Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C[C:4](=[O:9])[CH2:5][CH2:6][CH2:7]C)=[N-].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH3:22]COCC>>[CH2:22]([O:19][S:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)(=[O:21])=[O:20])[O:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCC(=O)C=[N+]=[N-]
Reactant: CCOCC
Product: CCCCOCOS(=O)(=O)c1ccc(OC)cc1
Yield: 70.3 %

Procedure:
A 1.0 g quantity of 1-diazo-2-hexanone is dissolved in 50 ml of ether, and 2.5 g of p-methoxybenzenesulfonic acid is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter repeated to afford 1.6 g of 2-oxahexyl-p-methoxybenzene sulfonate in the form of a colorless transparent oil (Compound 35). Yield 70.3%.
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:29]1([NH:34][C:35]2[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]([S:43][CH3:44])[N:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.C(OCC)(=O)C.O>[CH2:11]([O:10][C:8](=[O:9])[NH:7][CH2:6][C:5]1[C:4](=[O:18])[N:34]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:35]2[N:36]=[C:37]([S:43][CH3:44])[N:38]=[CH:39][C:40]=2[CH:41]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOC(=O)CCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1

Procedure:
3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68 g, 26.58 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (28 mL, 28 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15 g, 13.29 mmol) was then added neat and the reaction mixture was brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as pale yellow waxy solid (1.67 g, 29.6%). 1H NMR δ (400 MHz, CDCl3) 8.57 (s, 1H), 7.56 (s, 1H), 7.26–7.36 (m, 5H), 5.93 (m, 1H), 5.56 (t, J=6.1 Hz, 1H), 5.08 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 2.60 (s, 3H), 2.30 (m, 2H), 2.05 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(I)cc1)OCC
Reaction time: 8 h

Procedure:
4-iodobenzyl chloride and triethyl phosphite were put in a three-necked flask equipped with a reflux condenser, to which toluene was added and heated with stirring for 8 hours under reflux. The mixture was purified by the common method, to obtain diethyl 4-iodobenzylphosphonate.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2c1
Yield: 77.4 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-(hydroxymethyl)phenylboronic acid (66.12 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 80 mg (76%) of 3-(4-(hydroxymethyl)phenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[C:2]1([CH:1]([OH:8])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(O)c1ccccc1
Reaction time: 14 h
Yield: 98.7 %

Procedure:
Ethyl benzoylacetate (1) (19.21 g; 0.10 mol) was dissolved in 95% ethanol (100 mL) in a pressure bottle. The bottle was purged with nitrogen and 5% palladium on carbon (960 mg; 5 weight %) was added. The vessel was placed under 45 psi H2 and shaken on a Parr apparatus for 14 hours, at which time H2 uptake had halted and thin layer chromatographic analysis indicated (1) was present. The reaction mixture was suction-filtered through Celite with a top sand layer (to prevent channels) and eluted with ether to remove the catalyst. The filtrate was concentrated to afford (2), racemic ethyl 3-phenyl-3-hydroxypropionate (19.17 g; 99%) which was pure by tlc and 1H nmr analysis. 1H nmr (300 MHz, CDCl3): 7.4-7.2 (5H, m); 5.130(1H,dd,J=4.36, 8.48 Hz); 4.178 (2H, q, J=7.17 Hz); 3.2(1H, br s); 2 764(1H, dd, J=8.58, 16.30 Hz); 2.691 (1H, dd, J=4.33, 16.33 Hz); 1.259(3H, t, J=7.17 Hz). IR (neat film, cm-1) 3450 (s,b); 1720(s); 1605(w). EIMS (m/e): 194 (M+); 165 (2%, M+ - Et); 149 (5%, M+ -EtO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCCCC1)c1ccc(Br)cc1
Yield: 26.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclohexylamine (0.46 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclohexylbenzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 10.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+:13]>CN(C)C=O>[C:3]([N:13]1[C:7]2[CH2:8][CH2:9][CH:4]([C:3]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])[CH2:5][C:6]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of 291 mg of benzyl 1,2,3,4-tetrahydrocarbazole-3-carboxylate, as obtained in Example 50, in 2 ml of N,N-dimethylformamide was added, with ice-cooling, to a suspension of 87 mg of sodium hydride (55% w/w dispersion in mineral oil) in 4 ml of N,N-dimethylformamide. 0.12 ml of benzoyl chloride was added to the reaction mixture which was then stirred for 1 hour. After this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 10 g of silica gel with a 5:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 384 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[C:43](Cl)[N:44]=1)[C:38]([O:40][CH3:41])=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:43]2[CH:42]=[C:37]([CH:36]=[C:35]([Cl:34])[N:44]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc(Cl)nc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 56 mg of methyl 2,6-dichloroisonicotinate, 95 mg of potassium phosphate, 6 mg of bis(tri-tert-butylphosphine)palladium(0), and 2.0 mL of dimethylacetamide was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 66 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinate as a pale yellow oily compound. ESI+: 614
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[C@H:17]([OH:20])[CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:21])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH3:22][C@@:23]12[C:39](=[O:40])[CH2:38][CH2:37][C@H:36]1[C@H:35]1[C@@H:26]([C:27]3[CH:28]=[CH:29][C:30]([OH:41])=[CH:31][C:32]=3[CH2:33][CH2:34]1)[CH2:25][CH2:24]2.C[C@@]12[C@@H]([OH:60])CC[C@H]1[C@H]1[C@@H](C3C=CC(O)=CC=3CC1)CC2>>[CH3:1][C@@:2]12[C@@H:18]([OH:19])[C@H:17]([OH:20])[CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:21])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH3:22][C@@:23]12[C@@H:39]([OH:40])[CH2:38][CH2:37][C@H:36]1[C@H:35]1[C@@H:26]([C:27]3[CH:28]=[CH:29][C:30]([OH:41])=[CH:31][C:32]=3[CH2:33][CH2:34]1)[CH2:25][CH2:24]2.[CH3:1][C@@:2]12[C@@H:18]([OH:19])[C@H:17]([OH:20])[CH2:16][C@H:15]1[C@@H:14]1[CH2:13][C:12]([C:11]3[CH:10]=[C:9]([OH:21])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2)=[O:60]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C(=O)C[C@H]3[C@@H]1C[C@@H](O)[C@@H]2O

Procedure:
A series of estriol and estradiol derivatives was prepared by Walker et al.. Steroids. Volume 21, 259-283 (1973) with substituents at the 6-position. These specific 6-oxo derivatives were used to prepare immunogens with carrier proteins and were compared with randomly linked derivatives for their ability to elicit antibodies with minimal cross-reactivity with structurally similar analogs. It was found that random-linkage immunogens of estriol chloroformates with carrier proteins produced antibodies with 30-100% cross-reactivity, while those with a 6-oxo linked estriol had a 1-12% cross-reactivity with estrone and estradiol. This study suggests that linkage through the 6-position led to immunogens capable of producing antibodies with acceptable specificity However, each derivative required extensive complex synthetic procedures for its preparation, diminishing their convenience and utility in the preparation of immunogens; 6-oxoestriol itself was only produced in 11% yield.
Reaction SMILES: [N:1]1[C:6](=O)[CH2:5][CH2:4][N:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=12.O[P:13]([OH:16])([OH:15])=[O:14].P(Cl)(Cl)Cl>Cl>[N:1]1[C:6]([P:13]([OH:16])(=[O:14])[OH:15])([P:13]([OH:16])(=[O:14])[OH:15])[CH2:5][CH2:4][N:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=12
Reactant: O=C1CCN2C=CC=CC2=N1
Reactant: O=P(O)(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C1(P(=O)(O)O)CCN2C=CC=CC2=N1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5 g 3,4-Dihydropyrido-(1,2-a)-pyrimidin-2-one (Fluka) were melted at 80° C. with 5.5 g H3PO4 and mixed, while stirring, with 5.9 ml PCl3. After 20 hours at the given temperature, it was mixed with 70 ml 2N HCl, stirred for 8 hours at 100° C. and, after cooling, filtered off from the undissolved part. The filtrate was evaporated on a rotary evaporator and purified by ion exchanger chromatography on Amberlite IR 120 (H+ form) with water as eluent. The fractions obtained after electrophoresis were evaporated in a vacuum and the oil remaining behind, after dissolving in a little water, brought to crystallisation by the addition of acetone.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:11])=[C:6]([N+:18]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:18])[C:7]([N:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:11])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(C)CCCN(C)c1ccc(C2CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C2CC2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-cyclopropyl-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (Step 2, 600 mg, 2.16 mmol) was dissolved in 22 mL MeOH. Palladium (115 mg, 0.108 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as viscous red-brown oil. MS (M+H+)=248; Calc'd for C15H25N3=247.38.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[O:13])=[CH:4][C:3]=1[O:14]CC(C)=C.C(O[CH:23]([CH3:25])[CH3:24])(C)C.[CH2:26](N(CC)C1C=CC=CC=1)C>>[OH:14][C:3]1[C:4]([CH2:24][C:23]([CH3:25])=[CH2:26])=[C:5]2[C:9](=[C:10]([CH3:11])[C:2]=1[CH3:1])[N:8]([CH:12]=[O:13])[CH2:7][CH2:6]2
Reactant: CCN(CC)c1ccccc1
Reactant: CC(C)OC(C)C
Reactant: C=C(C)COc1cc2c(c(C)c1C)N(C=O)CC2
Product: C=C(C)Cc1c(O)c(C)c(C)c2c1CCN2C=O
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 2,3-dihydro-6,7-dimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (25.2 g, 0.103 mol) in N,N-diethylaniline (50 mL) was stirred at 200° C. for 8 hours under the nitrogen atmosphere. The reaction mixture was allowed to stand overnight, diisopropyl ether was added, the crystals were filtered, and recrystallized from ethanol to obtain 20.4 g of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:31]([C:32]4[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccc(F)cc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
Brown solid. MS (ESI): 551.09 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 4-fluoro-2-trifluoromethyl-benzenesulfonyl chloride and methanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][O:23]C(C4C=CC=CC=4)(C4C=CC(OC)=CC=4)C4C=CC(OC)=CC=4)[C@@H:18]([OH:19])[C@H:16]3[OH:17])[CH:13]=[N:14][C:7]=12.[C:47](OC(=O)C)(=[O:49])[CH3:48].C([O-])(O)=O.[Na+].[C:59](OCC)(=[O:61])[CH3:60]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([O:19][C:59](=[O:61])[CH3:60])[C@H:16]3[O:17][C:47](=[O:49])[CH3:48])[CH:13]=[N:14][C:7]=12
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(-c3cccs3)ccnc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
Compound 12 (120 mg, 0.19 mmol) was azeotroped three times with anhydrous pyridine. This was dissolved in anhydrous pyridine (1.9 ml), and 72 μl (0.76 mmol) of acetic anhydride was further added thereto. This mixture was stirred at room temperature for 7 hours and poured into 5% NaHCO3 (50 ml) and ethyl acetate (50 ml). The organic layer was washed once with saturated aqueous sodium chloride, dried over Na2SO4, and then evaporated under reduced pressure to remove the solvent. The residue was azeotroped twice with toluene and dissolved in CH2Cl2 (19 ml), followed by addition of 190 μl dichloroacetic acid at 0° C. This reaction mixture was stirred at 0° C. for 15 minutes. The mixture was poured into 5% NaHCO3 and extracted with CH2Cl2. The organic layer was washed once with saturated aqueous sodium chloride, dried over Na2SO4, and then evaporated under reduced pressure to remove the solvent. The product was purified by flash silica gel chromatography using a 2% methanol-methylene chloride solution as a solvent to give 77 mg of Compound 13 in a yield of 93%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:47][CH2:48][CH2:49][C:50]1([OH:53])[CH2:52][CH2:51]1)(=O)=O>CC(N(C)C)=O>[OH:53][C:50]1([CH2:49][CH2:48][CH2:47][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]5[C:23](=[O:35])[N:24]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:25]([CH3:28])[C:26]=5[CH3:27])=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:52][CH2:51]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Yield: 62.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (277 mg, 0.593 mmol), Cs2CO3 (560 mg, 1.724 mmol, Aladdin), and 3-(1-hydroxycyclopropyl)propyl methanesulfonate (334 mg, 1.724 mmol) in DMA (10 mL). The title compound was purified by a silica gel column chromatography (67:30:1:2 (v/v/v/v) EtOAc/CH2Cl2/CH3OH/Et3N) to afford the title compound as a white solid (210 mg, 62.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1cc(F)cc(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(F)cc(F)c3)cc2)c1C
Yield: 56.3 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.176 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3,5-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.14 g, 53%) as a solid. MS calcd. for C26H18ClF2O2S [(M−H)−] 467, obsd. 467.2.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[C:7]([N:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:2].[CH3:22][C@@H:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.C(O)(C)C>CO>[CH3:14][N:12]([CH3:13])[C:7]1[C:6]([NH:5][C:4]([NH:30][C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])=[N:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CC(C)O
Solvent: CO
Product: C[C@@H](NC(=NC#N)Nc1cccnc1N(C)C)c1ccccc1

Procedure:
A stirred mixture of the crude product from Step 3, (R)-(+)-α-methylbenzylamine (1.01 ml, 0.00782 mol), N-methylmorpholine (1.69 ml, 0.0154 mol) and isopropanol (20 ml) was refluxed, under nitrogen for 5 hours and then concentrated. The residue was chromatographed on silica gel first with mixtures of MeOH--CHCl3 containing from 1-10% MeOH to give an impure product which was rechromatographed on silica gel with mixtures of EtOAc-hexane containing from 1-50% EtOAc. The product obtained in this manner was dissolved in MeOH, decolorized with activated carbon and crystallized from MeOH-EtOAc-hexane to give 0.700 g of the titled product, mp 111°-128° C. (dec.).