Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[C:22]([O:24][CH3:25])=[O:23])=[N:14][CH:15]=1)#[N:9].[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([C:30]4[N:29]=[C:28]([C:27]([F:43])([F:42])[F:26])[O:32][N:31]=4)[CH:34]=3)[CH2:18][CH:17]2[C:22]([O:24][CH3:25])=[O:23])=[N:14][CH:15]=1)#[N:9]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COC(=O)C1CNCCN1c1ccc(C#N)cn1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CCN1c1ccc(C#N)cn1
Yield: 82 %

Procedure:
This compound was synthesized from methyl 1-(5-cyanopyridin-2-yl)piperazine-2-carboxylate TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (80 mg, yield 82%). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=1.0 Hz, 1H), 8.26-8.23 (m, 1H), 8.18 (s, 1H), 7.76-7.73 (dd, J=8.9 Hz, 2.1 Hz, 1H), 7.65-7.64 (m, 2H), 6.73-6.71 (m, 1H), 5.43 (m, 1H), 4.68 (m, 1H), 3.94-3.90 (m, 2H), 3.73-3.68 (m, 3H), 3.59 (m, 2H), 3.28 (m, 1H). MS (ESI) m/z: Calculated for C22H17F3N6O4: 486.13. found: 487.2 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.C1(C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH3:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Li+].[OH-]>C1COCC1.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:44][N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:20]1[N:19]=[C:18]([CH2:17][CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C@H:6]([CH2:5][C:4]([OH:3])=[O:25])[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3cccc(Cl)n3)ccc21
Reactant: CNc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1cccc(CCOc2ccc3c(c2)CC[C@H]3CC(=O)O)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
An oven-dried flask charged with ethyl{(1S)-5-[2-6-chloro-2-pyridinyl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 471, 100 mg, 0.277 mmol), Pd(OAc)2 (1.3 mg, 0.01 mmol), 2-di-t-butylphosphino)biphenyl (3.3 mg, 0.02 mmol), and sodium tert-butoxide (37.4 mg, 0.39 mmol) was purged with argon. Toluene (1 mL) and N-methyl aniline (59.6 mg, 0.56 mmol) were added, and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled to rt, loaded on an ion-exchange resin column (SCX sorbent, Varian, strong cation exchange), and eluted with MeOH followed with NH3 (1N solution in MeOH). The fractions containing the desired product were combined and then concentrated under reduced pressure. The crude ester was then dissolved in a mixture of THF (2 mL), H2O (2 mL), and EtOH (1 mL), to which LiOH (26.8 mg, 1.12 mmol) was added. The reaction mixture was stirred at rt for 18 h, concentrated under reduced pressure, and then purified by preparative HPLC. The fractions containing the desired fractions were concentrated under reduced pressure, and then dissolved in a mixture of CH2Cl2 and a saturated aqueous solution of NaHCO3. The aqueous phase was brought to pH 4 using HCl (1N aqueous solution), the organic layer separated, dried, and then concentrated to give the product (51.4 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.75 (m, 1H), 2.34-2.43 (m, 2H), 2.70-2.87 (m, 3H), 3.43-3.50 (m, 3H), 3.71 (s, 3H), 4.32 (t, 2H), 6.41 (d, 1H), 6.66 (d, 1H) 6.75 (s, 1H), 6.79 (d, 1H), 7.03 (d, 1H), 7.25 (d, 1H), 7.27 (d, 1H), 7.43 (t, 1H), 7.49-7.53 (m, 3H); LC-MS: RT=2.32 min, (M+H)+ 403.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[F:10][C:11]([F:36])([F:35])[C:12]1[CH:34]=[CH:33][CH:32]=[CH:31][C:13]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[N:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:28]([C:25]1[N:26]=[N:27][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[C:13]3[CH:31]=[CH:32][CH:33]=[CH:34][C:12]=3[C:11]([F:36])([F:35])[F:10])[CH2:21][CH2:20]2)=[CH:23][CH:24]=1)=[O:29]
Reactant: O=C(Cl)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: NCCc1ccccn1
Product: O=C(NCCc1ccccn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 28, making variations only as required to use 2-pyridin-2-ylethylamine in place of 2-aminopyridine to react with 6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]pyridazine-3-carbonyl chloride, the title compound was obtained as a white powder (30%). m.p. 151-154° C. 1H NMR (300 MHz, DMSO-d6) δ 9.07, 8.78, 8.43, 7.99-7.61, 7.52, 7.34, 3.79-3.60, 3.35-3.14. MS (ES+) m/z 485.3 (M+1).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[OH:19])[CH:14]=[O:15].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[O:19][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]=[O:15]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(C=O)cc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To a flask containing of dichloromethane (58 ml) was added powdered 4 A sieves (3.37 g, activated at 500° C. for 8 h), phenylboronic acid (3.53 g, 28.95 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (1.08 g, 5.79 mmol), copper (II) acetate (1.05 g, 5.79 mmol), pyridine (2.33 ml, 28.95 mmol) and triethylamine (4.0 ml, 28.95 mmol). The reaction flask was fitted with a drying tube and stirred overnight at room temperature. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 10% ethyl acetate in hexane) provided the title compound as a yellow solid (540 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.28 (t, j=8.0 Hz, 2H), 7.05 (t, j=7.2 Hz, 1H), 6.83 (d, j=8.4 Hz, 2H), 3.84 (s, 3H). M+1=263
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]([S:38](Cl)(=[O:40])=[O:39])([CH3:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:38]([CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, isopropylsulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Cl)=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22])=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccc(Br)cc2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-bromophenyl)-5-chloro-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazole (Intermediate-3, 0.100 g, 0.257 mmol) in DMF (3.0 mL) was added 3-methoxypropan-1-amine (0.035 g, 0.386 mmol) and DIPEA (1.0 mL). The reaction mass was stirred at 80° C. for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.92 (d, J=5.4 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 3.28 (s, 3H), 3.56-3.64 (m, 2H), 5.69 (m, 1H), 7.06-7.15 (m, 1H), 7.22-7.49 (m, 2H), 7.54 (d, J=10.2 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). MS (m/z): 441.19 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1.[NH4+].[Cl-]>CN(C=O)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:8]([C:15]([F:16])([F:17])[F:18])[CH:9]=2)=[N:23][CH:24]=1
Reactant: OCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: Clc1ccc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COc2ccc(Br)cn2)ccc1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-cyclohexyl-3-trifluoromethyl-phenyl)-methanol (258 mg, 1.0 mmol) in DMF (7 mL) is added sodium hydride (60% in mineral oil, 60 mg, 1.5 mmol) at 0° C. and the reaction mixture is stirred at 0° C. for 30 minutes. After the addition of a solution of 2-chloro-5-bromopyridine (231 mg, 1.2 mmol) in DMF (3 mL), the reaction mixture is stirred at 0° C. for 1 h and at room temperature for 18 hours. The reaction mixture is poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (19:1 hexanes/EtOAc) to give 5-Bromo-2-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]2([CH3:25])[CH3:24])[N:11]=1.C1C(=O)N([Br:34])C(=O)C1>C(#N)C>[Br:34][C:13]1[C:12]([N:16]2[C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][C:21]2([CH3:23])[CH3:22])=[N:11][C:10]([N:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]2([CH3:26])[CH3:1])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CCCC(C)(C)N1c1cccc(N2C(C)(C)CCCC2(C)C)n1
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1c1ccc(Br)c(N2C(C)(C)CCCC2(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Reaction was performed under air. To a ice-cooled solution of 2,6-bis(2,2,6,6-tetramethylpiperidin-1-yl)pyridine (1 g, 2.8 mmol) in acetonitrile (100 ml) was added NBS (0.45 g, 2.5 mmol) portion-wise over 30 min. The reaction mixture was stirred at −0° C. for 2 h, until the color of the solution disappeared and then stirred overnight at room temperature. The reaction was quenched with water (100 mL) and the product extracted by ethylacetate. The product was purified by column chromatography on silica gel and obtained as white solid (Rf=0.6 in Ethylacetate:hexane=1:20, Yield=0.53 g (43.4%))
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[NH:14][CH2:15][CH2:16][CH2:17][N:18]=2)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:27]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:27])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[NH:14][CH2:15][CH2:16][CH2:17][N:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(O)(C2=NCCCN2)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(C(Cl)(C2=NCCCN2)c2ccccc2)cc1

Procedure:
Under a nitrogen atmosphere, into a cold (0° C.) solution of (4-tert-butylphenyl)(phenyl)-1,4,5,6,-tetrahydropyrimidin-2-ylmethanol (2.7 g, 8.37 mmol) in CHCl3 was added SOCl2 (1.9 mL) over 10 minutes. The reaction mixture was heated at reflux temperature for 4 h and concentrated in vacuo. The resultant residue was dissolved in benzene and concentrated in vacuo to dryness twice. The final residue was crystallized from chloroform and ether to afford 2-[(4-tert-butyl-phenyl)(chloro)phenylmethyl]-1,4,5,6,-tetrahydropyrimidine as an off white solid (2.4 g, 84% yield, mp 79° C.). MS m/e (M+H)+ 341; 1H NMR (400 MHZ, DMSOd6) δ 1.26 (s, 9H), 1.90 (m, 2H) 3.43 (m, 4H), 7.26 (d, 2H), 7.35 (m, 2H), 7.48 (m, 5H), 9.42 (bs, 1H).
Reaction SMILES: [CH:1]([CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)=[CH2:2].Cl.FC(F)(F)C(O)=[O:13]>>[NH2:7][CH:3]([CH:1]=[CH2:2])[CH2:4][CH2:5][C:6]([OH:8])=[O:13]
Reactant: C=CC1CCC(=O)N1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: C=CC(N)CCC(=O)O

Procedure:
In this reaction 5-vinyl-2-pyrrolidinone (structure 1) is subjected to an acidic hydrolysis thereby producing the desired compound, 4-amino-5-hexenoic acid (structure 2). This acidic hydrolysis is carried out using techniques known in the art. Typically, the 5-vinyl-2-pyrrolidinone is contacted with a strong acid such as hydrochloric acid or trifluoroacteic acid at a temperature above 60° C. in an aqueous solvent system. The 4-amino-5-hexenoic acid is recovered by concentration as is known in the art. The acidic hydrolysis followed by recrystallization produces a yield of 4-amino-5-hexenoic acid of 57-67%. The spent recrystallization liquor can be saved, concentrated, redissolved in ethanol and a second recrystallization can be carried out on this residue which increases the yield of final product by another 10-11%. The yield of 4-amino-5-hexenoic acid which is produced by this process is from 57-67% with one recrystallization and from 70-79% when a second recrystallization is carried out.
Reaction SMILES: CC(C)=O.[C:5]1([CH:11]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:12][CH2:13][O:14][C:15]([C:17]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH3:33])[NH:19][C:18]=2[CH3:34])=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>O>[C:35]1([CH:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:12][CH2:13][O:14][C:15]([C:17]2[C:18]([CH3:34])=[N:19][C:20]([CH3:33])=[C:21]([C:30]([OH:32])=[O:31])[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[O:16])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 ml of acetone was added to 50.7 mg (0.100 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester. 130 mg (0.240 mmol) of cerium ammonium nitrate suspended in 1 ml of water was added and stirred at room temperature for 10 minutes. After adding water and extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[CH2:5]P(=O)(OC)OC.[H-].[Na+].[OH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.CCOCC>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[CH:5]=[CH:32][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][OH:20])=[CH:35][CH:34]=1
Reactant: COc1ccc(OC)c(CP(=O)(OC)OC)c1
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c(C=Cc2ccc(OCCCCCCO)cc2)c1
Temperature: 6 °C
Reaction time: 1.5 h

Procedure:
A mixture of dimethyl 2,5-dimethoxybenzylphosphonate (2.92 g, 11.2 mmol) and sodium hydride (60% in oil, 1.08 g, 27.0 mmol) in dry DMF (92 ml) was cooled with in an ice-bath under argon. To this was added dropwise a solution of 4-(6-hydroxyhexyloxy)benzaldehyde (13) (2.50 g, 11.3 mmol) in dry DMF (55 ml). The reaction mixture was stirred at 6° C. for 1.5 h and then at room temperature for 4 h. Ether (300 ml) and water (250 ml) were added and the mixture shaken well. The organic layer was separated and washed with water (4×250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/methanol; 19:1 yield (14) (1.89 g, 47%) as an oil; δH (CDCl3) 1.46 (4 H, m, CH2), 1.60 (2 H, m, CH2), 1.79 (2 H, m, CH2), 3.65 (2 H, t, J =6.6 Hz, OCH2), 3.81 (3 H, s, OCH3), 3.83 (3 H, s OCH3), 3.96 (2 H, t, J=6.5 Hz, OCH2), 6.76 (1 H, dd, JH3', JH4 '=8.9 Hz, JH6',H4' =3.0 Hz, H4'), 6.82 (1 H, d, JH4',H3' =8.9 Hz, H3'), 6.87 and 7.45 (4 H, AA'BB', PhH), 7.03 (1 H, d, J=16.5 Hz, vinylic H), 7.13 (1 H, d, JH4',H6' =3.0 HZ, H6') and 7.31 H, d, J=16.5 Hz, vinylic H); δc (CDCl3) 25.5, 25.6, 29.2, 32.6, 55.7, 56.2, 62.8, 67.8, 111.3, 112.2, 113.1, 114.5, 120.7, 127.6, 127.7, 128.7, 130.4, 151.2, 153.7 and 158.7.
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)#[N:5].Cl.[NH2:17][OH:18].[OH-].[Na+]>ClCCCl.O>[F:14][C:12]([F:15])([F:13])[C:9]1[CH:10]=[CH:11][C:6]([C:4](=[N:17][OH:18])[NH2:5])=[N:7][CH:8]=1
Reactant: N#Cc1ccc(C(F)(F)F)cn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCCl
Product: NC(=NO)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
180 ml of ethanol were added to a solution of 22 g of 2-cyano-5-trifluoromethylpyridine in 180 ml of 1,2-dichloroethane under stirring at room temperature, followed by drop-wise addition thereto of a solution of 9.8 g of hydroxylamine hydrochloride in 17 ml of water. An aqueous solution of 5.6 g of sodium hydroxide in 17 ml of water was drop-wise added to the resulting mixture. After completion of the drop-wise addition, the reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled, and stripped of insolubles by filtration. The filtrate was subjected to distillation under reduced pressure to remove therefrom the solvent. The resulting residue was washed with hexane. The precipitated solid was filtered off to obtain 25 g of 5-trifluoromethyl-2-pyridinecarboxamide oxime having a melting point of 130° to 133° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[NH2:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH:48]=O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH2:48][NH:33][C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25]([NH:24][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:35])=[O:34])=[CH:42][CH:41]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Oc2cccc(CNc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)C(=O)O)c2)cc1
Reaction time: 7 h
Yield: 76 %

Procedure:
Reductive amination was carried out using (2S)-(2-amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester (123 mg, 0.25 mmol), 3-(4-tert-butyl-phenoxy)-benzaldehyde (130 mg, 98%, 0.5 mmol), acetic acid (0.7 mmol), sodium triacetoxyborohydride (131 mg, 97%, 0.6 mmol) and DCE (2.5 mL). The mixture was stirred for 7 h. Purification by flash chromatography (ethyl acetate/hexanes 1:9) gave the title compound as colorless oil (139 mg, 0.19 mmol, 76% yield).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:23][CH:20]1[CH2:21][OH:22]>>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([NH:16][CH2:23][CH:20]([OH:19])[CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CO1
Reactant: Nc1ccc(C2=NOC(c3ccccc3)N2)cc1
Product: OCC(O)CNc1ccc(C2=NOC(c3ccccc3)N2)cc1

Procedure:
0.9 g of 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(2-ethoxycarbonyl-2-N-butylsulfonyl-aminoethyl)phenoxymethyl]-2-oxazolidinone [obtainable as in Example 1 by reacting 4-(5-phenyl-1,2,4-oxadiazolin-3-yl)aniline with 2,3-epoxy-1-propanol to give N-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-2,3-dihydroxypropylamine, reacting with diethyl carbonate in the presence of tert-butoxide to give 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone, esterifying with methanesulfonyl chloride and reacting with Na p-(2-ethoxycarbonyl-2-N-butylsulfonylaminoethyl)phenolate] is dissolved in 50 ml of methanol and hydrogenated on Raney nickel. The reaction mixture is subsequently filtered and the filtrate is concentrated in vacuo. The resulting product is treated with 20 ml of hot ethyl acetate and, after cooling, filtered off with suction. 3-[4-(N-benzoylamidino)phenyl]-5-[4-(2-ethoxycarbonyl-2-N-butylsulfonylaminoethyl)phenoxymethyl]-2-oxazolidinone is obtained.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][N:7]([CH3:22])[C:8]([C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:11]=1[C:12](OC)=[O:13])=[O:9])#[N:5]>CO>[OH:13][C:12]1[C:11]2[C:10](=[CH:19][CH:18]=[C:17]([O:20][CH3:21])[CH:16]=2)[C:8](=[O:9])[N:7]([CH3:22])[C:6]=1[C:4]#[N:5]
Reactant: COC(=O)c1cc(OC)ccc1C(=O)N(C)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(=O)n(C)c(C#N)c(O)c2c1
Yield: 145.3 %

Procedure:
NaOMe (4.4M in MeOH, 1.2 mL, 5.3 mmol) was added to a solution of the ester 126 (0.69 g, 2.6 mmol) in MeOH (20 mL). The resulting mixture was heated at reflux for 2 h. It was then cooled and concentrated. 1M HCl in ether (5.5 mL) was added and the mixture filtered and concentrated to give the product 127 as a tan solid (0.87 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH:21]=1.[Br:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55](Br)=[CH:54][CH:53]=2)=[CH:48][CH:47]=1.CC(C)([O-])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:25]=[CH:24][C:23]([N:26]([C:55]2[CH:54]=[CH:53][C:52]([C:49]3[CH:48]=[CH:47][C:46]([Br:45])=[CH:51][CH:50]=3)=[CH:57][CH:56]=2)[C:27]2[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH:21]=1
Reactant: c1ccc(-c2ccc(Nc3ccccc3-c3ccccc3)cc2)cc1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Brc1ccc(-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccccc3-c3ccccc3)cc2)cc1
Yield: 72.4 %

Procedure:
Toluene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of triphenylphosphine (0.2 g, 0.8 mmol) and Pd(OAc)2 (0.05 g, 0.2 mmol). The mixture was bubbled with nitrogen for 15 min, then N-([1,1′-biphenyl]-4-yl)-[1,1′-biphenyl]-2-amine (3.4 g, 10.5 mmol), 4,4′-dibromobiphenyl (6.6 g, 21.0 mmol), sodium tert-butoxide (2.0 g, 21.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 12 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene. The solvent was removed in vacuo and the residue was purified by flash chromatography using 20% toluene/hexane to afford N-([1,1′-biphenyl]-4-yl)-N-(4′-bromo-[1,1′-biphenyl]-4-yl)-[1,1′-biphenyl]-2-amine (4.2 g, 73% yield) as a white solid.