Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3(C#N)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCC2c3ccccc3CSc3ccccc32)CC1
Yield: 68.6 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(11-cyano-6,11- dihydrodibenzo[b,e]thiepin-11-yl)propyl]piperidin-4-ol (430mg) in THF 10ml) was added 1M lithium aluminum hydride THF solution (1.5 ml) and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled with ice, water (0.06 ml), then 15% aqueous sodium hydroxide (0.06 ml), then water (0.18 ml) were added carefully. The granular salt was filtered off and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (280mg). 1H-NMR (CDCl3) d: 1.55-1.80(4H,m), 2.03-2.16(2H,m), 2.25-2.52(6H,m), 2.72-2.80(2H,m), 3.90(1H,brs), 4.48(1H,brt), 4.68(1H,brs), 6.96-7.45(12H,m). MS m/z: 464(M+1)
Reaction SMILES: C([Mg]Cl)=C.[Cl:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:12])(C)Cl.O1C[CH2:16][CH2:15][CH2:14]1>>[Cl:5][CH2:6][CH2:7][CH2:8][SiH2:9][CH:12]=[C:15]([CH3:16])[CH3:14]
Reactant: C[Si](C)(Cl)CCCCl
Reactant: C1CCOC1
Agent: C=C[Mg]Cl
Product: CC(C)=C[SiH2]CCCCl
Reaction time: 2 h
Yield: 92 %

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 500 mL (0.73 mol) a tetrahydrofuran solution of 1.46M vinylmagnesium chloride, to which 119.8 g (0.7 mol) of chloropropyldimethylchlorosilane was added dropwise over 2 hours at an internal temperature of 25-50° C. The reaction solution was stirred for 2 hours. A salt formed was removed by filtration. By subsequent distillation, the target compound, chloropropyldimethylvinylsilane was collected as a fraction having a boiling point of 82° C./5 kPa in an amount of 104.4 g (yield 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cnccn2)co1

Procedure:
The title compound was prepared by a method analog to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyrazine. The title compound (2 mg) was obtained as a pale solid, m/z 327 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)=O)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][CH2:19]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(C(=O)C1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
A solution of (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylcarbonyl)amine (2.21 g, 5 mmol) in tetrahydrofuran (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.38 g, 10 mmol) in tetrahydrofuran (10 ml) at 0° C., under a nitrogen atmosphere. The mixture was heated at reflux temperature for 2 hours and cooled to room temperature. Water (380 ml) was added dropwise to the mixture, followed by 15% sodium hydroxide (380 ml), and additional water (1550 μL). The mixture was stirred at room temperature for about 15 minutes and filtered. The filtrate was washed and rinsed with dichloromethane. Evaporation of the solvent gave a colorless oil, which solidified upon standing. Recrystallization from ethyl acetate/hexane (1:1) gave (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine as colorless crystals (1.02 g).
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.CN[C@@H]1CCCC[C@H]1NC.I[C:22]1[C:23](=[O:48])[NH:24][C:25](=[O:47])[N:26]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][C@H:35]3[C@:33]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)([CH2:34]3)[CH2:32]2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+].[NH:55]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[N:56]1>C1(C)C=CC=CC=1.[Cu]I>[O:47]=[C:25]1[NH:24][C:23](=[O:48])[C:22]([N:55]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[N:56]2)=[CH:27][N:26]1[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][C@H:35]2[C@:33]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)([CH2:34]2)[CH2:32]1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: N#Cc1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccn(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Copper(1+) iodide (50.1 mg, 0.263 mmol), (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (0.166 ml, 1.053 mmol), 5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 133 mg, 0.263 mmol) and K2CO3 (76 mg, 0.553 mmol) were dissolved in Toluene (1 ml) to give a blue suspension with a white precipitate. 1H-pyrazole-3-carbonitrile (commercially available from Tyger, 29.4 mg, 0.316 mmol) was added thereto. After shaking at 110° C. for 18 h, the reaction mixture was filtered and the solvent evaporated. The obtained residue was purified by flash chromatography (eluent: pure EtOAc for 4CV, then from pure EtOAc to EtOAc/MeOH 9:1 in 10 CV, then EtOAc/MeOH 9:1 for 10 CV; 12M column) to obtain 14.5 mg of our target compound that was further purified on a SCX cartridge and eluted with a 2M solution of ammonia in MeOH. The resulting solution was evaporated in vacuo to obtained 10.9 mg of title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: Cc1c(N=C2NC3(CCCC3)CS2)ccc([N+](=O)[O-])c1C
Product: Cc1c(N=C2SCC3(CCCC3)N2C2CCCC2)ccc([N+](=O)[O-])c1C

Procedure:
2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2,3-dimethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2,-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26])=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][CH2:23][C@@H:9]2[CH2:10][C@@H:11]([S:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][NH:8]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)c3ccc(F)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2CN[C@H](CCC(=O)c3ccc(F)cc3)C2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.539 g (1.14 mmol) (2R,4R)-2-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 10 ml CH2Cl2 was treated at 0° C. with 0.43 ml TFA. After 30 min the reaction was warmed up to room temperature (2 h) and evaporated to give (2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-one; compound with trifluoro-acetic acid, MS: 374 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]=[CH:13][N+:14]([O-:16])=[O:15])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:8]
Reactant: O=C(O)c1cc(Br)ccc1NC=C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(Br)cc2c1O

Procedure:
29 g (101 mmol) of 5-bromo-2-(2-nitro-vinylamino)-benzoic acid (Example 1a) and 11.9 g (121 mmol) of potassium acetate in 129 ml (152 mmol) of acetic anhydride are stirred for 1.5 h at 120° C. The precipitate is filtered off and washed with acetic acid until the filtrate is colorless, then is washed with H2O and dried in vacuo to give the title compound. ES-MS: 269, 271 (M+H)+, Br pattern; analytical HPLC: tret=2.70 min (Grad 1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[C:7]2=[O:15].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([CH2:25]Cl)=[CH2:24])[CH:20]=[CH:19][CH:18]=1>CO.[I-].[K+]>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:25][C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[N:22]=1)=[CH2:24])([CH3:14])[C:7]2=[O:15]
Reactant: C=C(CCl)c1cccc(Cl)n1
Reactant: CC1C(=O)c2ccc(Cl)cc2C1=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(CC1(C)C(=O)c2ccc(Cl)cc2C1=O)c1cccc(Cl)n1
Yield: 87 %

Procedure:
In 20 ml of methanol was dissolved 1.32 g of 85% potassium hydroxide, and then 3.89 g of 5-chloro-2-methylindan-1,3-dione, 3.76 g of 6-chloro-2-(1-chloromethylvinyl)pyridine and 0.05 g of potassium iodide were added to the solution. After refluxing under heating for 3 hours, the solvent was evaporated and water was poured. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and with a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to obtain 6.02 g of the compound No. 115 shown in Table 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:7][CH:6]=2)=[CH:9][C:10]=1[CH:16]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:25])([CH3:26])[C:17]1=[O:27])[CH3:15]
Reactant: CCc1ccc(-c2ccc(I)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 120 °C
Yield: 76.2 %

Procedure:
A mixture of 4-(4′-iodo-4-ethyl-biphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.200 g, 0.42 mmol), trimethylsilylacetylene (0.10 ml, 0.47 mmol), copper(I) iodide (4 mg, 0.023 mmol), bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.023 mmol), triphenylphosphine (0.022 g, 0.084 mmol) and diethylamine (0.65 ml) in anhydrous N,N-dimethylformamide (0.25 ml) is heated at 120° C. under microwave irradiation for 25 minutes. This mixture is then allowed to cool to room temperature and filtered through diatomaceous earth (additional washing with dichloromethane). The solvent is removed under reduced pressure and the residue is purified by flash column chromatography on silica gel (hexane/ethyl acetate 9:1 to 3:1 ratio) to yield 4-[4-ethyl-4′-(trimethylsilylethynyl)biphenyl-3-yl]-2,2,6,6-tetramethylpyran-3,5-dione (0.143 g) as a white solid which is used without further purification in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=O)[CH:5]=[CH:4][N:3]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].[CH3:20][N:21]=[C:22]=[S:23]>CO.O>[SH:23][C:22]1[N:21]([CH3:20])[C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2](=[O:1])[CH:7]=2)=[N:10][N:11]=1
Reactant: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Reactant: CN=C=S
Solvent: O
Solvent: CO
Product: Cn1c(S)nnc1-c1ccn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 105.8 %

Procedure:
The title compound of Example 20.1 (19.0 g, 67.0 mmol) was stirred in methanol (150 mL) and heated to 60° C. Methyl isothiocyanate (5.04 mL, 73.7 mmol) was then added via a syringe. After stirring for 40 minutes, a solution on NaOH (2.95 g, 73.7 mmol) in water (30 mL) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The aqueous residue was neutralized, extracted with chloroform, and the organic layer dried over sodium sulfate and concentrated. The residue was purified by silica gel using ethyl acetate to give the product (24.0 g, 56%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]2[C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[CH3:15])[CH3:2]>CO.O1CCOCC1.[C].[Pd]>[NH2:12][C:8]1[C:6]2[O:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:15])[C:5]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCc1oc2c([N+](=O)[O-])cccc2c1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CCc1oc2c(N)cccc2c1C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of 2-ethyl-3-methyl-7-nitrobenzo[b]furan (1.00 g) in a mixture of methanol (15 ml) and dioxane (10 ml) was added 10% palladium carbon (100 mg) and the above mixture was hydrogenated at 3 atom for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 7-amino-2-ethyl-3-methylbenzo[b]furan (858 mg) as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:11]([CH2:16][O:17][C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([NH2:23])=[O:22])=[CH:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:11]([CH2:16][O:17][C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([NH2:23])=[O:22])=[CH:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4=CCCCC4)ccc3C2)c1F
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4CCCCC4)ccc3C2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.4 %

Procedure:
To a solution of 3-(5-Cyclohex-1-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide (0.01 g, 0.25 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 100 mg). The reaction mixture was stirred at 25° C. for 48 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and evaporated to dryness under reduced pressure to give the title compound as white solid (0.01 g, 10%). 1H NMR (DMSO-d6, 400 MHz); δ 1.40 (m, 6H), 1.72 (m, 4H), 2.63 (m, 1H), 5.66 (s, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.83 (br s, 1H), 7.89 (d, J=8.40 Hz, 1H), 7.99 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (403.33), HPLC (method II) Rt=18.76 min.
Reaction SMILES: [OH:1][CH:2]([C:18]1[O:19][C:20]([C:23]2[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=2)=[CH:21][N:22]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C:2]([C:18]2[O:19][C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:1])=[CH:10][CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(O)CCc3ccc(Oc4ccccc4)cc3)o2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
Methyl 6-(2-(1-Hydroxy-3-(4-phenoxyphenyl)propyl)oxazol-5-yl)pyridine-2-carboxylate (779 mg, 1.81 mmol) was dissolved in anhydrous CH2Cl2 (26 mL) and Dess-Martin periodinane (1.151 g, 2.715 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 90 min. The addition of saturated aqueous NaHCO3 quenched the reaction and the organic layer was washed with saturated aqueous Na2S2O3 then saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes) to provide methyl 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a yellow oil (711 mg, 92%): 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, 1H, J=7.5 Hz), 8.01-8.00 (m, 2H), 7.95 (t, 1H, J=7.5 Hz), 7.30 (t, 2H, J=7.5 Hz), 7.22 (d, 2H, J=8.5 Hz), 7.06 (t, 1H, J=7.0 Hz), 6.97 (d, 2H, J=7.5 Hz), 6.93 (d, 2H, J=8.5 Hz), 4.02 (s, 3H), 3.46 (t, 2H, J=7.5 Hz), 3.08 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 187.2, 165.0, 157.4, 157.3, 155.5, 152.3, 148.5, 146.4, 138.2, 135.2, 129.7, 129.6, 127.9, 125.1, 123.2, 123.0, 119.1, 118.5, 53.0, 40.8, 28.9; HR ESI-TOF m/z 429.1444 (M+H+, C25H20N2O5, requires 429.1445).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][NH2:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCC1CCCCO1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2 H) 1.32-1.45 (m, 2 H) 1.77-1.91 (m, 4 H) 2.40-2.46 (m, 3 H) 3.37-3.49 (m, 1 H) 3.65-3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25-8.65 (m, 3 H) 8.80-9.01 (m, 1 H) 12.36-13.83 (m, 1 H). MS m/z [M+H]+ 418.2.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]C1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>C(Cl)Cl.C1C=CC=CC=1>[I:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
Ethyl 17-hydroxy-heptadecanoate 79 (264 mg, 0.84 mmol), Ph3P (262 mg, 1 mmol) and imidazole (94 mg, 1.39 mmol) were dissolved in the mixture of CH2Cl2 (3 ml) and benzene (3 ml) and cooled to 0° C. Solid 12 (254 mg, 1 mmol) was added and the reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched by addition of MeOH (0.5 ml), diluted with EtOAc and washed with the aqueous NaHCO3—Na2S2O3 solution, dried over Na2SO4 and evaporated. Chromatography in hexane-EtOAc (97:3) afforded the product 80 (321 mg, 90%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)O
Yield: 89.9 %

Procedure:
A solution of 3-(3-chloro-benzyloxy)-phthalic acid dimethyl ester (1.9 g, 5.8 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(3-chloro-benzyloxy)-phthalic acid as an off-white solid (1.6 g, 87% yield). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (2.5 g, 12 mmol), cyclopentanone (3.3 g, 36 mmol) and HOAc (0.7 g, 12 mmol) in methanol (25 mL ) was NaCNBH3 (2.5 g, 40 mmol) added in portions at room temperature. The solution was stirred at room temperature overnight to give a quantitative yield of the title compound. GC/MS (70 eV) M=265 (30%).