Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40][N:39]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from ({4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.8:1) as a white solid, MS (ESI+): m/z=508.2 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14]C)=[O:12])[CH3:2].[H-].[Na+].[CH:28](OCC)=[O:29]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:28][OH:29])=[O:25])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CO)c1c(C(=O)OC)ccn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-[2-(ethyloxy)-2-oxoethyl]-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (18.51 g) in dry tetrahydrofuran (300 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 70.0 g) was added portionwise and stirring continued for 15 minutes after complete addition. Ethyl formate (9.12 ml) was added to the reaction mixture and stirred for 30 minutes after which time an exotherm was observed and controlled by cooling the reaction mixture to room temperature with an ice bath. The reaction mixture was stirred for a further 3.5 h. The reaction mixture was cooled in an ice bath and quenched by addition of the minimum amount of methanol then evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride, the aqueous layer was removed and acidified to pH 1 with a 2M solution of aqueous hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated to afford an oil consisting of two layers. The top layer was discarded and the lower layer isolated to afford the title compound as a brown oil (17.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CCCC(N)CCC
Reactant: Cc1cc(C(=O)O)ccc1O
Product: CCCC(CCC)NC(=O)c1ccc(O)c(C)c1

Procedure:
Prepared in a similar manner as described in example 4 using 4-hydroxy-3-methyl benzoic acid and 4-heptylamine. MS (M+H, 250.2).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2ccccc2n1
Temperature: 80 °C

Procedure:
The commercially available 4-hydroxy-2-methylquinoline (6.522 g, 41 mmol) was added portionwise to POCl3 (35 mL) in a round flask at 0° C. with stirring. The homogenous suspension was then immersed into a pre-heated at 80° C. oil bath and continuously refluxed for 4 h. The reaction mixture was cooled to room temperature and the excess POCl3 was distilled out under reduces pressure. The residue was treated carefully with ice (150 g) and then with saturated NaHCO3 aqueous solution (200 mL). The mixture was extracted with CH2Cl2 (100×3 mL), dried over Na2SO4, and evaporated in vacuo to dryness to give known 4-chloro-2-methylquinoline,52 6.10 g (84.14%) as oil, which was pure enough for using in next step. 1H NMR (DMSO) δ 2.61 (3H, s, Me), 7.66 (1H, s, ArH), 7.67-7.71 (1H, m, ArH), 7.82-7.85 (1H, s, ArH), 8.01 (1H, d, J=6.7 Hz, ArH), 8.12-8.14 (1H, s, ArH). Anal. Calcd. for (C10H8ClN): C, 67.62; H, 4.54; N, 7.89. Found: C, 67.62; H, 4.54; N, 7.89.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].COC1C=CC(CCN2CCC[C@H]2C[N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][S:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)=CC=1.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:55]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:49])=[O:48])=[CH:43][CH:42]=1>CCCCCC.COCCOC>[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:55][N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][S:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)(=[O:48])=[O:49])=[CH:45][CH:46]=1
Reactant: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
Lithium diisopropylamide (4.3 ml of a 1.5M solution in hexane) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1 for source) (1.0 g) in DME (25 ml) and the mixture stirred at room temperature for 15 minutes, treated with (S)-1-(4-methylphenylsulphonyl)-2-(4-methylphenylsulphonyloxymethyl)pyrrolidine (3.9 g) (prepared by the method of P. Karrer and K. Ehrhardt, Helv. Chim. Acta, 34, 2202 (1951)), heated under reflux for 2.5 hours, allowed to cool to room temperature, quenched with 2M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution initially using hexane as eluant and changing to hexane/ethyl acetate (90:10). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless solid, (0.93 g, 44%), m.p. 88°-90° C., [α]589 25 -115° (c=0.62 in ethanol).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[CH:9]([OH:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1sc2c(c1-c1ccccc1)C(=O)C(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1sc2c(c1-c1ccccc1)C(O)C(C)C2
Reaction time: 8 h

Procedure:
A solution of 2,5-dimethyl-3-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-4-one (4.4 g, 18 mmol) in 50 mL of ether was slowly added to a solution of LiAlH4 (0.35 g, 9 mmol) in 50 mL of ether and stirred overnight. The resulting suspension was poured into a mixture of ice and water, the organic layer was isolated, while the water layer was extracted with ether (3×50 mL). The combined organic layers were washed with water, dried over MgSO4 and evaporated off to dryness. The 2,5-dimethyl-3-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ol so obtained was dissolved in 100 mL of benzene, added of 1 g of p-toluenesulfonic acid and was refluxed for 10 min. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness. The residue was passed through a column packed with Al2O3 by using hexane as eluent. The evaporation of the yellow fraction was given the crystallized product. Yield 1.5 g (37% based on the starting ketone).
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][CH2:13]S(C)(=O)=O)[CH2:4]1)=[O:2].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>CC(C)=O>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:28]3[CH2:29][CH2:30][N:31]([CH2:13][CH2:12][CH:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:3]([CH:1]=[O:2])[CH2:4]4)[CH2:32][CH:33]=3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)CCC1CN(C=O)c2ccccc21
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CC(C)=O
Product: O=CN1CC(CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
From 19b and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 183-5° C. (from acetone). 1H NMR (DMSO-d6, the spectrum shows hindered rotation which is eliminated by heating above 100° C.) δ 1.60-1.80 (m, 1H), 1.95-2.10 (m, 1H), 2.35-2.55 (m, 4H), 2.70 (t, 2H), 3.15 (s, 2H), 3.35-3.55 (m, 1H), 3.65 (dd, 0.76H), 3.90 (dd, 0.24H), 4.10 (t, 0.76H), 4.30 (t, 0.24H), 6.15 (s, 1H), 6.95-7.15 (m, 2H), 7.25 (t, 1H), 7.35 (d, 1H), 7.40-7.50 (m, 3H), 7.80 (d, 0.76H), 7.90 (d, 0.24H), 8.50 (s, 0.24H), 9.05 (s, 0.76H), 11.20 (s, 1H). MS m/z (%): 406 (MH+, 100%), 377 (5%), 244 (15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>C(O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cn3cc(C)ccc3n2)cc1
Reaction time: 19 h

Procedure:
67 g (0.62 mole) of 2-amino-5-methylpyridine, 86 g (1.02 mole) of sodium bicarbonate and 143 g (0.527 mole) of ethyl 4-(2-bromoacetyl)benzoate are introduced into 1 l of ethanol. The mixture is brought to reflux for 3 hours and left standing for 19 hours, and the solid formed is recovered by filtration, washed copiously with water and dried. It is recrystallized in a dichloromethane/methanol mixture. M.p. 228°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:32][CH:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 64.5 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (802 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (638 mg, 3.0 mmol) were coupled together in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (100 mL) followed by cooling to 0° C. and filtration to yield product as a red solid (900 mg, 65%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.15 (AA′XX′, J=8.6 Hz, 2H), 8.06 (AA′XX′, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 5.61 (d, J=7.5 Hz, 1H), 4.28 (m, 1H), 4.18 (dd, J=5.0, 7.2 Hz, 1H), 3.18 (s, 3H), 2.34 (s, 3H), 1.39 (d, J=6.3 Hz, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CCOCC>C1C=CC=CC=1>[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCc1ccccc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCCCCc1ccccc1CBr
Temperature: 0 °C

Procedure:
A solution of 10 g of phosphorus tribromide in 50 ml of benzene is added dropwise over a period of 15 minutes to a stirred mixture of 6.6 g of 2-nonylbenzyl alcohol and 50 ml of benzene. The reaction mixture is heated under reflux for 30 minutes and, after cooling, ice-water and ether are added. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. Chromatographic purification of the residue on silica gel with petroleum ether yields 2-nonylbenzyl bromide in the form of a colourless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C=O)cc2)CC1

Procedure:
A solution of 3-(N-Boc-piperidin-4-yl)propyl iodide 1-1 (5.0 g, 14.2 mmol) (preparation described in EP 478,328), 4-hydroxybenzaldehyde 1-2 (1.73 g, 14.2 mmol), Cs2CO3 (9.2 g, 28.4 mmol) and DMF (50 ml) was stirred at ambient temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) provided 1-3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:4].C(OCC)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1CC(=O)O
Reaction time: 18 h

Procedure:
Next, to the solution of (S)-1-benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester (2.50 g, 9.01 mmol) in methanol (30 mL)/ethyl acetate (30 mL) is added Pd/C (300 mg) and the mixture is stirred under an atmosphere of hydrogen (H2 balloon) for 18 hours. The catalyst is filtered through a Celite pad and the filtrate is evaporated under reduced pressure to give the title compound; HPLC Retention time 0.94 minutes (condition C): MS 188.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Reaction time: 44 h
Yield: 71.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester [4.89 g, 14.53 mmol, (E):(Z)=3:1] in ethanol (36 mL) was slowly treated with 10% palladium on activated carbon (244.5 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure for 44 h. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (3.50 g, 71%) as a colorless viscous oil: FAB-LRMS m/e calcd for C18H26O4S (M+H)+ integer mass 338, found 339.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][O:6][P:5](=[O:16])([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[O:4][CH2:3]1.C(OO)(=[O:20])C.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:3][O:4][P:5](=[O:16])([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]3[CH:12]([O:20]3)[CH2:11]2)[O:6][CH2:7]1
Reactant: CC(=O)OO
Reactant: CC1(C)COP(=O)(OCC2C=CCCC2)OC1
Solvent: O
Solvent: ClCCl
Product: CC1(C)COP(=O)(OCC2CCC3OC3C2)OC1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 15.5 g (0.058 mol) 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinanoxymethyl)-1-cyclohexene, and 100 mL of methylene chloride. Peracetic acid (13.76 g, 35 wt. % in acetic acid; 0.058 mol) in methylene chloride (60 mL) was added dropwise to above mixture over 20 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 100 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×100 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[NH:29])=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]2[N:30]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:29]=2)=[CH:19]1
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Product: O=C1Cc2cnc(Cc3c[nH]c4ccccc34)nc2-c2ccccc2N1
Yield: 80 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1OS(C(F)(F)F)(=O)=O.[CH3:30][N:31](C)C=O>CCOCC.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)=[CH:5][C:6]=1[CH3:16])#[N:31]
Reactant: CN(C)C=O
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-(3,5-dimethyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.80 g, 0.00643 mol) and zinc cyanide (1.51 g, 0.0128 mol) in N,N-dimethylformamide (15.0 mL, 0.194 mol) was degassed with nitrogen for 15 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.74 g, 0.00064 mol). The reaction mixture was heated at 100 Celsius for 4 h. The mixture was diluted with ether, washed with aq. sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified on silica gel, eluting with 0 to 10% EtOAc in hexane, to generate the titled compound (1.08 g, 53.66%). LCMS (M+H) 313.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C1COCC1>[CH3:25][S:26]([NH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1)(=[O:28])=[O:27]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 10 ml of THF, 0.56 ml (4.0 mmol) of triethylamine and 230 mg (2.0 mmol) of methanesulfonyl chloride are added. The mixture is stirred overnight at RT, the solvent is removed in vacuo and the crude product is subjected to an aqueous work-up and extracted with dichloromethane. The isolated product is dissolved in 10 ml of DMF, 8 mmol 12.5 mmol of 1M NaOH solution are added and the mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude product subjected to HPLC chromatography. Yield after two steps: 170 mg, 30%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.53 g (7.2 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.58 g (15.6 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methanol to give 2.00 g (61 percent of theoretical) of the above-named product as colorless crystals which melted at 156.5°-158° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 6)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[N:6]=1>C(O)(C)C>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=1
Reactant: CNC
Reactant: Clc1cncc(Cl)n1
Solvent: CC(C)O
Product: CN(C)c1cncc(Cl)n1
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Cuprous chloride (50 mg) is added to a solution of dimethylamine (36 g, 0.8 mole) in 260 ml of isopropanol. 2,6-Dichloropyrazine (49.9 g, 0.33 mole) is added to the mixture with stirring and cooling to maintain the temperature at 35°-40° C. After 3/4 hr. the cooling bath is removed and the reaction mixture is stored at ambient temperature for 16 hours and finally at 42°-48° C. for 3 hours. The solvent is removed under vacuum and the residue is dissolved in dilute hydrochloric acid. The aqueous solution is extracted with ether and then made basic with solid sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to obtain 49 g of product, melting point 46°-8° C.