Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4.C(N(CC)CC)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.Cl>C(Cl)Cl>[CH:26]1([C:29]([N:18]2[CH2:17][CH2:16][C@@:13]34[C:14]5[CH:15]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=5[CH2:6][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:30])[CH2:28][CH2:27]1
Reactant: Oc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reaction time: 2 h

Procedure:
The product XXXI of Step (a) (0.005 m) and triethylamine (1.5 ml) in methylene chloride (30 ml) is treated with a solution of cyclopropylcarbonyl chloride (0.0055 m) in methylene chloride (5 ml). After stirring for 2 hours the mixture is treated with dilute hydrochloric acid. The layers are separated, the methylene chloride layer is washed with water, and the aqueous layers are extracted with two more portions of methylene chloride. The combined methylene chloride layers are dried (MgSO4), filtered and concentrated to give the title product.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][C:24]([CH2:25][N:26]([CH3:27])[C:16]([C:11]1[C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[N:26]([CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])[CH3:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:18])=[O:28])[CH3:22]
Reactant: O=C(O)c1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reactant: CCOC(=O)CNC
Product: CCOC(=O)CN(C)C(=O)c1ccc(C(=O)c2cccnc2C(=O)N(C)CC(=O)OCC)cc1

Procedure:
Using the compound obtained in Step 1 (1.46 g) and N-methylglycine ethylester (3.0), substantially the same reaction and work-up as in Reference Example 2-Step 2 were conducted to give N-ethoxycarbonylmethyl-3-[4-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)benzoyl]-N-methyl-2-pyridinecarboxamide as a colorless oil (2.5 g)
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16].Cl>C(O)C.O>[OH:23][C:22]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH:21]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (10 g, 92.6 mmol) in absolute ethanol (100 mL) is added dry K2CO3 (15.3 g, 111 mmol) and followed by slow addition of diethylacetylene dicarboxylate (10.6 g, 62.03 mmol) and the reaction mixture is heated at 85° C. for 12 h. The reaction mixture is then cooled to rt and 38 mL of 6N HCl is added dropwise. The reaction mixture is diluted with 150 mL water, extracted with ethylacetate. The organic layer is washed with water twice, dried over Na2SO4 and concentrated under vacuum. The residue is triturated with MTBE and the solid formed is filtered, washed with MTBE and dried to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.12 (bs, 1H), 7.72-7.70 (m, 2H), 7.51-7.47 (m, 2H), 7.37-7.34 (m, 1H), 5.93 (s, 1H), 4.26 (q, J=4.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). MS (ESI+): 233.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].CI.[C:24](=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([N:7]([CH3:24])[C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C(=O)N(C)c1c([N+](=O)[O-])ccc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of the product from Example 87 (0.87 g, 3 mmol), methyl iodide (0.51 g, 3.6 mmol) and cesium carbonate (1.17 g, 3.6 mmol) in 15 mL of acetonitrile was stirred at room temperature for 2 hours. The inorganic salts were removed by filtration and the filtrate evaporated. The residue was dissolved in methylene chloride, filtered and evaporated. The product was then used without further purification (0.86 g, 93% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[BH4-].[Na+]>C(Cl)Cl.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NCc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To L-leucine methyl ester hydrochloride (1.427 g, 7.855 mmol), 4-bromobenzaldehyde (1.451 g, 7.855 mmol), and MgSO4 (0.1 g/mmol, 1 g) in CH2Cl2 (20 mL) was added triethylamine (840 μL, 8.25 mmol) dropwise and the reaction mixture was stirred overnight. The heterogeneous solution was filtered over celite, the filter cake washed several times with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was dissolved in a minimal amount of MeOH and NaBH4 (300 mg, 7.855 mmol) was added portionwise at 0° C. and the reaction mixture was stirred for 3.5 hours. The reaction was quenched with water and the product was extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford methyl (2S)-2-[(4-bromobenzyl)amino]-4-methylpentanoate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13](O)=O>>[CH3:1][N:2]1[CH:13]=[N+:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:4]=[C:3]1[S-:12]
Reactant: O=CO
Reactant: CNC(=S)NNc1ccccc1
Product: Cn1c[n+](-c2ccccc2)nc1[S-]

Procedure:
To 150 ml of formic acid was added 18.1 g of 4-methyl-1-phenylthiosemicarbazide obtained in the above process and the mixture was heat-refluxed for 20 hours. After cooling the reaction mixture and crystals thus formed were collected by filtration and recrystallized from methanol to provide mesoionic 4-methyl-1-phenyl1,2,4-triazolium-3-thiolate as light yellow crystals.
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[F:18][CH:19]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1.Cl[C:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=1>>[F:18][CH:19]([CH:29]1[CH2:30][CH2:31][N:32]([C:36]2[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=2)[CH2:33][CH2:34]1)[C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cccc(C#CC(F)C2CCNCC2)n1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1cccc(C#CC(F)C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 237, using Compound 251a instead of Compound 237a and 2-chloro-3-nitro-6-picoline instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 9:1, affording the title product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20]Br.O>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(C2(C#N)CCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution (15 mL) of methyl 2-chloro-3-(cyanomethyl)benzoate (1.50, 7.16 mmol) produced in Example C61(iii) in dimethylsulfoxide was cooled at which the solution did not solidify, sodium hydride (60%, 869 mg, 21.7 mmol) was slowly added, and the mixture was stirred at room temperature for 30 min. To the suspension was added dropwise 1,3-dibromopropane (1.45 mL, 14.3 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was slowly added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→50/50) to give the title compound (714 mg, 40%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The compound was prepared as described in Example 116(d) from 39 mg (0.16 mmol) of 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylic acid, 32 mg (0.32 mmol) of 2-aminothiazole, 267 mg (0.68 mmol) of HATU and 65 mg (0.64 mmol) of triethylamine. Yield: 4 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=O)[CH3:20]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:19]1[CH3:20]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(=O)Nc1ccccc1Cl
Product: Cc1nc2ccccc2n1-c1ccccc1Cl
Yield: 61 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-(2-chlorophenyl)-acetamide (102 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (74 mg, 61%). 1H NMR (DMSO) δ 2.63 (s, 3 H), 7.34 (d, J=7.9 Hz, 1 H), 7.41 (t, J=7.9 Hz, 1 H), 7.48 (t, J=7.9 Hz, 1 H), 7.64 (d, J=8.6 Hz, 2 H), 7.82 (d, J=7.9 Hz, 1 H), 7.92 (d, J=8.6 Hz, 2 H).
Reaction SMILES: C(O)(=O)C.C(O)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[C:19]1[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]([CH3:32])[N:20]=1>[Fe].C(OCC)(=O)C>[NH2:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([Cl:8])=[C:10]([C:19]2[C:23]([C:24]([F:25])([F:26])[F:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]([CH3:32])[N:20]=2)[CH:11]=1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cc(N)c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 2 h

Procedure:
8 g (0.14 mol) of iron powder, 53 ml of glacial acetic acid and 24 ml of ethanol were heated to 70° C. and the mixture was treated with 11.7 g (29 mmol) of 3-(2,4-dichloro-5-nitrophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole. After the mixture had been stirred for 2 hours at reflux temperature, it was treated with 200 ml of ethyl acetate. It was then filtered through kieselguhr. The filtrate was concentrated. Yield: quantitative.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH2:21][CH2:22][CH3:23])=[C:4]([F:24])[CH:3]=1.[CH2:25](Br)[C:26]#[CH:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][C:26]#[CH:25])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH2:21][CH2:22][CH3:23])=[C:4]([F:24])[CH:3]=1
Reactant: C#CCBr
Reactant: CCCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(2-propynyloxy) -phenyl]-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.34 ppm (d,1H), 6.98 ppm (d,1H), 6.60 ppm (s,1H), 4.76 ppm (m,2H), 4.39 ppm (m,2H), 2.56 ppm (t,1H), 1.67 ppm (m,2H), 0.85 ppm (t,3H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:10][C@@H:9]2[CH2:11][OH:12])=[CH:4][C:3]=1[F:13].[Na].[H-].[Al+3].[H-].[H-]>COCCOC.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:10])[CH2:9][CH2:11][OH:12])=[CH:4][C:3]=1[F:13]
Reactant: OC[C@H]1O[C@@H]1c1ccc(Cl)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Na]
Solvent: CCOCC
Solvent: COCCOC
Product: OCC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
((2R,3R)-3-(4-Chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol) was dissolved in 1,2-dimethoxyethane (150 mL) and cooled to 0° C. Sodium bis (2-methohyethoxy) aluminum hydride (“Red-Al”) (17.46 mL, 57.28 mmol) was added dropwise. The mixture was agitated for 3 hours at room temperature, diluted with ether (250 mL) and quenched with HCl solution (20 mL, 6M HCl+60 mL water). After agitating for 30 minutes, the aqueous phase was separated and extracted twice with ethyl acetate. The combined organics were washed with brine, dried with MgSO4, and evaporated to give (S)-1-(4-chloro-3-fluorophenyl)propane-1,3-diol (10.5 g, 51.31 mmol, 98.55% yield) as thick oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C@H:16]1[CH2:18][O:17]1.[Cl-].[NH4+]>O1CCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:15][C@@H:16]([OH:17])[CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
4,4′-Dibromobiphenyl (0.62 g, 2.0 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tri-n-butylmagnesium lithium in tetrahydrofuran was added under a nitrogen atmosphere at 0° C., which was stirred at the same temperature for 1 hour, followed by addition of (2S)-2-methyloxirane (0.15 mL, 2.2 mmol). The temperature of the reaction solution was raised to room temperature, followed by stirring for 30 minutes, and subsequently a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.23 g, 0.79 mmol) as a white solid (yield 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=4)=[O:39])=[CH:7][CH:6]=3)[C:16]=12
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)c1
Temperature: 25 °C

Procedure:
cis-3-(4-Aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.123 mmol) was dissolved in pyridine (3.5 mL) then cooled to 0° C. m-Tolylisocyanate (18 mg, 0.135 mmol) was added and the reaction was allowed to warm to room temperature over 16 hours. The reaction mixture was concentrated under reduced pressure to yield a pale yellow oil (200 mg). Purification was achieved by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column). The desired product was collected as a white solid (52 mg). HPLC-RT: 12.58 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=540.1.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH3:27][O:28][CH2:29][C:30](O)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[F:26][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:17][CH:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:30][CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)[CH2:19]1
Reactant: COCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCN1CCC(C2CN(c3cccc(CO)c3F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and methoxy acetic acid (47 mg) was mixed with dichloromethane (3 ml), and WSC hydrochloride (100 mg) and HOBt (70 mg) was added thereto, followed by stirring at room temperature for 3 hours. A 1 M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF solution (0.66 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)-2-methoxyethan one (106 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COC(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 170 mg, 0.86 mmol) and (3S,2S)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester (Preparation 21A, 174 mg, 0.83 mmol) were coupled under similar conditions to EXAMPLE 43 using HOBt (142 mg, 0.93 mmol), EDCI (200 mg, 1.04 mmol), DIPEA (0.32 ml, 1.87 mmol) in DMF (10 ml). The crude product was purified by chromatography on silica gel eluting with hexane/ethyl acetate (25:75) to give the title compound as a colourless oil. δH (CDCl3): 3.04 (4H, 2dd), 3.74 (3H, s), 4.36 (1H, br s), 4.63 (1H, m), 4.98 (1H, ddd), 6.66 (1H, s), 6.96 (1H, d), 7.18-7.35 (5H, m), 7.48 (1H, s), 8.63 (1H, s).
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([N:51]5[CH:55]=[CH:54][CH:53]=[N:52]5)=[CH:47][C:46]=4[C:56]([F:59])([F:58])[F:57])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[N:51]1([C:48]2[CH:49]=[CH:50][C:45]([CH2:44][NH:43][C:41]([N:38]3[CH2:37][CH2:36][CH:35]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]5[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=5)=[CH:61][CH:60]=4)[CH2:40][CH2:39]3)=[O:42])=[C:46]([C:56]([F:58])([F:57])[F:59])[CH:47]=2)[CH:55]=[CH:54][CH:53]=[N:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(-n5cccn5)cc4C(F)(F)F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(-n2cccn2)cc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 65 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-[4-(1H-pyrazol-1-yl)-2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide (0.18 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.09 g, 0.13 mmol)
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:31][CH2:32][CH2:33]Br>C(O)C>[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:33][CH2:32][Br:31])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1
Yield: 21.1 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.11 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.30 g, 21%).