Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH2:22]([C@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH2:26]1)[CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:22]([C@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=3)=[O:35])=[CH:32][CH:31]=2)[CH2:26]1)[CH2:23][CH3:24]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)C1
Reactant: CCCCCCCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc([C@H]3CC[C@H](CCC)C3)cc2)cc1

Procedure:
4.1 g of 4-n-octylphenol and 1.6 g of pyridine are dissolved in 10 ml of toluene, the solution is warmed to 100°, 5.0 g of 4-(trans-3-n-propylcyclopentyl)benzoyl chloride (cf. Example 2) are added dropwise, and the mixture is left to react for 3 hours. The pyridine hydrochloride is subsequently filtered off under suction, and the filtrate is washed with water, dried and freed from solvent in vacuo. After crystallization of the residue from petroleum ether, 4-octylphenyl 4-(trans-3-propylcyclopentyl)-benzoate is obtained; m.p. 36°, c.p. 40.7°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH3:18])=[N:14][NH:15][C:16]=2[NH2:17])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Cl:19][C:20]1[C:21]([OH:29])=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[CH:25]=O>FC(F)(F)C(O)=O>[Cl:19][C:20]1[CH:27]=[C:24]([C:25]2[C:3]3[C:4](=[C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]4=[CH:11][C:2]=3[F:1])[C:12]3[C:13]([CH3:18])=[N:14][NH:15][C:16]=3[N:17]=2)[C:23]([F:28])=[CH:22][C:21]=1[OH:29]
Reactant: Cc1n[nH]c(N)c1-c1cc(F)cc2c1OCCO2
Reactant: O=Cc1cc(Cl)c(O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3cc(Cl)c(O)cc3F)c3c(F)cc4c(c3c12)OCCO4
Reaction time: 12 h
Yield: 4.2 %

Procedure:
A solution of 4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-methyl-1H-pyrazol-5-amine (109 mg, 0.338 mmol) and 5-chloro-2-fluoro-4-hydroxybenzaldehyde (60 mg, 0.338 mmol) in trifluoroacetic acid (2.0 mL) was heated to 75° C. and allowed to stir for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford 5.8 mg (4.2%) of 2-Chloro-5-fluoro-4-(6-fluoro-11-methyl-2,3-dihydro-9H-[1,4]dioxino[2,3-f]pyrazolo[3,4-c]isoquinolin-7-yl)phenol as a white powder: 1H NMR (400 MHz, d4-MeOH): 7.67 (d, J=7.6 Hz, 1H), 7.07 (d, J=13.2 Hz, 1H), 6.85 (d, J=10.8 Hz, 1H) 4.59-4.56 (m, 4H), 2.99 (s, 3H); MS (EI) for C19H12ClF2N3O3: 404 (MH+).
Reaction SMILES: [CH3:1][SH:2].C[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13](\[NH:17][C:18]([CH:20]1[CH2:22][C:21]1([CH3:24])[CH3:23])=[O:19])/[C:14]([OH:16])=[O:15].N#N>CO>[CH3:23][C:21]1([CH3:24])[CH2:22][CH:20]1[C:18]([NH:17]/[C:13](=[CH:12]\[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][S:2][CH3:1])/[C:14]([OH:16])=[O:15])=[O:19]
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Reactant: CS
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: CSCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Temperature: 25 °C

Procedure:
A stream of CH3SH gas was bubbled through a solution of 162 mg (3 mmoles) of sodium methoxide in 5 ml of methanol for 10 min. with cooling in an ice bath. The solution was allowed to warm to room temperature and 332 mg (1 mmole) of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid was added. The solution was heated under reflux for 30 min. in a N2 atmosphere. Most of the methanol was evaporated under reduced pressure, the residue 2.5N HCl. The precipitated oil was extracted with ether (3×). The ether extracts were washed with water, saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 178 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methylthio-2-octenoic acid, m.p. 82°-84° C. Homogeneous by TLC (toluene-acetic acid, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH:20]=O)C(O)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24].[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>C(O)C>[OH:24][N:23]=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)[CH2:19][CH2:20][C:25]([OH:26])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: NO
Reactant: COc1ccc(-c2ccc(C(CC=O)C(=O)O)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Yield: 86.4 %

Procedure:
In a manner similar to Example 4, Step (c), (4′-methoxy-biphenyl-4-yl)-4-oxo-butyric acid (1.08 g, 0.00380 mol) was allowed to react with hydroxylamine hydrochloride (0.316 g, 0.00455 mol) in the presence of sodium carbonate (0.485 g, 0.00458 mol) in absolute ethanol (20 mL) to give 0.983 g of 4-hydroxyimino-4-(4′-methoxy-biphenyl-4-yl)-butyric acid as a pale yellow solid; mp 157-160° C.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:24]1([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I98) (34 mg, 0.057 mmol) was dissolved in DCM (4 mL) and TFA (0.4 mL) was added. The resulting mixture was stirred for 16 hours at room temperature then concentrated under reduced pressure. The residue was suspended in 10% aqueous NaOH (2 mL) and brine (3 mL) then extracted with ethyl acetate (4×5 mL). The combined organic phases were washed with brine, dried (sodium sulphate) and evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (25) (27.5 mg, 98%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.72-7.66 (m, 2H), 7.26-7.20 (m, 3H), 7.20-7.13 (m, 3H), 6.90 (s, 1H), 3.49 (s, 2H), 3.37 (s, 2H), 3.14-2.98 (m, 4H), 2.67 (t, J=4.7 Hz, 4H), 2.26 (s, 4H). LCMS Method C: rt 4.52 min; m/z 499.1 [M+H]+; m/z 497.1 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)Cc1c(-c2ccc(O)c(I)c2)nn2c(C)cc(C)nc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cc1c(-c2ccc(OC)c(I)c2)nn2c(C)cc(C)nc12
Reaction time: 8 h
Yield: 952.4 %

Procedure:
To a solution of 4 (30 mg, 0.063 mmol) in DMF (5 mL) was added K2CO3 (300 mg, 2.2 mmol) and MeI (100 μL×2M, 0.2 mmol). The reaction was stirred overnight and the solvent was removed under vacuum and the residue was purified by silica gel column chromatography (EtOAc as eluent) to give 1 (29 mg, 0.60 mmol, 95%). 1H NMR (CD3OD, 400 MHz) δ 1.15 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 2.77 (s, 3H), 3.43 (q, J=7.2 Hz, 2H), 3.58 (q, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.97 (s, 2H), 6.80 (s, 1H), 7.06 (d, J=8 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 8.09 (s, 1H). ESI MS m/z: [M+H]+ C21H26IN4O2: calculated 493.1, found 493.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[C:29]1[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][CH:30]=1>CCCCCCC.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:34]=1)=[O:36])[CH3:39]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)n1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and ethyl 6-bromo-2-pyridinecarboxylate (commercially available) using a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow foam (89%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:19])[CH:13]=1>C(N(CC)CC)C>[Br:19][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cn1c(Cl)nc2ccccc21
Solvent: CCN(CC)CC
Product: Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
Triethylamine (18 ml) was added to a mixture of 2-chloro-1-methyl-1H-benzimidazole (7.2 g) and p-bromophenol (22.5 g) at room temperature. The mixture was stirred at 120° C. for 6 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with 1 N NaOH aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10%-15% EtOAc in hexane) to give 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole (3.2 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:19][CH2:20]1
Reactant: Cn1nc(Br)c(=O)[nH]c1=O
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cn1nc(N2CCC(Oc3cc(F)ccc3Cl)CC2)c(=O)[nH]c1=O

Procedure:
The compound 90 (white powder) is prepared from the triazine 2e and from the intermediate 8b according to the synthesis method 1 in toluene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([S:11][CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18]O>C(O)(C(F)(F)F)C(F)(F)F.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([S:11]([CH3:12])=[O:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: COc1c(SC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 g of 5-tert-butyl-2-methoxy-1-methylsulphanyl-3-nitro-benzene are dissolved in 15 ml of 1,1,1,3,3,3-hexafluoroisopropanol, combined with 1.1 ml of a 9 M solution of hydrogen peroxide in water and stirred for 5 hours at ambient temperature. Then the mixture is cooled to 0° C. and diluted with 10% aqueous sodium thiosulphate solution. The mixture is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26](=[O:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[CH2:29]1COCC1.C[Mg]Cl.[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:28])([CH3:29])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: C1CCOC1
Reactant: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Into a 100 mL round-bottomed flask was added 1-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanone (1.04 g, 2.73 mmol) and THF (20 mL) to give an off-white suspension. The reaction suspension was cooled to about −30° C. Then methylmagnesium chloride (3 M in THF, 3.65 mL, 10.9 mmol) was added over about 5 min. The reaction was stirred at about −30° C. for about 30 min. A saturated solution of NH4Cl (50 mL) was slowly added to the reaction suspension, followed by the addition of DCM (50 mL). The layers were partitioned and the aqueous solution was extracted with DCM (2×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents removed under reduced pressure to give the title compound (0.86 g, 79%). The product was combined with other product from additional reactions (7.5 g total) and the material was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH 1:0 to 9:1) to give an off-white solid. The material was dissolved in DMSO (35 mL) at about 80° C. and then cooled to about 0° C. Then water (200 mL) was added to form a precipitate that was collected by filtration. The filter pad was washed with water and then triturated with 1-propanol using sonication and the solid collected by filtration. The solid was further triturated with 1-propanol using sonication and the solid collected by filtration and then dried in a vacuum oven at about 80° C. to give the title compound (5.05 g, 67% recovery). LC/MS (Table 1, Method g) Rt=1.78 min; MS m/z: 398.2 (M+M)+. 1H NMR (DMSO-d6) δ 8.53 (d,), 8.26 (m, 2H), 7.76 (m, 1H), 7.55-7.24 (m, 2H), 6.93 (m, 1H), 5.77 (s, 1H), 2.58-2.50 (m, 4H), 1.79 (s, 6H). mp 258-260° C.; Anal. calcd. for C19H14F2N6O2: C, 57.58; H, 3.56; N, 21.20; F, 9.59. found C, 57.42; H, 3.36; N, 21.22; F, 9.28.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1.O>ClCCl>[C:1]1([CH2:7][CH2:8][N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:41](=[O:42])[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)N(CCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylethylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 52 mg; 13C-NMR (CD3OD, rotamers): δ 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3, 54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6, 128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7, 173.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J37) (221 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (301 mg, 74%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[C:3]1=[O:20]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(F)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-fluorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 269°-270° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O[SiH](OCC)OCC)C.N[CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>[Rh].CC1C=CC(C)=CC=1>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:17]([CH3:16])[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: [Rh]
Agent: CCO[SiH](OCC)OCC
Solvent: C=CCN
Solvent: Cc1ccc(C)cc1
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C

Procedure:
A three-neck flask equipped with a reflux condenser, stirring rod and thermometer was charged with 14 grams of allylamine (0.25 mole), 41 grams of triethoxy silane (0.25 mole), 20 ml. of p-xylene and 0.1% by mole (calculated as rhodium), per mole of triethoxysilane, of [Rh(μ-P Ph2) (COD)]2, that is [rhodium(μ-diphenyl phosphide) (1,5-cyclooctadiene) dimer], and heated on an oil bath maintained at a temperature of 110° C. About 1 hour after the beginning of the reaction, the reaction temperature reached 110° C. At the end of the period the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 81% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 0.7% on a triethoxy silane basis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH:17]1[CH2:22][CH2:21][O:20][C:19]2[N:23]=[CH:24][CH:25]=[CH:26][C:18]1=2.O>CN(C)C(=O)C>[Br:12][C:9]1[CH:8]=[C:4]([C:5]([N:17]2[CH2:22][CH2:21][O:20][C:19]3[N:23]=[CH:24][CH:25]=[CH:26][C:18]2=3)=[O:7])[CH:3]=[C:2]([Br:1])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Br)c(O)c(Br)c1
Reactant: c1cnc2c(c1)NCCO2
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncccc21
Reaction time: 0.5 h
Yield: 31 %

Procedure:
3,5-dibromo-4-hydroxy-benzoic acid (65 mg, 0.22 mmol) was dissolved in N,N-dimethyl acetamide (1.5 ml) and then cooled to −5□. Thionyl chloride (0.024 ml, 0.33 mmol) was added thereto and stirred at −5□ for 30 minutes. 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine dissolved in N,N-dimethyl acetamide (0.7 ml) was added thereto and then stirred at −5□ for 20 minutes, and subsequently stirred at room temperature for 15 hours. Water was added and the mixture was extracted with dichloromethane, and then the (extracted) combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=1:1. The fractions containing the product were collected and evaporated to obtain pale-yellow solid (28 mg, 31%).