Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br:12]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[I:1]
Reactant: BrBr
Reactant: COc1ccc(I)cc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-Iodoveratrole (26.0 g, 0.0985M) in acetic acid (25 ml) was treated with bromine (6.5 ml, 0.127M) in acetic acid (30 ml) and stirred at room temperature for one hour. The mixture was diluted with water (300 ml) and treated with sodium bisulfite to discharge the excess bromine. The white solid was filtered, washed with water and dried in vacuo over P2O5 to give 4-bromo-5-iodoveratrole (33.0 g, 95% yield) as a white solid, mp 98°-100° C. (literature: Baker et al., J. Chem. Soc. 3986 (1961), mp 102°-104° C.). NMR (CDCl3) δ 3.83 ppm (s, 6H, (2x) OCH3), 7.06 (s, 1H, ArH), 7.21 (s, 1H, ArH).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=1)=[O:4].O=P(Cl)(Cl)[Cl:20].CN(C)C1C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:20][C:8]1[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:17])([CH3:16])[CH3:1])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2cc[nH]c2n1
Yield: 69.9 %

Procedure:
A mixture of 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-propionamide (210 g, 0.90 mol), POCl3 (828 g, 5.40 mol, 503 mL, 6.0 eq), benzyltriethylammonium chloride (411 g, 1.80 mol), N,N-dimethylaniline (220 g, 231 mL, 1.80 mol), and acetonitrile (2.0 L) was heated to reflux for 40-60 min, monitoring with HPLC. The solvent was evaporated on a rotary evaporator, and the residue was carefully (caution: exothermic and corrosive) and slowly added to ice water (16 L). The pH was adjusted to 7 with solid NaOH, and the resulting precipitate was collected by filtration. Drying afforded the title compound (159 g, 70% yield 70%, HPLC purity 100%). tR: 5.37 min. 1H-NMR (DMSO-d6) δ 12.35 (br. s, 1H), 10.06 (br. S, 1H), 7.54 (q, 1H), 6.52 (q, 1H), 1.25 (s, 9H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([N:12]2[CH2:13][C:14](=[O:16])[CH2:15][NH:11]2)=[O:26])=[CH:20][CH:21]=1
Reactant: O=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CNN(C(=O)Cc2ccc(F)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester, 4, (1 g, 4.5 mmol) in methanol (30 mL) is added Pd/C (100 mg). A balloon filled with hydrogen gas is placed over the flask and the mixture stirred for 3 hours. The solution is filtered to remove the catalyst and concentrated in vacuo to afford 0.8 g of the desired product as a yellow oil which is used without further purification.
Reaction SMILES: Cl[C:2]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[N:18]=[CH:17][N:16]=[C:15]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([NH:27][C:15]2[C:14]3[C:19](=[CH:20][C:21]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)=[C:12]([NH:11][C:2](=[O:3])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: CCOC(=O)C=CC(=O)Cl
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1

Procedure:
A solution of 3.00 g of ethyl 3-chlorocarbonyl-acrylate in 50 ml of tetrahydrofuran is added dropwise to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-quinazoline and 3.5 ml of diisopropylethylamine in 150 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture is stirred for a further hour while cooling with an ice bath and then stirred overnight at ambient temperature. Next, the solvent is largely distilled off in the rotary evaporator and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The brown, oily crude product is stirred with diethylether, the precipitate formed is suction filtered and washed with a little diethylether. Yield: 3.20 g (47% of theory), Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z=485, 487 [M+]*
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCSc2cc(Br)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Brc1ccc2c(c1)SCCCC2
Yield: 72.5 %

Procedure:
15.6 g of 8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one were dissolved in 70 ml of diethylene glycol. The solution was treated with 6.55 ml of hydrazine hydrate and 7.5 g of solid potassium hydroxide and heated to 180°-190° C. under reflux for about 30 hours. After cooling, the mixture was poured on to ice and extracted with ether. The organic phase was washed with water, dried and evaporated. Chromatography on silica gel with petroleum ether yielded 10.7 g of 8-bromo-2,3,4,5-tetrahydro-1-benzothiepine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](OC)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:32][NH2:33]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:33][CH3:32])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 60 °C
Reaction time: 22 h
Yield: 91.3 %

Procedure:
In a dried reaction flask, the crude methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxyl ate (prepared according to the step (2) of Example 1) (0.489 g, about 1.1 mmol) was dissolved in ethanol (22 mL). A 27% methylamine in ethanol solution (22.121 g) was added to the mixture. The resulting mixture was stirred at 60° C. for 22 h and filtered to produce a crude yellow solid, which was washed with ethanol to produce a purified product (0.436 g) in 91.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.BrC1C=CC=CC=1C#N>C(#N)C.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)I>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: N#Cc1ccccc1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#Cc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
A solution of 3.00 grams (0.015 mole) of 2-amino-5-bromobenzonitrile and 2.3 mL (0.021 mole) of phenylacetylene in 50 mL of acetonitrile was stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride were added in order. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, thin layer chromatographic (TLC) analysis of the reaction mixture indicated that no reaction had taken place. The reaction mixture was warmed to 70° C., where it was stirred for about 7.5 hours. An additional 0.38 gram of phenylacetylene was added, and the reaction mixture was warmed to reflux temperature where it was stirred during about an additional 16.5 hour period. After this time, TLC analysis of the reaction mixture indicated that it contained about a 1 to 1 mixture of starting bromobenzonitrile and product. An additional 5.0 mL of triethylamine and 0.09 gram of bis(triphenylphosphine)palladium(II) chloride catalyst was added to the reaction mixture, and the heating at reflux was continued during an additional 24 hour period. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate, and the solution was washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 15/10/75 tetrahydrofuran/methylene chloride/petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.85 gram of 2-amino-5-(2-phenylethynyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3](=[O:16])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[CH:17]([Mg]Cl)([CH3:19])[CH3:18].[Cl-].[NH4+].Cl>O1CCCC1>[C:6]([NH:5][CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3](=[O:16])[CH:17]([CH3:19])[CH3:18])(=[O:8])[CH3:7]
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1ccccc1)C(=O)C(C)C
Reaction time: 0.25 h

Procedure:
A solution of 2.30 g of N-acetylphenylalanine methyl ester (10.40 mmol) in 15 ml of tetrahydrofuran is chilled at -60° C. with dry ice/acetone bath. To the mixture is added dropwise 10.40 ml of 2M solution of isopropylmagnesium chloride in tetrahydrofuran (20.8 mmol) with stirring and the mixture allowed to stand for 15 minutes and returned to room temperature. The mixture was stirred for 3 hours. To the mixture is added saturated aqueous ammonium chloride under ice cooling, followed by the addition of 5% hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude product is chromatographed on a column of silica gel, eluting with methylene chloride and ethyl acetate (4:1) to give 1.40 g of the objective 4-acetylamino-2-methyl-5-phenyl-3-pentanone 5. Yield, 57.7%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
To a 500 mL round-bottomed flask was added 4-(trifluoromethyl)-cinnamic acid (231 mL, 116 mmol), DCM (7.44 mL, 116 mmol), thionyl chloride (17.7 mL, 243 mmol), and a few drops of DMF. The resulting mixture was stirred at reflux for about 1.5 hours and followed by LCMS (MeOH quench). Once no starting material was present, the solvents were reduced and the oil was used immediately in the next step.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]4[NH:34][CH2:35][CH2:36][CH2:37][N:38]=4)=[CH:27][CH:28]=3)=[O:23])[C:17]([OH:19])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O>C(O)C(C)C>[CH2:2]([O:18][C:17](=[O:19])[C@@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:14])[CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:27][CH:28]=1)=[O:23])[CH:1]([CH3:10])[CH3:8]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1
Solvent: CC(C)CO
Solvent: O=S(Cl)Cl
Product: CC(C)COC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.2 %

Procedure:
0.38 g (0.7 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-((5-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid (example 15) were dissolved in 7 ml of isobutanol. Under an inert gas atmosphere and under external ice cooling 0.19 ml of thionyl chloride were cautiously added. After stirring for 8 hours at room temperature the reaction was complete. The solvents were removed in vacuo to give a colourless foam which was purified by chromatography (silica gel; isopropanol/ethyl acetate/water (4/3/1; v/v/v)). The fractions containing the title compound were lyophilized to give 0.30 g of a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: Cc1cccc2nc(C=O)c(Br)c(=O)n12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc2nc(C(C)O)c(Br)c(=O)n12
Temperature: 9 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (1.4162 g, 5.30 mmol) in THF (53.0 mL) was added methyl-magnesium bromide 3 M in Et2O (2.65 mL, 7.95 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 2 h. After 2 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (1 H, dd, J=8.6, 7.0 Hz), 7.48 (1 H, d, J=9.4 Hz), 7.01 (1 H, d, J=7.0 Hz), 5.15 (1 H, d, J=6.7 Hz), 4.99 (1 H, qd, J=6.5, 6.3 Hz), 2.94 (3 H, s), 1.35 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=283.0 [M+1 (79Br)] and 285.0 [M+1 (81Br)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Al].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>O.C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Al]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1ccc(O)c(C2=CCCCC2)c1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
15.0 g (0.10 mol) of 4-tert-butylphenol and 7.2 g (0.035 mol) of aluminium isopropylate are added to 100 ml of xylene under nitrogen. To remove the resulting isopropanol, 30 ml of solvent are distilled off. The reaction mixture is heated to 100° C. and charged with 9.8 g (0.10 mol) of cyclohexanone and is then refluxed for 20 hours. The reaction mixture is cooled and charged with 40 ml of water and 10 ml of concentrated hydrochloric acid. The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=19:1 and the pure fractions are crystallised from methanol, giving 6.3 g (27%) of 4-tert-butyl-2-cyclohexen-1-yl-phenol, m.p. 90-93° C. (compound (109), Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[C:43]([F:50])[CH:42]=3)[O:36][C:35](=[O:37])[CH2:34][C:33](=[O:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:34]3[C:35](=[O:37])[O:36][C:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[C:43]([F:50])[CH:42]=4)[CH2:32][C:33]=3[OH:38])[N:10]=2)[CH:7]=1
Reactant: CC(O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CC(O)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc1F

Procedure:
The title compound was prepared analogously to Example B(97) where where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione (Example B(115) (was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:24]>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][O:19][CH3:24])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(COC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Stir 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (1.1 g, 3.9 mmol) in THF (20 mL). Add sodium hydride (0.78 g, 60% in mineral oil) and iodomethane (729 μL, 11.7 mmol). Stir at room temperature for 3 h. Concentrate to give the title product which is used directly in the next step without further purification.
Reaction SMILES: C([O:8][C:9](=O)[CH:10]([NH:19][C:20](=[O:38])[CH:21]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.[NH3:40].CO>>[C:9]([CH:10]([NH:19][C:20](=[O:38])[CH:21]([CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:8])[NH2:40]
Reactant: N
Reactant: O=C(NC(CCN1CCCCC1)C(=O)OCc1ccccc1)C(CC(=O)N1CCOCC1)CC1CCCCC1
Solvent: CO
Product: NC(=O)C(CCN1CCCCC1)NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To 2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-4-piperidin-1-yl-butyric acid benzyl ester (0.10 g, 0.18 mmol) was added NH3/MeOH (2.0 M, 10 mL) in a sealed tube and the mixture was stirred at room temperature for 3 days. The solvent was evaporated to give the title compound in 50% yield.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH:14][C@H:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[Si:10]([O:14][C@H:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCC[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 24 h
Yield: 97.6 %

Procedure:
4-Dimethylaminopyridine (0.199 g, 1.63 mmol), imidazole (6.73 g, 99 mmol) and TBDMS-Cl (20.6 ml, 59.3 mmol) was added to a stirred solution of (S)-3-hydroxypyrrolidin-2-one (5.0 g, 49.5 mmol) in DCM (198 ml) at RT. The reaction mixture was stirred for 24 h and then diluted with water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (50-80% EtOAc/hexanes) to afford (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (10.4 g, 97% yield) as a white solid: 1H NMR (500 MHz, chloroform-d) δ 6.15 (br. s., 1H), 4.28 (t, J=7.6 Hz, 1H), 3.40 (dddd, J=9.7, 8.5, 3.1, 1.2 Hz, 1H), 3.28 (dt, J=9.6, 7.4 Hz, 1H), 2.39 (dtd, J=12.7, 7.3, 3.1 Hz, 1H), 2.10-2.02 (m, 1H), 0.97-0.92 (m, 9H), 0.20-0.14 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([NH:25][CH3:24])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 52.1 %

Procedure:
4-Chloro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile (0.22 g, 0.74 mmol), methylamine (33% in ethanol, 0.7 mL, 5.6 mmol) and sodium cyanoborohydride (60 mg, 0.81 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 ml) for 6 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (70 mg, 0.60 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(5-methylamino-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile fumarate (134 mg, 42%) as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Add benzaldehyde (7.5 mL, 74 mmol) to a stirred solution of tyramine (10.00 g, 73 mmol) and anhydrous methanol (90 mL). Heat reaction to reflux for 1 h under nitrogen. Cool reaction to 0° C. and slowly add sodium borohydride (2.84 g, 75 mmol). Stir for 1 h at room temperature and then concentrate on a rotary evaporator. Add water (100 mL) and stir for 1.5 h at room temperature. Filter and wash with water to yield 10.11 g (61%) of 4-(2-benzylamino-ethyl)-phenol: mass spectrum (ion spray): m/z=228.1 (M+1); 1H NMR (DMSO-d6): 9.14 (br s, 1H), 7.29-7.18 (m, 5H), 6.96 (d, 2H), 6.65 (d, 2H), 3.69 (s, 2H), 2.67-2.60 (m, 4H), 2.02 (br s, 1H).