to the reaction. After 3, more hours the reaction was diluted with 50, mL DCM and solid NaHCO3, was added. After the bubbling subsided, the reaction mixture was dried over Na2SO4, filtered, and evaporated in vacuo to a residue. The residue was chromatographed over silica gel with 10-75% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. The residue was dissolved in acetone, evaporated in vacuo, dissolved in EtOAc and hexanes, evaporated in vacuo, treated with hexanes, and evaporated in vacuo. The material was dried under vacuum at 50° C. to give the product (R)-1-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropan-1-one as a glassy orange solid (0.155, g, 0.44, mmol, 28% yield). LC/MS: m/z=354.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6): 8.23-8.17, (3 H, m), 8.08, (1 H, t, J=7.9, Hz), 7.88, (1 H, dd, J=7.7, Hz, 0.9, Hz), 7.32-7.25, (2 H, m), 7.20-7.15, (2 H, m), 7.12, (2 H, d, J=9.0, Hz), 5.54-5.49, (1 H, m), 5.09, (1 H, d, J=7.0, Hz), 4.78, (1 H, t, J=5.5, Hz), 3.93-3.81, (2 H, m). Unless otherwise indicated all 1H NMR chemical shifts reported herein are denoted by the delta (δ) scale.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17]([C@H:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:33])[CH3:32])[CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[OH:8][CH:9]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17]([C@H:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:33])[CH3:32])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(O)c1ccccc12
Reaction time: 1 h

Procedure:
To a solution of 74 mg of N-[1(R)-[(2,3-Dihydro-3-oxo-spiro[1H-indene-1,4'-piperdin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methylpropanamide trifluoroactate (prepared as described in Example 74) in 10 mL of methanol 0° C. was added 37 mg of sodium borohydride and stirred for 1 h. The reaction was poured into 5 mL of saturated aqueous sodium bicarbonate solution and extracted with chloroform (3×10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous potassium carbonate, filtered, and concentrated to give a colorless foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:24])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][C:19]([O:22]C)=[CH:20][CH:21]=2)[CH:15]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:22]=[C:19]1[NH:18][CH:17]=[C:16]([C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([C:3]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11](=[O:24])[NH:12][N:13]=2)[CH:21]=[CH:20]1
Reactant: COc1ccc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cn1
Reactant: OB(O)c1ccccc1
Product: O=c1ccc(-c2cc(-c3[nH]c4ccccc4c3-c3ccccc3)c(=O)[nH]n2)c[nH]1

Procedure:
This compound is synthesized, starting from 4-(1H-Indol-2-yl)-6-(6-methoxy-pyridin-3-yl)-2H-pyridazin-3-one, and using phenyl boronic acid, analogously to example 173. Yield 30 mg. LC-MS (ES+) 381 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)OCC1>>[OH:10][C:14]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: ClCCc1ccccc1
Product: O=C1CCC(O)(CCc2ccccc2)CC1
Yield: 71 %

Procedure:
(2-chloroethyl)-benzene was reacted with 1,4-dioxa-spiro[4.5]decan-8-one corresponding to the conditions described in Example 24, step 1. The product was purified with 5:1 ether/n-hexane on a silica gel column. Compound (46) was obtained in a yield of 71% theoretical.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:11]=[CH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CCC=O)C1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
An oven-dried 3-neck 1 L round-bottom flask under nitrogen was charged with DCM (100 mL) and oxalyl chloride (1.98 mL, 22.6 mmol) and cooled to −60° C. DMSO (3.21 mL, 45.2 mmol) was added dropwise, and the reaction mixture was stirred for 5 min. A solution of tert-butyl 3-(3-hydroxypropyl)piperidine-1-carboxylate (5.00 g, 20.6 mmol) in DCM (100 mL) was added via addition funnel, and the reaction mixture was stirred for 20 min. TEA (14.3 mL, 103 mmol) was added, and the reaction mixture was warmed slowly to RT. The reaction mixture was poured into 2.5% NaHCO3 and extracted with methylene chloride. The combined organic layers were washed with 5% KHSO4 then brine, dried with anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (80 hexane/20 EtOAc). LRMS (M+H)+=242.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:3]1
Reactant: CN1CCc2cccc(C(=O)c3ccccc3)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1ccc2cccc(C(=O)c3ccccc3)c21
Yield: 85 %

Procedure:
A mixture of 2.4 grams (0.01 mole) of 1-methyl-7-benzoylindoline and 8.7 grams (0.1 mol) of manganese dioxide in 25 ml of methylene chloride was heated at reflux for 18 hours. The mixture was cooled and filtered. The filtrate was concentrated and the resulting residue was distilled to give 2 grams of 1-methyl-7-benzoylindole having a b.p. of 128° C./0.03 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11][S:12][C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1.[H-].[Na+].I[CH3:26]>CN(C)C=O>[CH3:26][N:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=[C:13]1[S:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:22])([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:8])[CH3:9]
Reactant: CC1(C)CCCC(C)(C)N1CCSc1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(SCCN2C(C)(C)CCCC2(C)C)nc2ccccc21
Reaction time: 1 h
Yield: 97 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 200 mg of the compound obtained in Example 9, and 30.4 mg of 60% sodium hydride was added to the solution, followed by stirring for about 1 hour. To the mixture was added 0.48 ml of iodomethane, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was extracted with 300 ml of chloroform, and the chloroform layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue was freed of the solvent by distillation under reduced pressure, and the resulting viscous brown liquid was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1 by volume) to obtain 202 mg (97%) of the titled compound as a pale yellow powder.
Reaction SMILES: [Na].Cl.C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1=O)=O)C.C(O)(=O)C.[CH:26]([NH2:28])=[NH:27]>C(O)C>[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:6](=[O:5])[NH:28][CH:26]=[N:27][C:9]=2[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Sodium metal (10.1 g, 0.44 mol) was added to ethanol (520 mL) and stirred at room temperature under nitrogen gas until a clear solution had formed. Ethyl-3-oxo-N-benzylpiperidine-4-carboxylate hydrochloride (56.5 g, 0.19 mol) and formamidine acetate (22.9 g, 0.22 mol) were then added and the reaction mixture heated under reflux for 40 hours. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between water (400 mL) and dichloromethane (400 mL). The aqueous phase was re-extracted with dichloromethane (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether (100 mL) and the product collected by filtration to give the title compound as a light brown solid (32.0 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[NH:17])[C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(Nc1ccc(Br)cc1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
4-bromoaniline (1.72 g, 10 mmol) was placed into a three-neck reactor, and the reactor was flushed with argon for 20 min. 50 mL anhydrous toluene was added. After cooling to 0° C., trimethylaluminum (7.5 mL, 2.0M solution in toluene, 15 mmol) was added slowly to keep the inner temperature below 18° C. After addition, the reaction mixture was warmed to room temperature and then stirred for additional 2 hrs. A solution of 2,6-difluorobenzonitrile (2.78 g, 20 mmol) in 50 mL anhydrous toluene was added, and the reaction mixture was heated to 80° C. After 18 hrs, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in CHCl3/MeOH (4/1, VAT). After being stirring for 20 min, the mixture was filtered and the residue was washed with a mixture of CHCl3/MeOH (4/1, V/V). The combined filtrates were concentrated in vacuo, and the resulting solid was stirred with a solution of Hexane/Ether (3/1, V/V). The intermediate was filtered and washed with additional Hexane/Ether (3/1, V/V) to give a white solid (2.4 g, 79% yield), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=O.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>C(O)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[N:18][NH:17][C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)NN
Reactant: Cc1cccc(-c2nc(C=O)c(C)[nH]2)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)NN=Cc1nc(-c2cccc(C)c2)[nH]c1C

Procedure:
A mixture of 5-methyl-2-m-tolyl-4-imidazolecarboxaldehyde (6.9 g, 0.034 mole), methyl carbazate (3.1 g, 0.034 mole). methylene chloride (70 ml) and acetic acid (1 drop) is refluxed for 1 hour. The precipitated white solid is collected by filtration to yield 7.1 g (0.026 mole), mp. 162°-164° c.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][C@@H:8]([NH2:33])[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[O:44]=[C:45](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@@H:8]1[C:9](=[O:10])[N:11]([C@H:12]([C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:45](=[O:44])[NH:33]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)CC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2)[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)OC(C)(C)C)C1=O
Temperature: 10 °C
Yield: 40.8 %

Procedure:
A solution of ((R)-3-amino-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (400 mg, 0.7 mmol) in tetrahydrofuran (3 mL) containing N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) was added via an addition funnel to diphosgene (0.059 mL, 0.49 mmol) in a 1:1 v/v mixture of toluene/tetrahydrofuran (6 mL) at −40° C. under an atmosphere of nitrogen with stirring. The reaction was stirred at this temperature for 20 minutes and then allowed to warm to 10° C. before quenching with ice/water (5 mL). After stirring for 2 minutes the mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with water (2×10 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 0 to 50% v/v ethyl acetate/hexanes to give ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid tert-butyl ester (120 mg, 29%). LC-MS: calcd for C27H29IN4O4 [M+H+] 601. Found 601
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][O:4]1.F[C:16]1[N:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[NH:24][C:23]2=[O:30])=[CH:18][C:17]=1[CH3:31].CN(C=O)C>O>[CH3:28][C:25]1([CH3:29])[NH:24][C:23](=[O:30])[N:22]([C:19]2[CH:20]=[N:21][C:16]([O:12][C:9]3[CH:8]=[CH:7][C:6]4[CH2:5][O:4][CH:3]([C:2]([F:1])([F:13])[F:14])[C:11]=4[CH:10]=3)=[C:17]([CH3:31])[CH:18]=2)[C:26]1=[O:27]
Reactant: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1F
Reactant: Oc1ccc2c(c1)C(C(F)(F)F)OC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1Oc1ccc2c(c1)C(C(F)(F)F)OC2
Temperature: 110 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
To a solution of 3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (enantiomer 1) (Intermediate 28, 20 mg, 0.098 mmol) and 3-(6-fluoro-5-methyl-3-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 6, 27.9 mg, 0.118 mmol) in DMF (1 mL) dipotassium carbonate (27.1 mg, 0.196 mmol) was added and the reaction mixture was stirred for 48 hours at 110° C. After cooling the mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by reverse phase flash chromatography on C18 column (MEGA BE Varian, 5 g) using water/acetonitrile from 100:0 to 0:100 as eluent affording the title compound (5 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=1.C(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:16][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2ccccc2Cl)n[nH]1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncc(-c2ccccc2Cl)nn1

Procedure:
A suspension of 53 g. of 6-(o-chlorophenyl)-1,2,4-triazin-3(2H)-one in 400 ml. of chloroform is cooled in an ice bath and 400 ml. of phosphorus oxychloride is added followed by 3 g. of N,N-dimethylformamide. The mixture is refluxed overnight and treated as described in Example 12, giving 3-chloro-6-(o-chlorophenyl)-1,2,4-triazine as white needles.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:7]([S:8][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of phenylmethanethiol (356 μl, 3.03 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (369 μl, 3.03 mmol) in dimethylformamide (5 mL) was added potassium carbonate (628 mg, 4.54 mmol). The reaction mixture was stirred at 60° C. for 2 hours, then cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-20% ethyl acetate in isohexane) to afford 2-(benzylthio)-4-(trifluoromethyl)pyridine (510 mg) as a colourless oil. LCMS (Method F, ES-API): RT 3.04 min, m+H=270.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].Cl>C(O)C.O.[OH-].[K+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:16][C:15](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1F
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
3-(3-fluoro-4-formyl-phenyl)-acrylic acid (500 mg, 2.57 mmol) was dissolved in ethanol/water (1:1, 10 ml) and 1.7M KOH (3 ml). To the resulting solution was added acetophenone (0.3 ml, 2.57 mmol). The mixture was stirred at room temperature overnight then acidified with 10% HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuo. The crude product was triturated in EtOAc and filtered to give 560 mg of 3-[3-fluoro-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(Oc2ccc(N)cc2N)cc1
Yield: 85 %

Procedure:
The resultant 1-[4-(2,4-dinitrophenoxy)phenoxy]dodecane (35.58 g, 0.080 mol) and ethanol (700 ml) and 10% Pd/C (1.78 g) were introduced into a 2-liter (l) reaction bottle. After hydrogen passed through the reaction under normal pressure for 4 hours, the reaction mixture was filtered and concentrated to obtain a crude product. The crude product was recrystallized with ethanol to obtain 1-[4-(2,4-diaminophenoxy)phenoxy]dodecane (26.15 g, 0.068 mol). Yield: 85%. Spectrum:IR (KBr) 3412, 3333, 2923, 2850, 1614, 1515, 1462, 1366, 1219, 1084 cm−1. 1H NMR (DMSO-d6, 300 MHz). δ6.8˜6.7 (m, 4H), 6.45 (d, J=8.3, 1H), 6.02 (d, J=2.2 Hz, 1H), 5.79 (dd, J=8.4, J=2.4 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.81 (t, J=6.3 Hz, 2H), 1.75˜1.55 (m, 2H), 1.40˜1.10 (m, 18H), 0.82 (t, J=6.3 Hz, 3H). 13C NMR (DMSO-d6, 75 MHz)δ 153.5, 152.7, 146.1, 140.9, 133.4,121.4, 116.8, 115.3, 103.2, 101.5, 68.0, 31.5, 29.2, 29.0, 28.9, 25.7, 22.3, 14.1.