Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C)c(Cl)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 2.3 %

Procedure:
To the solution of 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (89 mg, 0.395 mmol) in NMP (2 mL), was added K2CO3 (198 mg, 1.436 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (4 mg, 2.33% yield). LCMS: rt=3.54 min, [M+H+]=479
Reaction SMILES: [CH3:1][CH:2]1[O:7][S:6](=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[O:7][S:6](=[O:17])(=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
The crude tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.52 g, 10.7 mmol) is dissolved in acetonitrile (25 mL) and H2O (15 mL) is added. The solution is cooled in an ice bath and sodium periodate (3.4 g, 16.1 mmol) is added in one portion. After 5 min, the pH is adjusted to 7-8 by addition of saturated Na2HPO4 solution. Then RuCl3 (22 mg, 0.11 mmol) in H2O (0.5 mL) is added. The pH is kept between 6 and 9 by addition of Na2HPO4 solution. After 2 h, H2O (100 mL) is added and pH is adjusted to 6 by addition of 2M HCl solution. The reaction mixture is extracted with EtOAc and the organic layer is washed with NaHCO3 and brine and the washes are back extracted once with EtOAc. The combined organic layers are dried (MgSO4), filtered and concentrated. The crude product is purified via by flash column chromatography using a gradient elution of 5-80% ethyl acetate/hexanes which affords the title compound (1.63 g, 61%).
Reaction SMILES: C1(O)C=CC(C2C=CC(O)=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:24]1[CH:25]=[C:26]([C:32]#[N:33])[C:27](=[CH:30][CH:31]=1)[C:28]#[N:29])([O-])=O.Cl>CN(C)C=O.C1(C)C=CC=CC=1>[C:32](#[N:33])[C:26]1[C:27](=[CH:30][CH:31]=[CH:24][CH:25]=1)[C:28]#[N:29]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 278 %

Procedure:
To a 250 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added 4,4′-biphenol (10.0 g, 53.7 mmol), 4,4′-dibromodiphenylacetylene (8.93 g, 26.6 mmol), (PPh3)3CuBr (0.3 g), powdered anhydrous K2CO3 (11.1 g, 80.6 mmol), toluene (20 mL), and N,N-dimethylformamide (DMF) (100 mL). The resulting mixture was degassed with argon at ambient temperature. The Dean-Stark trap was filled with toluene and 5 mL was added to the reaction. The mixture was refluxed at 135-145° C. to remove the water by-product by azeotropic distillation under an argon atmosphere for 12 to 18 h or until no more water was observed being collected in the Dean-Stark trap. FTIR spectroscopy was used to confirm and monitor the formation of the desired oligomeric product. The toluene was then removed by distillation and the reaction mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (9.32 g, 53.9 mmol) was added in one portion and the resulting reaction mixture was heated at 80° C. for 6-8 h. The mixture was then allowed to cool to ambient temperature and poured into 500 mL of a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was dissolved in chloroform (200 mL), and washed with 200 mL of a 5% aqueous KOH solution, with 200 mL of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL of water until neutral. The solvent was removed in vacuo and the solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (19.2 g, 90% yield). IR [cm−1]: λ3075 (C═CH), 2232 (CN), 2202 (alkyne), 1585 (C═C), 1477 (aromatic), 1310 (aromatic), 1243 (C—O), 1172 (C—O), 977 (C—O), 837 (aromatic).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].OCC[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.B(F)(F)F.CCOCC.CCN(CC)CC>C(C#N)(C)=O>[C:8]([O:7][C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH3:23])[O:22][C@H:5]1[O:4][CH2:1][CH2:2][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:10])[CH3:9]
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(=O)OC1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)C#N
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNC(=O)OCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,2,3,4-tetra-O-acetyl-L-fucopyranose (200 g, 601.86 mmol) in AcCN (100 mL) and benzyl (2-hydroxyethyl)carbamate (140.96 g, 722.08 mmol) at 0° C. was added BF3.Et2O (427.7 g, 3.01 mol) dropwise over 2 hr. After stirring at rt for 16 hr, the reaction mixture was cooled to 0° C. and followed by the addition of Et3N (130 mL). The resulting mixture was concentrated and the residual was dissolved in CH2Cl2 (2.0 L), which was subsequently washed with sat. NaHCO3 (2×500 mL), water (2×500 mL) and brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/petroleum ether (1:3) to give the title compound. 1H NMR (CDCl3) δ 7.33-7.37(5H, m), 5.12-5.32(5H, m), 4.99-5.04(1H, m), 4.42-4.45 (1H, d), 3.87-3.94 (1H, m), 3.78-3.84 (1H, m), 3.66-3.70(1H, m), 3.42-3.44 (2H, m), 2.19 (3H, s), 2.05-2.12(6H, m), 1.25-1.30 (3H, d).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8].C([O-])(=O)C.[Na+].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>O>[O:22]=[C:17]1[CH2:18][CH2:19][CH2:20][C:21]2[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]1=2
Reactant: NCC(=O)CCC(=O)O
Reactant: O=C1CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Yield: 57.9 %

Procedure:
5-Aminolevulinic acid hydrochloride salt (13.7 g, 0.1 mol), sodium acetate (41 g, 0.2 mol), and 1,2-cyclohexanedione (11.2 g, 0.1 mol) were stirred for 20 hours in 200 ml of water at 50° C. The mixture was cooled and the solid product collected by vacuum filtration and washed with 50% ethanol in water. The product was slurry-washed in 100 ml of 50% ethanol in water, collected and dried under vacuum to give 3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid (12 g, 67% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6]1)[CH2:33][CH3:34]
Reactant: CCC[C@@H]1CC[C@H](CCC)N1
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC[C@@H]1CC[C@H](CCC)N1C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid from the Step E Example 44 in 1 mL DMF was added 23.0 mg HOBt, 23.3 mg cis-2,5-dipropylpyrrolidine from the Step A above, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 70-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.50 min. (m/Z=428.4, 450.3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:57]3[CH2:58][CH2:59][S:55][CH2:56]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1)N1CCSC1

Procedure:
113 mg (0.25 mmol) of the compound of Example 42A is reacted analogously to the synthesis of the compound of Example 1 with 25 mg (0.28 mmol) of thiazolidine. 91 mg (70% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:4]1[C:13]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].[CH3:25][Mg]Cl.[NH4+].[Cl-].Cl>C1COCC1>[OH:3][C:1]([C:4]1[C:13]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:25])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1nc2ccccc2cc1OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Toluene-4-sulfonic acid 2-acetyl-quinolin-3-yl ester (3.58 g, 10.5 mmol) in 40 mL of THF was cooled to around −20 to −25° C. Methyl magnesium chloride (5.25 mL of 3M solution in THF) was added dropwise over a period of 10 minutes. The reaction mixture was allowed to stir 18 hours at ambient temperature, and then was poured into saturated aqueous NH4Cl and acidified with 1N HCl to pH 5. The resulting mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated to dryness under reduced pressure to give 3.75 g of toluene-4-sulfonic acid 2-(1-hydroxy-1-methyl-ethyl)-quinolin-3-yl ester as an oil that solidified on standing.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc(C(N)=O)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2cnc(NC3CCNCC3)nc2)cc1

Procedure:
A solution of 4-[5-(4-carbamoyl-phenyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 0.78 mmol) in 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 298.4 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][C:18](C(O)=O)([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O>>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(C(=O)O)(C(=O)O)CC2
Agent: O=C=O
Product: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1

Procedure:
9-Benzoyl-1,2,3,4-tetrahydrocarbazole-3,3-dicarboxylic acid (3.7 g.) was heated at 170°-200°C., till carbon dioxide evolution ceased, to give 2.5 g. of the title compound; m.p. 188°-190°C. (benzene).
Reaction SMILES: [Cl:1][C:2]1[C:7](OC)=[C:6]([S:10]([CH3:13])(=O)=O)[CH:5]=[CH:4][C:3]=1[C:14](=[O:23])[CH:15]([C:21]#[N:22])[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].C(C(C(C1CC1)=O)C(C1C=CC(S(C)=O)=C(OC)C=1Br)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(C#N)=CC=1)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(C(F)(F)F)=CC=1SCCC)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(Cl)=C(Cl)C=1Cl)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(Cl)=C(Cl)C=1SC(F)(F)C(F)F)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(Cl)=C(Cl)C=1SCCF)=O)#N.C(C(C(C1CC1)=O)C(C1C=CC(SC)=CC=1C(F)(F)F)=O)#N>>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:13])[CH:5]=[CH:4][C:3]=1[C:14](=[O:23])[CH:15]([C:21]#[N:22])[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)C(C#N)C(=O)C2CC2)c1Cl
Agent: CCCSc1cc(C(F)(F)F)ccc1C(=O)C(C#N)C(=O)C1CC1
Agent: COc1c(S(C)=O)ccc(C(=O)C(C#N)C(=O)C2CC2)c1Br
Agent: CSc1ccc(C(=O)C(C#N)C(=O)C2CC2)c(C(F)(F)F)c1
Product: CSc1ccc(C(=O)C(C#N)C(=O)C2CC2)c(Cl)c1

Procedure:
1-(2--chloro-3-methoxy-4-methylsulfonylphenyl)-2-cyano-3-cyclopropylpropan-1,3-dione; 2-cyano-3-cyclopropyl-1-(2-bromo-3-methoxy-4-methylsulfinylphenyl)-propan-1,3-dione; 2-cyano-1-(4-cyanophenyl)-3-cyclopropylpropan-1,3-dione; 1-(4-choloro-2-N-methylsulfonyl-N-methylaminophenyl)-2-cyano-3-cyclopropyl-1,3-dione; 2-cyano-3-cyclopropyl-1-(2-n-propylthio-4-trifluoromethylphenyl)-propan-1,3-dione; 2-cyano-3-cyclopropyl-1-(2,3,4-trichlorophenyl)-propan-1,3-dione; 2-cyano-3-cyclopropyl-1-[3,4-dichloro-2-(1,1,2,2,-tetrafluoroethylthio)phenyl]-propan-1,3-dione; 2-cyano-3-cyclopropyl-1-[3,4-dichloro-2-(2-fluoroehtylthio )phenyl]-propan-1,3-dione; 2-cyano-3-cyclopropyl-1-[2-trifluoromethyl-4-methylthiophenyl]-propan-1,3-dione;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:18][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[O:29])=[CH:31][CH:32]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2c(N)cccc2F)cc1
Product: COc1ccc(NC(=O)c2c(F)cccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 66.3 %

Procedure:
Using the procedure described in Example 93, Part A, N-(4-methoxyphenyl)-2-amino-6-fluorobenzamide (1.9 mmol) and 4-tert-butylbenzoyl chloride (2.1 mmol) yielded 530 mg (65%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I(C1C=CC=CC=1)=[O:39]>ClCCl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[CH3:25])=[CH:22][CH:23]=3)[CH:14]2[OH:39])[CH:4]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:8]=1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reactant: O=Ic1ccccc1
Solvent: ClCCl
Product: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.7 %

Procedure:
N-[(1S)-1-(4-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-ethyl]cyclopropanecarboxamide (cf. Japanese Patent Application No. 2009-296889) (200 mg) was dissolved in dichloromethane (10 mL), and to the reaction solution was added Fe(salen) (12 mg) and iodosobenzene (98 mg). The resulting mixture was stirred at room temperature for 20 hours. Under reduced pressure, the solvent was distilled off and the residues were purified by silica gel column chromatography to obtain N-[(1S)-1-(4-{3-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}phenyl)ethyl]cyclopropane-carboxamide (24 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[CH:33]=[N:34][C:35]([NH2:39])=[C:36](Br)[CH:37]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OC(N1CCC(N2C=C(C3C(N)=NC=C(Br)C=3)C=N2)CC1)=O)(C)(C)C.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O.C(OC(N1CCC(N2C=C(C3C(N)=NC=C(C4C=CC5C(=CC=CC=5)C=4)C=3)C=N2)CC1)=O)(C)(C)C>CCOC(C)=O.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:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[CH:33]=[N:34][C:35]([NH2:39])=[C:36]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:37]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(Br)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cc(-c4ccc5ccccc5c4)cnc3N)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cc(Br)cnc3N)cn2)CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ccc5ccccc5c4)c3)cn2)CC1
Temperature: 105 °C

Procedure:
A solution of 2-naphthylboronic acid (43 mg, 0.25 mmol), Pd(PPh3)4 (23 mg, 0.020 mmol), and a mixture of 4-[4-(6-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-[4-(2-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (together 92.2 mg, 0.138 mmol) in 1,4-dioxane (3.5 mL, 45 mmol) in a sealable microwave tube was charged with a solution of Cs2CO3 (140 mg, 0.44 mmol) in H2O (0.90 mL, 50 mmol), flushed with nitrogen, sealed and irradiated in the microwave reactor at 105° C. for 60 min. More 2-naphthylboronic acid (11 mg, 0.064 mmol) and Pd(PPh3)4 (5.6 mg, 0.0048 mmol) were added, and the solution was heated in the microwave reactor at 105° C. for 30 min. Further 2-naphthylboronic acid (12 mg, 0.070 mmol) and Pd(PPh3)4 (4.5 mg, 0.0039 mmol) were added to the solution, which was then heated in the microwave reactor to 105° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 solution, water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. One obtained a mixture of the title compound and its regioisomer, 4-[4-(2-amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester, as yellow-brown solid. This mixture of regioisomers was separated using the MDPS. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.4 Hz, 1H), 7.99-7.45 (m, 10H), 4.60 (s, 2H), 4.39-4.21 (m, 3H), 2.98-2.85 (brm, 2H), 2.19 (brt, J=13.0 Hz, 2H), 2.05-1.89 (mc, 2H), 1.48 (s, 9H). MS(ES+): m/z=470.19 (100) [MH+]. HPLC: tR=2.85 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.71 g) and 2-nitroamino-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone (1.98 g) in pyridine (12 ml) was refluxed for 22 hr, allowed to cool and the pyridine evaporated at reduced pressure. The residue was washed by decantation with hot water, dissolved in dilute ethanolic hydrochloric acid, and the solvent evaporated yielding 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone. The residue was recrystallised from methanol/dilute ethanolic hydrochloric acid and from methanol/ethanol to give the 3.8 hydrochloride 1.4 hydrate (0.85 g) as a light buff solid m.p. 142°-5° C. Evaporation of the mother liquors and recrystallisation of the residue from methanol/ethanol yields more product (0.62 g) m.p. 138°-142° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6])[CH3:3].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:3][CH:2]([N:4]([CH2:9][C@@H:10]1[N:15]([C:24]2[N:25]=[CH:26][C:27]([C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[CH:28][N:29]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:6])=[O:7])[CH3:1]
Reactant: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1)S(C)(=O)=O
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Yield: 83.6 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-1-piperazinecarboxylate (0.315 g, 0.939 mmol, step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.287 g, 1.02 mmol, Intermediate D), DIPEA (0.492 mL, 2.82 mmol) and 1,4-dioxane (5 mL). The vial was sealed and heated at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and additional 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.082 g, 0.29 mmol, Intermediate D) was added. The mixture was heated at 100° C. for an additional 12 h. After allowing the reaction to cool to room temperature, the mixture was partitioned between water (50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic extracts was washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.455 g) as a light yellow foam.