Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=O)[CH2:13]C(O)=O.N1CCCCC1>C(O)(=O)C>[CH:12]([C:11]1[CH:10]=[C:8]([OH:9])[C:5]([O:6][CH3:7])=[CH:4][CH:3]=1)=[CH2:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=Cc1ccc(OC)c(O)c1
Yield: 51 %

Procedure:
A mixture of vanillin (2.50 g, 0.0164 mol), malonic acid (3.41 g, 0.0328 mol), piperidine (3–5 ml) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 1–7 minutes in parts. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 51% yield; 1H NMR (CDCl3) δ 6.96 (3H, m, 3,5,6-Ar), 6.70 (1H, dd, J=7.8 Hz, CH═CH2), 5.93 (1H, s, OH), 5.66 (1H, d, J=17.6, cis-CH═CH2), 5.19 (1H, d, J=10.9 Hz, trans-CH═CH2), 3.90 (3H, s, OMe); 13C NMR (CDCl3) δ 147.1 (C-1), 146.07 (C-2), 137.1 (CH═CH2), 130.7 (C-4), 120.4 (C-6), 114.9 (C-5), 111.8 (CH═CH2), 108.5 (C-3), 56.2 (OCH3).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[CH2:17]([NH2:20])[C:18]#[CH:19]>CO>[C:1]([NH:3][C:4]([NH:20][CH2:17][C:18]#[CH:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: CSC(=NCCSCc1nccs1)NC#N
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=NCCSCc1nccs1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(thiazol-2-yl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in U.S. Pat. No. 3,950,333] (4.40 g, 16.1 mmole) and propargylamine (8.8 ml) in methanol (35 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 16 hours. The reaction mixture was evaporated under reduced pressure, the residue dissolved in warm isopropanol, and then cooled and filtered to yield 2.26 g of product. Recrystallization from isopropanol with Darco treatment gave the title compound; mp 137.5°-139.5°.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH2:36]([O:38][C:39]([C:41]1([C:44]2[N:45]=[N:46][C:47](Cl)=[CH:48][CH:49]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1([C:44]2[N:45]=[N:46][C:47]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(c2ccc(Cl)nn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCOC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)nn2)CC1
Yield: 44 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridazin-3-yl)-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described in Example 1. Yield: 44% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:59][CH2:58][CH:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](OS(C)(=O)=O)[CH2:35][CH2:34]2)[C:29]1=[O:44]>C(#N)C>[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:55][CH2:56][CH:57]([C:60]([F:62])([F:61])[F:63])[CH2:58][CH2:59]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@@H:36]([F:18])[CH2:35][CH2:34]2)[C:29]1=[O:44]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (0.436 g, 1.36 mmol) in 5 ml of acetonitrile. Add water (0.05 ml. 2.72 mmol) and stir for 10 minutes. Add Methanesulfonic acid trans-4-{(R)-3-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-2-oxo-pyrrolidin-1-yl}-cyclohexyl ester (Preparation 24) (0.458 g, 0.68 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.036 g (9%) of the title compound: Mass spectrum (apci) m/z=599 (M+H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].S(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:4][CH2:3][C@H:2]1[CH2:5][CH2:6][CH2:7][N:1]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: OC[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Temperature: 90 °C

Procedure:
D-Prolinol (2.72 g, 25.0 mmol), 4-pyrrolidinophenethyl mesylate (6.06 g, 22.5 mmol) and sodium carbonate (3.45 g, 25.0 mmol) were added to acetonitrile (150 ml), and they were heated at 90° C. under reflux for 3.5 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. 1 M hydrochloric acid was added to the organic layer and pH of the aqueous layer was kept at 1 to extract the intended product in the aqueous layer. 4 M sodium hydroxide was added to the aqueous layer to adjust pH of the aqueous layer to 14, and the intended product was extracted from the precipitates thus formed with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (4.96 g, 85%).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[S:15]([CH3:18])(=[O:17])=[O:16].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:15]([N:14]([CH3:13])[CH:19]1[CH2:20][CH2:21][N:22]([C:2]([Cl:1])=[O:4])[CH2:23][CH2:24]1)(=[O:16])=[O:17]
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C1CCN(C(=O)Cl)CC1)S(C)(=O)=O
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (0.61 g, 2.08 mmol) in CH2Cl2 (30 mL) at −78° C., was added a solution of N-Methyl-N-piperidin-4-yl-methanesulfonamide (preparation described in the patent GB2000136) (1.00 g, 5.20 mmol) and pyridine (0.92 mL, 11.4 mmol) in CH2Cl2 (20 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded 0.53 g (40%) of the title compound as a light yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[S:8]1(=[O:33])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([N:24]([CH3:26])[CH3:25])=O)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:30][CH2:31][CH2:32][C:10]2=[N:9]1.[H-].O>C1COCC1>[O:33]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[CH2:22][N:24]([CH3:26])[CH3:25])[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:30][CH2:31][CH2:32][CH:10]2[NH:9]1
Reactant: CN(C)C(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reaction time: 3 h

Procedure:
3.72 ml (3.72 mmol) of a 1M solution of LiAlH4 in THF are added dropwise to a suspension of 577 mg (1.49 mmol) of the product obtained in Step D in 20 ml of THF. The reaction mixture is observed passing into solution and stirring is carried out at ambient temperature for 3 hours. The excess of hydride is hydrolysed by the dropwise addition of water until the evolution of gas ceases. The suspension is stirred for 10 minutes, 20 ml of water are added, and extraction is carried out with AcOEt. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated, and the residue is chromatographed on a silica column (CH2Cl2/MeOH 95/5) to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1.[CH:19]([Mg]Br)=[CH2:20].[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH:19]=[CH2:20])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1
Reactant: C=C(c1ccccc1)c1nc(Cl)nc(Cl)c1C=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)c1c(Cl)nc(Cl)nc1C(=C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4-dichloro-6-(1-phenylvinyl)pyrimidine-5-carbaldehyde (200 mg) in THF (3.6 mL) at −78 C. was added vinylmagnesium bromide (0.79 mL, 1M solution in THF) dropwise, and the reaction mixture was stirred at −78° C. for 20 min. Saturated NH4Cl was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate (×3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give the title compound (156 mg) as a colorless oil. The crude product was used directly for the next step.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:8][N:9]1[CH2:15][CH:14]2[CH:16]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([O:19][C:18]([N:17]([CH3:25])[CH:16]1[CH:11]2[CH2:12][CH2:13][CH:14]1[CH2:15][N:9]([CH2:8][C@H:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:10]2)=[O:24])([CH3:22])([CH3:21])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(C[C@H](N)COc1ccc(C#N)cc1)C2
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CCC(C1)C2N(C)C(=O)OC(C)(C)C

Procedure:
Methyl chloroformate (0.24 mL, 3.2 mmol) was added, at 0° C., to a mixture of tert-butyl 3-[(2S)-2-amino-3-(4-cyanophenoxy)propyl]-3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (see step (vii) above; 1.2 g, 2.9 mmol) and TEA (1.2 mL, 9 mmol) in DCM (30 mL). The mixture was allowed to reach rt over the course of 3 h, after which time a saturated solution of Na2CO3 was added. The organic phase was separated, dried and evaporated to give a crude product that was purified by chromatography on silica gel. This gave 0.6 g (45%) of the sub-title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[NH:28][C:27](=[O:36])[C:26]([C:37]([O:39]CC)=[O:38])=[CH:25]4)[CH:21]=2)=[O:14])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Li+].O>C(O)C>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][C:31]=3[C:32]([F:35])([F:33])[F:34])[NH:28][C:27](=[O:36])[C:26]([C:37]([OH:39])=[O:38])=[CH:25]4)[CH:21]=2)=[O:14])=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4cc(C(=O)OCC)c(=O)[nH]c4cc3C(F)(F)F)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a suspension of the compound of Example 18 (1.13 g, 1.97 mmol) in ethanol (30 ml) was added 1 mol/L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) and successively water (15 ml), and, after stirring for 4 hours at room temperature, the mixture was allowed to stand statically overnight. After stirring for 16 hours at 30° C., ice water was added to the reaction mixture and the insolubles were filtered off. Then, the pH value was brought to 4 with 3 mol/L hydrochloric acid and solvent was distilled off. Water was added to the residue obtained, the precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure. After the powder obtained was suspended into water (40 ml), 1 mol/L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) was added and the mixture was stirred for 30 minutes at 50° C. Ice water was added to the reaction mixture, the insolubles were filtered off, then the pH value was brought to 4 with 3 mol/L hydrochloric acid, and solvent was distilled off. Water was added to the residue obtained, the precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 757 mg of title compound as pale yellow powder.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1(C)C=CC=CC=1>[C:39]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][NH:20][C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:32])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:27][CH2:26]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)c1nc2ccccc2n1-c1nc(NCC2CCNCC2)nc(N2CCOCC2)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(CNc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)-1,3,5-triazin-2-amine (50 mg) and pyridine (2 mL) was added acetic anhydride (14 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added toluene, followed by concentrating under reduced pressure. The residue was dissolved in dichloromethane, and silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, and subsequently chloroform:methanol) to obtain N-[(1-acetylpiperidin-4-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-amine (44 mg) as a white powder.
Reaction SMILES: [C:1](=[N:35]O)([C:8]1[CH:34]=[CH:33][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:31]O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:31][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:1]([NH2:35])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:33]=2)=[CH:19][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: ON=C(c1ccccc1)c1ccc(OCCCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(OCCCCOc2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The dioxime from Step 2 (6.3 g) is dissolved in ethyl alcohol saturated with ammonia gas (220 ml) and Raney nickel W-6 (2.3 g) added. The mixture is subjected to 650 psi hydrogen pressure and heated to 90° for twenty-two hours. The catalyst is removed by filtration and the solvent is removed by distillation to yield 4.1 g (69% of theory) of colorless crystals mp 120°-123°.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (tert-butyl)(phenylsulfonyl)amine (17.43 g, 81.83 mmol) in 180 ml dry THF in an ice bath was added nBuLi (66 ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33 ml, 143.06 mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4 hr. The reaction mixture was then cooled in an ice bath before HCL (82 ml, 3M) was added dropwise. This was allowed to stir at room temperature for 3 hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=1 with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vacuo to about 50 ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65 g, 57mml, 70%) ES-MS(M+H)+=258.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)c(Cl)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
0.4 g of Raney nickel is added to a solution of 2.37 g (9.31 mmol) of 1-(2-chloro-4-nitrobenzyl)piperidine in 100 mL of THF and hydrogenated at ambient temperature and 3 bar hydrogen. After hydrogen uptake has ended, the catalyst is filtered off and the filtrate is evaporated down. Yield: 1.88 g (90% of theory); C12H17ClN2 (M=224.73); calc.: molecular ion peak (M+H)+: 255/7 (Cl); found: molecular ion peak (M+H)+: 255/7 (Cl); Rf value: 0.20 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][CH:17]=1)#[CH:11]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:11]#[C:10][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:15]=[CH:16][CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C#Cc2nc(Cl)ncc2F)c1)C(F)(F)F
Yield: 77.6 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.56 g, 9.4 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and TEA (0.164 g, 0.23 mmol). After heating the reaction at 60° C. for 30 min. N-(3-ethynylphenyl)-2,2,2-trifluoroacetamide (1.0, 4.69 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed onto silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off white solid. ES-LC/MS m/z=344 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:29][C:28]=1[F:27]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 5, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=534.1 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH:20]=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][N:31]=[CH:20][CH2:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: NOCc1ccccc1
Agent: Cl
Product: C(CCc1nc(-c2ccccc2)c(-c2ccccc2)o1)=NOCc1ccccc1

Procedure:
The process described in Method A was followed. 3-(4,5-Diphenyl-1,3-oxazol-2-yl)propanal (416 mg, 1.5 mmol, see Pridgen L. N. et al in Tetrahedron Lett., 25(27), 2835 (1984)) and O-benzylhydroxylamine hydrochloride (319 mg, 2.0 mmol) were used to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)=[CH:5][NH:4][N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH:22]([N:25](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN>CN(C=O)C.C1COCC1>[CH3:22][NH:25][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([C:6]2[C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:4][CH:5]=2)[CH:8]=[N:9][CH:10]=1
Reactant: O=C(O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
45.0 mg (159 μmol) of the compound from Example 44 are dissolved in 1 ml DMF, 1.9 mg (16 μmol) 4-N,N-dimethylaminopyridine, 24.7 mg (191 μmol) N,N-diisopropylethylamine and 100 mg (191 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 15 min. 120 μl (239 μmol) of a 2 M solution of methylamine in THF are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 120 μl (239 μmol) of the 2 M solution of methylamine in THF are added and the mixture is stirred again overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).