Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1
Reactant: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](NCc4ccccc4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1nnc([C@@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3N)n1
Yield: 87 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-1-phenyl-6-(2-methyl-2H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Description 33b; 357 mg, 0.77 mmol) was dissolved in ethanol (10 mL) and treated with 1,4-cyclohexadiene (5 mL), followed by 10% palladium on activated charcoal (300 mg). The suspension formed was heated at reflux for 72 hours, then cooled and filtered. The filtrate was concentrate to give the title compound as a gum (239 mg, 0.67 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:11](=O)[CH2:12][CH3:13])[CH:10]=1.C(OP([CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:11]([CH2:12][CH3:13])=[CH:25][CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:10]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CCC(=O)c1cc(OCOC)ccc1OC
Product: CCOC(=O)C=CC=C(CC)c1cc(OCOC)ccc1OC

Procedure:
In a manner similar to Example 63(c), by reacting 3.9 g (17 mmol) of 3-(5-methoxymethoxy-2-methoxyphenyl)-3-propanone with 8.7 g (34.8 mmol) of ethyl 4-diethylphosphonocrotonate, ethyl 5-(5-methoxymethoxy-2-methoxyphenyl)hepta-2,4-dienoate is obtained which is converted to ethyl 5-(5-hydroxy-2-methoxyphenyl)hepta-2,4-dienoate with concentrated sulphuric acid in ethanol 800 mg (17%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[NH2:23])=O)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH3:27])[N:3]=1>CC(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([S:26][CH3:27])[C:5]([C:24]#[N:25])=[C:6]([S:8][CH2:9][C:10]2[NH:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[N:23]=2)[N:7]=1
Reactant: CSc1nc(N)nc(SCC(=O)Nc2cc(C(F)(F)F)ccc2N)c1C#N
Solvent: CC(=O)O
Product: CSc1nc(N)nc(SCc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C#N
Temperature: 120 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a 10 mL recovery flask was added 2-(2-amino-5-cyano-6-methylsulfanyl-pyrimidin-4-ylsulfanyl)-N-(2-amino-5-trifluoromethyl-phenyl)-acetamide (and regioisomer) (10 mg, 0.0241 mmol) and AcOH (2 mL). The solution was stirred at 120° C. for 1 h. The reaction mixture was concentrated. The resulting film was resuspended in 1:1 CH3CN/H2O and lyophilized to give 2-amino-4-methylsulfanyl-6-(6-trifluoromethyl-1H-benzoimidazol-2-ylmethylsulfanyl)-pyrimidine-5-carbonitrile as a tan powder (9 mg, 94%). LC/MSD (HP Series 1100 MSD) Expected MW: 396.04, Observed M+H, 397.0, Retention time: 1.49. Analytical LC: 98%, Retention time: 4.46 (11 minute run). 1H-NMR, DMSO-d6, Varian 400 MHz δ 12.69 (m, 1H), 8.10 (bs, 1H), 7.91-7.79 (d, 1H), 7.76-7.64 (dd, 1H), 7.51-7.46 (dd, 1H), 4.68 (s, 2H) ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:23])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:4]([Si:1]([O:8][CH2:9][CH:10]1[O:23][C:13]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=[CH:21][C:12]=2[CH2:11]1)([CH3:3])[CH3:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1O)CCCC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC1Cc2ccc3c(c2O1)CCCC3
Yield: 80.9 %

Procedure:
Treatment of (±)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-5,6,7,8-tetrahydronaphthalen-1-ol (5.75 g, 0.017 mol) with triphenylphosphine (4.71 g, 0.018 mol) and diethylazodicarboxylate (3.12 g, 0.018 mol) generally according to the procedure described for Intermediate 5 provided 4.38 g (80%) of (±)-tert-butyl(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethoxy)dimethylsilane as a colorless oil. Rf=0.71 (silica, ethyl acetate:hexanes 1:5); Anal. calcd. for C19H30O2Si: C, 71.64; H, 9.49. Found: C, 71.4; H, 9.62.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][O:27]CC1C=CC=CC=1.O>CN(C=O)C.CO.[Pd]>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:14])([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:15][CH:16]=1
Reactant: CCC(C)(Oc1ccc(O)cc1)C(=O)OC
Reactant: BrCCCOCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCC(C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Temperature: 45 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate (5 g, 22.32 mmol) in 30 mL DMF was added cesium carbonate (8.7 g, 26.7 mmol) followed by benzyl 3-bromopropyl ether (7.7 g, 33.6 mmol). The solution was stirred at 45° C. for 24 hr, cooled and poured over water. Extraction with AcOEt followed by washing the extracts with water, drying over anhydrous Na2SO4 and concentrating under reduced pressure gave the crude residue. Purification over silica gel using AcOEt/hexanes furnished the desired alkylated derivative (8.25 g). This product was taken up in MeOH (75 mL) and hydrogenated over 10% Pd/C at 40 psi to provide methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (6.23 g, quantitative).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([OH:18])[C:4]=1[CH:5]=[O:6])[CH3:2].CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>ClCCl.O>[CH2:1]([C:3]1[C:4]([CH:5]=[O:6])=[C:7]([O:18][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:28])=[O:26])[CH:8]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:10]=1)[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 2-ethyl-6-hydroxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.56 g, 6.24 mmol) and Et3N (2.61 mL, 18.72 mmol) in dichloromethane (20 mL) was slowly added Tf2O (2.10 mL, 12.84 mmol) at −78° C. The mixture was stirred at −78° C. for 1 hour. The mixture was diluted with H2O and extracted with dichloromethane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was dissolved in Hexane-EtOAc(4:1), filtered through a plug of silica gel and filtrate was concentrated to give trifluoro-methanesulfonic acid 3-ethyl-2-formyl-5-(tetrahydro-pyran-2-yloxy)-phenyl ester (2.06 g, quant.). 1H NMR (400 MHz, CDCl3δ 12.39 (s, 1H), 10.08 (s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.50 (s, 1H), 3.80 (m, 1H), 3.66 (m, 1H), 3.07 (m, 2H), 2.00-1.50 (m, 6H), 1.26 (m, 3H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][C@@H:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C.C(OC(C)C)(C)C>[ClH:1].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:14][C@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CS[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccc(CS[C@H]2CCNC2)cc1
Reaction time: 0.5 h

Procedure:
106 ml of a 4N ethyl acetate solution of hydrogen chloride were added, whilst ice-cooling, to a solution of 27.50 g of (3R)-1-t-butoxycarbonyl-3-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (2) above] dissolved in 100 ml of ethyl acetate, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 25° C. for 2 hours. At the end of this time, the mixture was diluted with 200 ml of diisopropyl ether, and the crystals which precipitated were collected by filtration, to give 20.84 g of the title compound as colorless crystals, melting at 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:10]1[CH2:12][CH2:11]1
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(Cl)c(C2CC2)c1
Temperature: 100 °C

Procedure:
20 g (73 mmol) of 1,4-dichloro-2-iodobenzene, 9.4 g (110 mmol) of cyclopropylboronic acid, 32 g (147 mmol) of potassium phosphate, 421 mg (0.7 mmol) of bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and 1096 mg (1.5 mmol) of 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphine)ferrocene (CTC-Q-PHOS) are dissolved in 600 ml of toluene and heated at 100° C. overnight. 100 ml of water are added to the cooled solution, and the mixture is extracted twice with toluene (100 ml). The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography, giving the title compound as a colourless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[CH3:16])=O.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.O.[NH2:26][NH2:27]>ClCCl.CN(C=O)C.C1COCC1.O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:16])=[CH:9][NH:10]2)=[CH:6][C:5]=1[C:3]([NH:26][NH2:27])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cc2c(C)c[nH]c2cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2[nH]cc(C)c2cc1C(=O)NN

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme V or VI to form a compound of the invention
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:7]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=[O:21])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.O>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:7]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=[O:21])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COCc2ccccc2C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(COCc2ccccc2C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.8 %

Procedure:
A mixture of 450 mg of 2-butyl-5-[(2-carboxyphenyl)methoxymethyl]-4-chloro-1-[[2'-(1-triphenylmethyltetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazole, 7.5 ml of acetic acid, 3.7 ml of H2O and 2 ml of THF is stirred at room temperature for 10 hours. The solvent s are evaporated off under reduced pressure and the residue is taken up in H2O, alkalinized with 10% NaOH, an insoluble part is filtered off, the resulting solution is extracted with ether and acidified to pH 4.5 with 5N HCl. The obtained precipitate is filtered and washed with H2O. 0.2 g of a white solid are obtained (70% yield). M.p. 109°-111° C. 1H NMR (CDCl3), δ: 0.84 (t, 3 H); 1.27 (m, 2 H); 1.54 (m, 2 H); 2.39 (t, 2 H); 4.43 (s, 2 H); 4.60 (s, 2 H); 5.14 (s, 2 H); 6.80-8.12 (m, 12 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (32 g, 74.2 mmol) and Et3N (22.5 g, 226 mmol) in CH2Cl2 (400 mL) was added a solution of MsCl (10.1 g, 89 mmol) in CH2Cl2 (50 mL) at 0-5° C. After addition, the reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was washed with water (200 mL) and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layers was washed with 10% citric acid (60 mL), sat. NaHCO3 (60 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 100%), which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][CH3:19])=[CH:4][C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][C:27]([C:29]2([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]2)=[O:28])=[CH:23][C:22]=1[N:38]=[C:39]=S.CC(C)N=C=NC(C)C>C1COCC1>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][C:27]([C:29]2([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]2)=[O:28])=[CH:23][C:22]=1[NH:38][C:39]1[N:18]([CH3:19])[C:3]2[CH:4]=[C:5]([O:13][CH2:14][CH:15]([F:16])[F:17])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:2]=2[N:1]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)n(C)c2cc1OCC(F)F
Temperature: 25 °C

Procedure:
A mixture of ethyl 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate (0.737 g; 2.68 mmol; crude material from step (g)) and N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.900 g; 2.68 mmol) in THF (100 mL) was stirred over night at rt. DIC (0.338 g; 2.68 mmol) was added and the mixture was stirred for 6 h at rt. Another portion of DIC (0.169 g; 1.34 mmol) was added and the mixture stirred for another 6 h at rt. The mixture was concentrated and purified by column chromatography to give the sub-title compound. Yield: 0.790 g (51%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=C1C=C(O)C(=Cc2ccccc2Cl)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccccc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 60%, with a melting point of 176° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:32])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][C:5]([OH:32])=[O:4])[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)=[O:31])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc([C@H]2CC[C@H](CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (47.8 mg, 1.19 mmol) was added to trans-{4-[4-(3-tert-butoxycarbonylaminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (50 mg, 0.12 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. Acetonitrile was added thereto and cooled to obtain a filtrate, and the filtrate was filtered and separated to obtain the desired compound (47 mg, 97%) as a white solid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[N:11][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:13][N:14]=1>C(OCC)(OCC)OCC>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:12]1[N:11]=[C:10]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:2]=[N:8][C:9]2=[N:14][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ncc(-c2cccs2)nc1NCc1ccc(O)cc1
Solvent: CCOC(OCC)OCC
Product: Oc1ccc(Cn2cnc3ncc(-c4cccs4)nc32)cc1
Yield: 67.6 %

Procedure:
A solution of 4-[(3-amino-6-thiophen-2-yl-pyrazin-2-ylamino)-methyl]-phenol trifluoroacetic acid salt (10 mg, 0.024 mmol) in triethyl orthoformate (1.5 mL) was refluxed for 4 hours. The starting material was disappeared completely. After evaporation of triethyl orthoformate, the crude product was crystallized in hexane-dichloromethane system to provide 4-(6-thiophen-2-yl-imidazo[4,5-b]pyrazin-1-ylmethyl)-phenol as a brown solid (5 mg).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][C:20](Cl)=[CH:19][N:18]=1)=[O:16].[NH4+].[Cl-]>>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][C:20]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1ncc(Cl)nc1N
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Product: COC(=O)c1ncc(OCC(F)(F)F)nc1N
Reaction time: 0.33 h

Procedure:
A mixture of 2,2,2-trifluoro-ethanol (6.9 ml, 96 mmol) and cesium carbonate (1.56 g, 4.8 mmol) was stirred for 20 min, 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester [28643-16-5] (600 mg, 3.2 mmol) was added and the mixture was stirred at rt for 42 h. To complete the reaction the mixture was heated to reflux for another 3 h. Saturated aq. NH4Cl was added and the mixture was extracted with EtOAc, the combined organic layers were washed with saturated aq. sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 3:7) to provide the title compound as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=1[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
This compound is made in a substantially similar manner as exemplified in Preparation 26 staring from 4-tert-butyl-phenyl boronic acid and 4-bromo-3,5-dimethyl phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:20])[CH:18]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:19])=[CH:15][CH:16]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CCC(=O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C(=O)c2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (142.8 mg, 1.0 mmol), 1-(4-fluorophenyl)-1-propanone (183.5 mg, 1.2 mmol), palladium acetate (6.7 mg, 0.030 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.3 mg, 0.045 mmol), t-BuONa (115.6 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 18.5 h. 1-(4′-Fluorophenyl)-2-(4′-methoxyphenyl)-1-propanone (206.7 mg) was obtained with a yield of 80% as liquid. 1H NMR (300 MHz, CDCl3) δ 8.01-7.93 (m, 2H, ArH), 7.22-7.15 (m, 2H, ArH), 7.14-6.99 (m, 2H, ArH), 6.87-6.80 (m, 2H, ArH), 4.59 (q, J=7.0 Hz, 1H, CH), 3.74 (s, 3H, OCH3), 1.50 (d, J=7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 198.8, 165.3 (d, J=252.7 Hz), 158.5, 133.3, 132.8 (d, J=2.6 Hz), 131.3 (d, J=8.6 Hz), 128.6, 115.4 (d, J=21.2 Hz), 114.4, 55.1, 47.0, 19.4; 19F NMR (282 MHz, CDCl3) δ −105.7; IR (neat) v (cm−1) 3071, 2974, 2932, 2869, 2837, 1682, 1598, 1514, 1505, 1455, 1409, 1372, 1336, 1302, 1247, 1180, 1157, 1114, 1101, 1035, 1006; MS (70 eV, EI) m/z (%): 259 (M++1, 1.10), 258 (M+, 6.27), 135 (100); HRMS calcd for C16H15O2F (M+): 258.1056. Found: 258.1057.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.II.[CH3:29][O:30][C:31](=[O:34])[CH2:32]Cl>O.C1(C)C=CC=CC=1>[C:31]([CH2:32][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:30][CH3:29])=[O:34]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Methylchloroacetate (233 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with toluene (2×500 ml). The combined organic layers were washed with brine and concentrated under vacuum to yield 4-((carbomethoxy)methoxy)benzaldehyde as an oily material (380 g, Y=95%, P=99%).