Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:19]([N:15]([CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH3:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Reaction time: 3 h
Yield: 887.5 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55. 5 mmol), N-methyl-N-dodecylethanolamine (13.5 g, 55.5 mmol) and triphenylphosphine (16.0 g, 61.0 mmol) in dry tetrahydrofuran (200 ml) was treated at 22° C. with diisopropyl azodicarboxylate (12.3 g, 61.0 mmol) added dropwise over 50 min. After 3 h at 22° C., the reaction mixture was evaporated under reduced pressure and the residue was triturated with hexane. The solid formed was filtered, washed with hexane and the combined filtrate was chromatographed on silica gel using a gradient of ethyl acetate in hexane (20%-60%) as eluent. Distillation under vacuum then gave 18.0 g (75%) of 3-{4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl} propanoic acid, methyl ester as a clear oil: b.p. 180-183° C./0.02 torr (bulb to bulb distillation, air bath temperature).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisobutylaluminum hydride solution (1 M in hexane, 5.0 mL, 5.0 mmol) was added at 0° C. to a solution of 4-pentafluoroethyl-benzonitrile (1.00 g, 4.52 mmol) in DCM (5 mL), then after 2 h another portion of diisobutylaluminum hydride solution (5 mL) was added and the reaction stirred at RT for 16 h, then carefully poured onto 50% aq. sulfuric acid solution (4 mL). Water (45 mL) was added, and the mixture is extracted three times with DCM. The organic layer was subsequently washed with brine and 1 M potassium sodium tartrate solution, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded crude 4-pentafluoroethyl-benzaldehyde (390 mg) as a yellow liquid, which was added at RT to a solution of 2-(4-chlorophenyl)ethylamine (269 mg, 1.73 mmol) in methanol (2 mL), then after 18 h sodium borohydride (65 mg, 1.73 mmol) was added at 0° C. After 1 h the reaction mixture was partitioned between ether and water, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (431 mg, 26%). Light yellow oil, MS (ISP) 364.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][C:16]2[CH:21]=C[CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[N:24]1C=CC=C(N=C=O)C=1>>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])([CH3:23])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][C:16]2[CH:21]=[N:24][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)CCN(C(=O)Nc2ccccc2)c2cc(C#N)ccc21
Reactant: O=C=Nc1cccnc1
Product: CC1(C)CCN(C(=O)Nc2cccnc2)c2cc(C#N)ccc21

Procedure:
The title compound was prepared from 7-cyano-3,4-dihydro-4,4-dimethyl-1(2H)-quinoline (compound of example 1, part J) and 3-pyridylisocyanate by the same method as described in example 1, part K. The product was obtained as a colorless powder; m.p. 183°-185° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:16][CH2:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:21]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a stirred solution of ethyl acrylate (141 g, 1.41 mole) and N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (Compound D17 of EP 0363085, 435 g, containing approximately 75% of D17, 1.4 moles) in dichloromethane (2.5L) at -5° C. was added trifluoroacetic acid (16.1 g, 0.14 mole) in dichloromethane (100 ml) ensuring that the temperature did not rise above 0° C. This mixture was then transferred by cannula to stirred, refluxing dichloromethane (50 ml) over 40 minutes at such a rate as to maintain gentle reflux. The reaction mixture was then refluxed for a further 1h before cooling to room temperature. It was then washed with saturated aqueous potassium carbonate, dried (Na2SO4), and concentrated in vacuo to a gum which was distilled to afford the title compound (D1) as a clear oil (286 g, 88%) b.p. 120°-150° C. at 4 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[IH:10].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[I:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: I
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
4-Chloro-2-methylthiopyrimidine (5 g, 31.15 mmol) was added dropwise to a cooled 57% aqueous hydriodic acid solution (0° C.). Stirring was continued at 0° C. for 30 minutes, before warming to ambient temperature and stirring for 24 hours. Aqueous sodium bicarbonate was then carefully added and the resultant suspension basified to pH 9 by addition of sodium carbonate. The mixture was extracted with ethyl acetate and the extracts dried over magnesium sulfate and concentrated by reduced pressure. The resultant solid was dissolved in boiling isohexane and cooled by refridgeration overnight. The resultant solid was filtered and dried to afford the title compound as colourless needles (5.4 g, 69%); NMR Spectrum: (CDCl3) 2.55 (s, 3H), 7.40 (d, 1H), 7.98 (d, 1H); Mass Spectrum: M+H+ 253.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C=O)C>[N:19]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CN2CCCC2)n1
Temperature: 80 °C
Yield: 67.4 %

Procedure:
K2CO3 (66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate 67 (45.0 g) and pyrrolidine 68 (34 g, 0.48 mol) in DMF (300 mL). The reaction mixture was heated at 80° C. for 12 h. H2O (300 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 69 (36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:15]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH3:17])[C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(C)OC(C)C
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n(C)c1=O
Yield: 73.1 %

Procedure:
A mixture of 5-chloro-2-methylaminobenzophenone (1.23 g), diethyl malonate (1.6 g) and piperidine (0.1 ml) was heated for 3 hours at 170°-180° C. After cooling, the mixture was treated with isopropyl ether to give crystals, which were recrystallized from ethanol to afford ethyl 6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylate (1.25 g, 73.1%). mp 124°-125° C. The product was identical with the compound obtained in Reference Example 12.
Reaction SMILES: [NH2:1][C@H:2]([C:16]([O:18]CCN(CC)CC)=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:12]([CH3:14])=[O:13])[C:9]([CH3:11])=[O:10].[NH:26](C(OC(C)(C)C)=O)[C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38](ON1C(=O)CCC1=O)=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32].C(OCC)(=O)C>C([O-])(O)=O.[Na+].CC(C)=O>[NH2:26][C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38]([NH:1][C@H:2]([C:16]([OH:18])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:9]([CH3:11])=[O:10])[C:12]([CH3:14])=[O:13])=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CCOC(=O)[C@@H](N)CCCNC(=N)N(C(C)=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N(C(C)=O)C(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 121.8 %

Procedure:
22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2 was dissolved in 300 ml of 5% NaHCO3. 24 g of Boc-Asp(OEt)-Pro-OSu in 150 ml of acetone was added into the reaction mixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetate was added into the mixture. The ethyl acetate solution was washed with water (3×100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid was added into the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to yield 32 g of H-Asp(OEt)-Pro-Arg(diAc)*OCH2CH2N(CH2CH3)2.2TFA.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)(=[O:34])=[O:33])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a mixture of (S)-piperidine-2-carboxylic acid benzyl ester hydrochloride (5.00 g, 19.5 mmol) and triethylamine (5.50 mL, 39.1 mmol) in dichloromethane (150 mL) was added 3-fluorobenzenesulfonyl chloride (3.80 g, 19.5 mmol). The mixture was stirred at room temperature for 5 h as it turned to a white suspension. The suspension was washed twice with distilled water. The organic layer was then dried over magnesium sulfate and concentrated to afford 9 g of crude oil. Flash column chromatography on silica gel (ethyl acetate/n-heptane) provided 6.51 g (88.3%) of the title compound as a yellow oil.
Reaction SMILES: COC1C=C(C=CC=1OCCCC)[CH2:6][N:7]([C@H:18]([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[H-].[Na+].N1C(C)=CC=CC=1C.C(Cl)(Cl)=[O:50]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][C@H:18]([N:7]2[CH2:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:10][C:6]2=[O:50])[CH3:30])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: O=C(Cl)Cl
Reactant: CCCCOc1ccc(CN(CC(O)c2cccc(Cl)c2)[C@H](C)Cc2ccc(OC)c(OC)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H](C)N2C[C@@H](c3cccc(Cl)c3)OC2=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g. of (R)-N-(3-methoxy-4-n-butoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine (obtained in Example 2) in 45 mL of toluene is added to 406 mg. of sodium hydride at room temperature. The mixture is stirred for one hour, 1.29 mL of 2,6-lutidine are added, and stirring is continued for 30 minutes. The reaction mixture then is added with stirring to 5.74 mL of a 20% solution of phosgene in toluene which has been cooled to 0° C. Excess phosgene is destroyed with 3N sodium hydroxide and the reaction mixture diluted with toluene, washed sequentially with 3N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated to yield (R,R)-3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-(3-chlorophenyl)oxazolidin-2-one. This is further purified by stirring in heptane at 55° C. for 15 minutes, filtering, washing with additional heptane, and recrystallization from 5:4 ethyl acetate:heptane to yield white crystals. Gas chromatography indicates the chemical purity is 99.3% and HPLC indicates the de is 99.6%.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH2:23])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[O:36])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2c(Sc3ccc(N)s3)ccnc2cc1OCCCN(C)C
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.2 %

Procedure:
5-({7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), para-fluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=O>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=[N:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(CN=Cc1cc(Cl)cc(Cl)c1)OCC
Temperature: 114 °C
Reaction time: 2.5 h

Procedure:
The 2,2-Diethoxy-ethylamine (1852.5 g; 1.00 equiv; 13.63 moles), 3,5-dichloro-benzaldehyde (2453 g; 1.00 equiv; 13.60 moles), and Toluene (12 L) is charged to a 22 L flask equipped with a Dean Stark trap, condenser, nitrogen inlet, overhead stirring, and thermocouple. The light yellow reaction is warmed to reflux. Solvent begins distilling at 88° C. A total of ˜650 mL distillate (˜240 mL of water) is collected. The temperature is increased to 114° C. during the distillation. NMR after 2 hr at reflux shows the product. The heat is shut off after 2.5 hr. The solution is gravity filtered into a carboy through fluted filter paper to remove a few particulates (including a small section of glass tubing, which is most likely from the 3,5-dichloro-benzaldehyde). The filtered solution is concentrated using Buchi flask with the water bath set at 45° C. Once the solvent stops coming over, the temperature is increased to 70° C. with full vacuum and held for ˜1.5 hr to remove any residual toluene. The weight of (3,5-Dichloro-benzylidene)-(2,2-diethoxy-ethyl)-amine is 4059.3 g (102.9% of theory). Mass Spectrum (LCMS) m/z=291.2) (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Yield: 71.9 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (1.78 g, 7.51 mmol), 1-iodopropane (1.92 g, 11.3 mmol), and potassium carbonate (4.15 g, 30.0 mmol) in acetonitrile (50 mL) was heated in a pressure vessel at 80° C. for 24 hours. The reaction was cooled and the acetonitrile was removed under reduced pressure. The solids were dissolved in methylene chloride/water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The resultant residue was purified by chromatography on SiO2 (10% MeOH/CH2CL2 with 0.2% NH3) to give 1-[3-(methyloxy)-4-nitrophenyl]-4-propylpiperazine as a pale yellow solid (1.5 g, 5.4 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (t, J=7.32 Hz, 3H), 1.51-1.61 (m, 2 H), 2.34-2.42 (m, 2 H), 2.59 (s, 4 H), 3.38-3.45 (m, 4 H), 3.95 (s, 3 H), 6.31 (d, J=2.20 Hz, 1 H), 6.42 (dd, J=9.34, 2.38 Hz, 1 H), 8.00 (d, J=9.52 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-n3cccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[C:48]([NH:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[N:18]1)(=[O:50])[CH3:49]
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 μl (0.11 mmol) of N,N-diisopropylethylamine were added to a solution of 60 mg (0.10 mmol) of the compound of Example 58A in 1 ml of dichloromethane. The mixture was cooled to 0° C., 10 μl (0.10 mmol) of acetic anhydride were then added and stirring was continued at 0° C. for 1 h. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a little DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 50 mg (83% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:43]1([CH2:49][CH:50]=O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O)(=O)C>ClC(Cl)C>[C:43]1([CH2:49][CH2:50][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH:2]2[CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[C:25]([O:27][CH3:28])=[O:26])=[O:14])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Yield: 79.1 %

Procedure:
The product from Example 22B (0.2486 g, 0.50 mmol) and sodium triacetoxy borohydride (0.2235 g, 1.05 mmol) were suspended in dichloroethane (10 mL). The reaction flask was equipped with stir bar and spetum, then flushed with N2. Phenylacetaldehyde (0.10 mL, 0.85 mmol) was added followed by glacial acetic acid (0.2 mL, 3.4 mmol). After 1 hour of stirring at ambient temperature, the reaction mixture was quenched with water (20 mL) then partitioned between ethyl acetate/water. The aqueous phase was extracted with ethyl acetate (2×15 mL). The combined organic fractions were washed sequentially with aqueous saturated NaHCO3 (1×25 mL), water (1×25 mL), and brine (1×25 mL), dried (MgSO4), filtered and concentrated in vaco. The crude material was purified via column chromatography (2% to 5% methanol/dichloromethane) to afford the titled compound (0.1913 g, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.99 (s, 1 H) 8.43 (s, 1 H) 7.80 (d, J=7.80 Hz, 1 H) 7.69 (d, J=8.48 Hz, 1 H) 7.48 (t, J=8.14 Hz, 1 H) 7.25 (m, 5 H) 7.04 (m, 1 H) 6.95 (d, J=7.46 Hz, 1 H) 6.71 (d, J=8.14 Hz, 1 H) 6.51 (t, J=6.95 Hz, 2 H) 4.03 (s, 3 H) 3.72 (m, 1 H) 3.37 (m, 3 H) 3.13 (m, 1 H) 2.82 (m, 3 H) 2.59 (m, 1 H) 1.89 (m, 1 H) 1.55 (m, 1 H). MS (ESI) m/z 484 (M+H)+, 482 (M−H)−.