Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(CCCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-3-phenylpropyl-1,2-oxaphosphorin 2-oxide (72.3 mg, 68%) which is a title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH2:31])[CH:25]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:17]([C:14]([CH3:15])([O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=2)[CH3:16])=[O:19])[CH:25]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cccc(-c3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and C-biphenyl-3-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO5 [M−H]−: 462.
Reaction SMILES: O[S:2]([OH:5])(=[O:4])=[O:3].[O:6]=[S:7](=[O:9])=[O:8].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>[CH2:12]([C:11]1[C:12]([CH2:11][CH2:10][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:13][CH2:14][CH3:15])=[C:13]([S:7]([OH:9])(=[O:8])=[O:6])[C:14]([S:2]([OH:5])(=[O:4])=[O:3])=[C:15]2[C:10]=1[CH:12]=[CH:11][CH:10]=[CH:16]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCC
Reactant: O=S(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCCCCCc1c(S(=O)(=O)O)c(S(=O)(=O)O)c2ccccc2c1CCCCCCCCCCCC

Procedure:
This example shows the feasibility of producing a heavy-phase concentrate of didodecylnaphthalene disulfonic acid using the double-sulfonation and controlled washing technique described above. 211 grams of didodecylnaphthalene synthesized by the alkylation of naphthalene with tetrapropylene using aluminum chloride catalyst and nitrobenzene solvent was diluted with an equal weight of heptane. This solution of "DDN" in heptane was sulfonated in two treats with 122 grams of 20% oleum per treat. After each oleum treat, the spent acid was allowed to separate and was then drawn off. The sulfonation was carried out at a temperature of 40° C. The overall mole ratio of available SO3 to alkylate was approximately 2.0:1. 441 grams of crude sulfonic acid in heptane was recovered from the reaction. 110 milliliters of heptane and 270 milliliters of hot water were added to the crude sulfonic acid in a separatory funnel and mixed well. On standing, a dense heavy-phase settled to the bottom. It contained 56.1% didodecylnaphthalene sulfonic acid in a total weight of 34.3 grams. the upper organic layer was washed several times with water. All of the washes including the heavy-phase wash were combined and yielded an additional 20.4 grams of disulfonic acid for a total yield of 39.6 grams of didodecylnaphthalene disulfonic acid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[N:7]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=2)C(OCC)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.[C:35]1([CH3:41])C=CC=C[CH:36]=1.C1C[O:45]CC1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:12])[N:7]([C:21]2[CH:31]=[CH:30][CH:29]=[C:23]([C:35]([OH:45])([CH3:41])[CH3:36])[CH:22]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: C[Mg]Br
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)cc2)n(-c2cccc(C(C)(C)O)c2)n1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of Example C (220 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at −78° C. under N2. After stirring for 1 h, the mixture was allowed to rise to RT and stirred for another 2 h. The reaction mixture was quenched with saturated NH4Cl and aqueous HCl solution (10%), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography to afford 1-{5-t-butyl-2-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea (174 mg, 81%). 1H NMR (DMSO-d6): 9.11 (s, 1H), 8.34 (s, 1H), 7.59 (s, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.31-7.28 (m, 3H), 6.34 (s, 1H), 5.13 (s, 1H), 1.42 (s, 6H), 1.27 (s, 9H); MS (ESI) m/z: 428 (M+H+).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[C:1]1([S:7]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzenesulfonyl chloride (1 g, 5.66 mmol) in THF (20 mL) were sequentially added triethylamine (1.97 mL, 14.15 mmol) and piperazine (2.92 g, 33.9 mmol). The reaction was stirred at room temperature for 1 hour before it was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate to 10/1 dichloromethane/methanol) to give 22 as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[CH2:3][C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:1][C@@H:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[CH2:3][C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C[C@H](CC(=O)N1CCCC1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@H](CC(=O)N1CCCC1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-amide (125 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added TFA (0.5 mL, 6.49 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water. The resultant precipitate was collected via filtration and washed with water and EtOAc. The solid was dissolved in 10% MeOH/CH2Cl2 and washed with water. The aqueous layer was back-extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to afford 64 mg (66%) of 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-amide as an off-white solid. MS: (M+H)+=466; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.07 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 7.97 (d, J=1.1 Hz, 1H), 7.28 (dd, J=8.7, 1.5 Hz, 1H), 4.36-4.54 (m, 1H), 4.16 (s, 3H), 3.40 (t, J=6.6 Hz, 2H), 3.10-3.25 (m, 2H), 2.52-2.76 (m, 2H), 1.61-1.90 (m, 4H), 1.38 (d, J=6.8 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH2:2]1.[N:6]1[C:10]2C=CC=C[C:9]=2[NH:8][CH:7]=1.N1[CH:19]=[CH:18]N=C1>>[N:8]1[CH:9]=[CH:10][N:6]([CH2:18][CH2:19][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C1COCO1
Reactant: c1ccc2[nH]cnc2c1
Product: c1cn(CCC2OCCO2)cn1

Procedure:
NMR CDCl3 : 2.25 and 4.35: CH2 's of the ethyl; 3.85 to 4.00: CH2 's of the dioxolane; 4.87: CH dioxolane; 7.29-7.45-7.81: 4H benzimidazole; 7.92: H in position 2 of the imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]([NH2:33])[CH3:32])[N:30]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:33][CH:31]([C:29]3[N:30]=[C:26]([CH3:25])[S:27][CH:28]=3)[CH3:32])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: Cc1nc(C(C)N)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3csc(C)n3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), 1-(2-Methylthiazol-4-yl)-ethylamine hydrochloride (22 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light peach colored solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][O:39]C=O)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:42]>CO.O1CCCC1>[ClH:42].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][OH:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Yield: 97.7 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 5.0 g.) and conc. hydrochloric acid (3.34 g.) in methanol (35 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 2-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 4.73 g.).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].[C:17]1([C:29]2[CH:34]=[CH:33]C=[CH:31][CH:30]=2)[CH:22]=[CH:21][C:20](C(=O)CCCC)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:29]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:34]=[CH:33][C:9]([C:8]2([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:31][CH:30]=1
Reactant: [Li]CCCC
Reactant: CCCCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1(c2ccc(-c3ccccc3)cc2)CC(O)=CC(=O)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 1 using 13 g ethyl acetoacetate, 5.3 g of NaH 60% dispersion in oil, 60 mL of 1.6M n-butyl lithium in hexane, 21 g of 1-[1,1'-biphenyl]-4-yl-1-pentanone and 300 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction mixture afforded a solid which was washed with CH2 Cl2 and two times with ethyl acetate (m.p. 165°-170° C). 1H NMR(d6 -DMSO) δ 0.7-1.9 (m, 7 H), 2.0 (m, 2 H), 3.0 (s, 2 H), 4.9 (s, 1 H), 7.3-7.8 (m, 9 H), 11.3 (s, 1 H).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:8]/[C:9](/[CH3:14])=[CH:10]\[C:11]([O-:13])=[O:12].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)([O-:17])=[O:16]>C(O)(C)C>[CH3:5][C:3]1[NH:8][C:9]([CH3:14])=[C:10]([C:11]([OH:13])=[O:12])[CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N+:15]([O-:17])=[O:16])[C:2]=1[C:1]([OH:7])=[O:6]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)[O-]
Reactant: C/C(N)=C/C(=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2ccccc2[N+](=O)[O-])C(C(=O)O)=C(C)N1
Yield: 66.7 %

Procedure:
In 30 ml of isopropyl alcohol was dissolved 1 g of 2-nitratoethyl acetoacetate, 1.1 g of 3-nitratopropyl 3-aminocrotonate and 0.79 g of 2-nitrobenzaldehyde. The solution was treated in the manner described in Example 1 to obtain a residue, which was then subjected to column chromatography on silica gel (eluted with n-hexane-acetone=5:2) and recrystallized from ether to obtain 1.11 g of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nitratoethyl) ester-5-(3-nitratopropyl) ester.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[N:42][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[N:42][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-1-(6-isopropoxypyridin-3-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.39 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.30 g, 68%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Se].[OH2:14]>>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH:1]=[O:14])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: O
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Se]
Product: O=CC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
6.60 (40 mmol) 4-nitroacetophenone was dissolved in 30 ml of diozane and 5 g, (45 mmol) selenium dioxyde was dissolved in 2.2 ml water and mixed. The mixture was refluxed for 16 hours with continuous stirring. The reaction mixture was passed through an alumina column to remove selenium. The solvent was evaporated in vacuum. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[O:43])[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(C(=O)c3ccccn3)CC2)n1
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield via the procedure outlined for Example 3 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and picolinoyl chloride hydrochloride to give a white glass: 1H NMR (CDCl3, 300 MHz) δ 8.65 (bs, 1H), 7.83 (t, 1H, J=7.5), 7.72 (d, 1H, J=7.5), 7.40 (t, 1H, J=5.7), 7.24-7.21 (m, 2H), 7.12-7.04 (m, 4H), 6.73 (d, 2H, J=8.1), 3.96-3.78 (m, 4H), 3.75-3.55 (m, 6H), 3.10 (s, 3H), 2.80 (t, 2H, J=6.6), 2.65-2.60 (m, 2H), 1.95-1.89 (m, 2H); low resolution MS (ES+) m/e 588 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1)): Rf=0.62.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[CH:21][C:20]=2[CH3:26])=[C:15]([C:27]#[CH:28])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[CH:35]2.C(N(CC)CC)C>CN1C(=O)CCC1.[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>[C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[CH:21][N:22]=[CH:23][C:24]=2[CH3:25])=[C:15]([C:27]#[C:28][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1ccc2ncccc2c1
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)cncc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ncccc2c1

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethylpyridin-4-yl)-6-ethynylpyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate (E1a desilylated according to the general method exemplified for F1a) (50 mg, 0.12 mmol), 6-iodoquinoline (89 mg, 0.35 mmol), copper(I) iodide (2.2 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and triethylamine (64 μl, 0.47 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 1 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 28 mg (45%). HPLC-MS: M+H=536; tR=1.79 min (*Method—3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][O:34]CC[Si](C)(C)C)[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][OH:34])[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:30][CH2:31]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)C[C@H](CC(=O)O)C(=O)N2CC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(CO)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (rac) 2-((2′S,3′R,S′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-5′-yl)acetic acid (Example 62, Step K) (47 mg, 0.078 mmol) in DCM (0.8 mL) at room temperature was added 0.2 mL TFA. The reaction mixture was stirred at room temperature for 19 h before concentrating under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:16]([CH2:17]O)=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH2:5]([N:12]1[C:16]([CH2:17][Cl:3])=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CCl)n2Cc2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
Thionyl chloride (0.90 ml, 1.48 g, 12.4 mmol) was added dropwise to a stirred suspension of 1-benzyl-4-chloro-5-(hydroxymethyl)-2(4-nitrophenyl)imidazole (18.5 g, S.4 mmole) in chloroform (15 ml) at room temperature. The brown solution was stirred for 2.5 hours then evaporated to dryness. Toluene (12 ml) was added to the residue and evaporated to dryness. The residue was dissolved in chloroform (20 ml) and used in the next step for introduction of the cyano functional group.
Reaction SMILES: [NH2:1][NH2:2].[C:3]1(=O)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[O:4]1>O.CC(O)=O>[C:5]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3](=[O:4])[NH:2][NH:1]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of hydrazine (392 μL, 13.1 mmol) in water (6 mL) and HOAc (2 mL) is added 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (2 g, 13.1 mmol). The reaction mixture is refluxed for 3 h, then cooled down to room temperature and the precipitate is collected by filtration, washed with water and dried under vacuum to give 2,3,5,6,7,8-hexahydro-phthalazin-1,4-dione (40) (2.09 g, 96%).