Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:47]([NH:50][CH2:51][CH2:52][CH3:53])[CH2:48][CH3:49]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:14]([N:50]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][CH3:49])=[O:16])[CH:7]=1
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Dissolve commercially available monomethyl 5-nitroisophthalate (3.000 g, 14.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.238 g, 16.89 mmol), 1-hydroxybenzotriazole hydrate (2.587 g, 16.89 mmol) and 4-dimethylaminopyridine (0.172 g, 1.407 mmol) and triethylamine (5.885 mL, 42.22 mmol) in dichloromethane (309 mL) and stir the mixture at room temperature for 0.5 h. Add dipropylamine (2.026 mL, 14.78 mmol) and triethylamine (5.885 mL, 42.22 mmol) and stir the mixture overnight. Concentrate and redissolve the residue in ethyl acetate and wash with two portions each of 5% aqueous potassium hydrogen sulfate solution, 5% aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (3.885 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42].O>CN(C=O)C>[CH3:42][O:41][CH2:40][CH2:39][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6]
Reactant: COCCBr
Reactant: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cccc(O)c4)c3)ncnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
41 mg (0.1 mmol) 4-[3-(3-Hydroxy-benzoylamino)-benzylamino]-quinazoline-8-carboxylic acid amide were dissolved in 1 ml DMF. 97 mg (0.3 mmol) Cs2CO3 and 15 mg (0.11 mmol) 1-Bromo-2-methoxy-ethane were added. The mixture was stirred for 5 days at 50° C. Water was added to the reaction mixture, the percipitate was filtered and dried. 15.9 mg, off-white solid.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:20](Cl)=[N:19][S:18][N:17]=1>CN(C=O)C>[C:11]([O:10][C:8]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:20]2[C:16]([Cl:15])=[N:17][S:18][N:19]=2)[CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of t-butyl 1-homopiperazine carboxylate (45 mmol, 9 g) and DMF (50 ml) was heated to 100° C. 3,4-dichloro-1,2,5-thiadiazole (23 mmol, 2.2 ml) was added dropwise to the mixture with stirring. The resulting mixture was stirred at 100° C. for 2 days. Mixture was quenched with ice/water and extracted with ethyl acetate (3×). The combined organic layer was washed with water (2×) and Sat. sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude was purified on a silica column using 20% ethyl acetate/hexanes to give 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (5.8 g). The material thus obtained was converted into the title compound by following the same procedures as in Example 1. 1H NMR (CDCl3) 9.52 (s, 2H), 7.838 (s, 2H), 7.508 (s, 1H), 7.321-7.307 (d, 2H), 6.769 (br. s, 1H), 5.464 (s, 2H), 3.925-3.851 (m, 4H), 3.820-3.790 (t, 2H), 3.612-3.582 (t, 2H), 1.987-1.959 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCCCCC
Reactant: O=Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1C=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Palladium acetate (96 mg) was added to a deaerated mixture of 2-bromobenzaldehyde (7.40 g, 40 mmol), 1-tridecyne (12.2 g, 68 mmol) and triphenylphosphine (320 mg) in dry triethylamine (160 ml) and the mixture was stirred at 105° C. under a nitrogen atmosphere overnight. After cooling, the precipitated triethylamine hydrobromide was filtered off and the filtrate was evaporated to a crude red oil. Chromatography on silica gel eluting with dichloromethane:petroleum ether [bp 60°-80° C.](1:1) afforded 7.12 g (63%) of the title compound of bp0.05 212° C. (Kugelrohr), M+ 284.2141 (C20H28O requires; 284.2140).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[N:6].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[CH3:1][O:2][CH2:3][CH2:4][C:5](=[NH:6])[O:10][CH2:8][CH3:9]
Reactant: CCO
Reactant: COCCC#N
Agent: Cl
Product: CCOC(=N)CCOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
3-Methoxypropanenitrile (5.0 g, 58.8 mmol) was dissolved in anhydrous ethanol (50 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo. The residue was slurried with hexanes (50 mL) and sonicated for 10 min. The solids were allowed to settle and the solvent was removed by decantation. This was repeated (3×). The solid was collected and dried under high vacuum for 5 h to afford ethyl 3-methoxypropanimidate hydrochloride (6.2 g, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.03 (br s, 1H), 11.22 (br s, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.60 (t, J=5.9 Hz, 2H), 3.23 (s, 3H), 2.87 (t, J=5.9 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:22][CH2:21]2)=[N:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.[C:48]1(C)C=CC=C[CH:49]=1.COC(OC)N(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Si:31]([O:30][C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([N:19]2[C:48]([CH3:49])=[N:1][C:2]3[C:3]2=[N:4][C:5]([N:8]2[C:12]4[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=4[N:10]=[CH:9]2)=[N:6][CH:7]=3)[CH2:21][CH2:22]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(C#N)cc43)ncc2N)c2ccccc21)(c1ccccc1)c1ccccc1
Agent: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: Cc1nc2cnc(-n3cnc4ccc(C#N)cc43)nc2n1[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A 50 ml round bottom flask was charged with 0.09 g (0.14 mmol) of 3-(5-amino-4-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (prepared from 3-(5-nitro-4-thiocyanatopyrimidin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile and (1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-amine via same procedure as in Example H, step 1 and Example B, step 3). 20 ml of toluene was then added, followed by 0.028 g (0.21 mmol) of N,N-dimethylformamide dimethylacetal, and a catalytic amount of pyridinium p-toluenesulfonate. The resulting mixture was stirred at 100° C. overnight (condenser used with flask). The mixture was cooled to room temp, diluted with 100 ml EtOAc and washed with approx 10 ml water. The organic layer was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH in DCM), to give 0.06 g (65%) of the titled compound. Compound was single peak by HPLC and had an M+H of 660 by MS.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>C1COCC1>[O:16]=[C:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[O:9][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)ON1C(=O)CCC1=O
Yield: 46.1 %

Procedure:
A solution of 10.0 g (0.088 mol) of glutaric anhydride in 50 mL of dry THF under argon was treated with 10.0 g (0.087 mol) of N-hydroxysuccinimide and heated to reflux for 3.5 hours The reaction was concentrated at reduced pressure to an oil. The oil was crystallized from 50 mL of ethyl acetate to yield 9.2 g (46%) of 5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxo-pentanoic acid which was treated with 16 mL of thionyl chloride and heated at 45° C. for 3 hours under argon. The reaction mixture was concentrated at reduced pressure to a white solid which was triturated with a small amount of ether and collected by suction filtration. The product was dried overnight at high vacuum to yield 8.7 g (88%) of 18 as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[P:11](Cl)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:11]([O:16][CH2:17][CH3:18])(=[O:12])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(Cl)OCC
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccco1

Procedure:
A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N,N,N′N′-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at −78° C. for 0.5 h. Diethyl chlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:29]2[O:33]C(C)(C)[O:31][C:30]2=O)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:37][OH:38].CC#N>CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@@H:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C@H:29]([OH:33])[C:30]([NH:37][OH:38])=[O:31])=[CH:8][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@@H]2OC(C)(C)OC2=O)cc1
Solvent: CC(C)O
Solvent: CC#N
Product: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@H](O)C(=O)NO)cc1
Reaction time: 0.75 h
Yield: 66 %

Procedure:
To a solution of (5S)-5-((1R)-4-(4-ethoxyphenyl)-1-{[4-(4-fluorophenyl)-1-piperazinyl]carbonyl}butyl)-2,2-dimethyl-1,3-dioxolan-4-one (120 mg; 0.24 mmol; 1.0 eq.) in iPrOH (1 mL) was added an aq. solution of hydroxylamine (50%, 71 μl; 1.2 mmol; 5.0 eq.) and the reaction mixture was stirred for 45 min. CH3CN (4 mL) was then added and the resulting mixture was purified by chromatography by reverse-phase preparative HPLC (gradient from 25% to 45% of CH3CN containing 0.1% TFA, in water containing 0.1% TFA). The collected fractions were lyophilized to give the title compound (19) as a white solid (75 mg, 66%). 1H NMR (CDCl3, 300 MHz) δ 7.1-6.99 (m, 6H), 6.80 (d, J=8.2 Hz, 2H), 4.26 (m, 1H), 4.06 (m, 1H), 3.96 (t, 2H, J=6.8 Hz), 3.80 (m, 1H), 3.63 (m, 2H), 3.40 (m, 1H), 3.23-3.00 (m, 4H), 2.58 (m, 2H), 1.85-1.52 (m, 4H), 1.38 (t, J=6.9 Hz, 3H). M−(ESI): 472.1; M+(ESI): 474.6. HPLC: Rt: 3.2 min (HPLC purity: 93.7%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1.Br[C:14]([CH3:26])([CH3:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=[O:16].C(OCC)C>C1COCC1.CCCCCC.O>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[C:14]([S:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1F
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(CSC(C)(C)C(=O)c2ccc(F)cc2F)cc1
Yield: 100.1 %

Procedure:
In 180 ml of THF was suspended 2.4 g (60 mmol) of 60% sodium hydride having been washed with hexane, and 9.4 g (61 mmol) of 4-methoxy-α-toluenethiol was added dropwise to the suspension while stirring under ice-cooling. After being stirred for 10 minutes, the mixture was added dropwise to a solution of 15.0 g (57 mmol) of 2-bromo-1-(2,4-difluorophenyl)-2-methylpropan-1-one in 225 ml of THF with stirring under ice-cooling. To the reaction mixture were added diethyl ether and water, and the organic layer was separated, washed with water and then with a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of hexane and ethyl acetate (10:1). The solvent was removed by distillation under reduced pressure to obtain 19.2 g (95%) of 1-(2,4-difluorophenyl)-2-((4-methoxyphenyl)methylthio)-2-methylpropan-1-one as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(c2cccc(Br)c2)CC1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
To a solution of 1,3-dibromobenzene (10 g, 42 mmol) in toluene (424 mL), were added ethyl isonipecotate (6.5 mL, 42 mmol), rac-BINAP (2.0 g, 3.2 mmol), NaOtBu (4.9 g, 51 mmol) and Pd2(dba)3 (0.97 g, 1.1 mmol). The mixture was heated at 80° C. for 4 h and diluted with water and ethyl acetate and separated. The organic phase was dried over unhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate 10:0 to 9:1) to give the titled compound (5.6 g, 42%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:35]=[CH2:36])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@@:16]3([OH:34])[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@H:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]3)=[CH:12][CH:11]=2)[CH:9]=1.[CH3:37]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:35]=[CH2:36])=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C@@:16]3([O:34][CH3:37])[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[O:22])[C@H:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]3)=[CH:14][CH:15]=2)[CH:9]=1
Reactant: CI
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
NaH (60% in oil) (106 mg, 2.65 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (740 mg, 1.474 mmol) and methyl iodide (0.166 mL, 2.65 mmol) at 0° C. in DMF and stirred at this temperature and allowed to warm up to r.t. overnight. The reaction was then quenched with saturated NH4Cl solution and ether. The ether layer was washed with brine, dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-40% EtOAc in hexanes) to give semi purified product (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-1,2-dicarboxylate (333 mg, 0.645 mmol, 44% yield) as a clear oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 1.01-1.06 (m, 2H) 2.52 (dd, J=13.12, 8.85 Hz, 1H) 2.78-2.87 (m, 1H) 2.97 (d, J=5.19 Hz, 3H) 3.65 (s, 1H) 3.67-3.75 (m, 3H) 3.77 (d, J=8.85 Hz, 3H) 3.96-4.08 (m, 1H) 5.21 (d, J=10.99 Hz, 1H) 5.68 (d, J=17.40 Hz, 1H) 6.59 (ddd, J=17.47, 11.06, 2.29 Hz, 1H) 7.26 (d, J=2.14 Hz, 1H) 7.29-7.35 (m, 3H) 7.35-7.40 (m, 2H) 7.56 (d, J=8.24 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:20].[K+].[K+]>>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:20])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nnc(-c2ccc(C#N)cc2)o1
Agent: OO
Agent: [K+]
Product: CC(C)c1nnc(-c2ccc(C(N)=O)cc2)o1
Yield: 1544.4 %

Procedure:
The title compound was prepared according to the procedure described in step 1 of Intermediate-59 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzonitrile (0.500 g, 2.34 mmol), 50% H2O2 (5.0 mL), K2CO3 (0.097 g, 0.070 mmol) to afford 0.250 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.3 (s, 3H), 1.35 (s, 3H), 3.33 (m, 1H), 7.56 (br s, 1H), 8.06 (s, 4H), 8.16 (br s, 1H); MS (m/z): 232.30 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1.C(OC(C)C)(C)C>C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 6 M aqueous NaOH solution (200 ml, 1.200 mmol) was added to a solution of tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-acetate (26.8 g, 62.7 mmol) in THF (200 ml) and methanol (200 ml) and the reaction was stirred at room temperature for 1 hour. The organic solvents were then distilled off and 6 M aqueous HCl (210 ml) was added to the residue at 0° C. The aqueous phase was extracted with methylene chloride (200 ml) and ethyl acetate (200 ml). The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The residue obtained was codistilled twice with diisopropyl ether. The yield was 21.92 g (94%).
Reaction SMILES: [C@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@H:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[CH:12]([O:17]C)([O:15][CH3:16])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C@H:1]1([C:12]([O:15][CH3:16])=[O:17])[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: O=C1OC(=O)[C@H]2CCC[C@@H]1C2
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydride 1 (3.85 g; 25 mmol) was combined with trimethyl orthoformate (4.10 mL; 37.5 mmol; 1.5 equiv) and methanol (8.2 mL). p-Toluenesulfonic acid (238 mg; 1.25 mmol; 0.05 equiv) was added and the reaction mixture was stirred overnight at ambient temperature to completely consume 1 and afford a single product by GC analysis. The solvent was removed at reduced pressure and the residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous NaHCO3 (10 mL), dried over MgSO4, and concentrated to afford 4.91 g (98%) of cis-2a which gave a single peak by GC analysis.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.C(C1NC(=O)N(CC2C=CC(OC)=CC=2)C1=O)(C)C.[CH3:43][C:44]1[C:45]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([C:59]3[CH:60]=[CH:61][C:62]([N:65]4[CH:69]([CH:70]([CH3:72])[CH3:71])[C:68](=[O:73])[N:67](CC5C=CC(OC)=CC=5)[C:66]4=[O:83])=[N:63][CH:64]=3)=[O:58])[CH2:53][CH2:52]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1>>[CH3:43][C:44]1[C:45]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([C:59]3[CH:60]=[CH:61][C:62]([N:65]4[CH:69]([CH:70]([CH3:71])[CH3:72])[C:68](=[O:73])[NH:67][C:66]4=[O:83])=[N:63][CH:64]=3)=[O:58])[CH2:55][CH2:56]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: COc1ccc(CN2C(=O)C(C(C)C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C(C)C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C(C)C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione (157 mg) described in Preparation Example 209 and by the reaction and treatment in the same manner as in Example 508, the title compound (138 mg) was obtained via 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([C:21]3[O:22][C:23]([C:26]4[N:31]=[C:30]([C:32]([O:34]C)=[O:33])[CH:29]=[CH:28][CH:27]=4)=[CH:24][N:25]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([C:21]3[O:22][C:23]([C:26]4[N:31]=[C:30]([C:32]([OH:34])=[O:33])[CH:29]=[CH:28][CH:27]=4)=[CH:24][N:25]=3)=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN(C)C)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2ccc(CCC(=O)c3ncc(-c4cccc(C(=O)O)n4)o3)cc2)cc1

Procedure:
Methyl 6-(2-(3-(4′-((Dimethylamino)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate was dissolved in THF/H2O (3:2, 2 mL) and LiOH was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 25 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-{2-[3-(4′-Dimethylaminomethyl-biphenyl-4-yl)-propionyl]oxazol-5-yl}-pyridine-2-carboxylic acid.