Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5]C=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)[N:3]=1.[CH:27]1[C:37]2[CH:36]=[CH:35][C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.N[C:46]1N=C(N)C(CBr)=CN=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:5])[CH:9]=[C:10]([CH2:46][C:38]2[C:34]3[CH:35]=[CH:36][C:37]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[NH:32][C:33]=3[CH:41]=[CH:40][CH:39]=2)[N:11]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1cc(Cc2cccc3c2C=Cc2ccccc2N3)nc(N)n1

Procedure:
9-[(2,4-Diaminopyrimidin-6-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminopyrimidin-5-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using dibenz[b,f]azepine (154 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-bromomethylpyrimidine hydrobromide (86 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16](O)=O>O>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2)=[C:2]2[NH:1][CH:16]=[N:12][C:11]=12
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: O=CO
Solvent: O
Product: Oc1nc2cc(Cl)c3nc[nH]c3c2nc1O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 0,3 g (1,35 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml formic acid was refluxed for 2 h. After cooling to 25° C., the reaction mixture was poured into 30 ml water to give 0,21 g (67%) 4-chloro-7,8-dihydroxy-lH-imidazo(4,5-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 7.37 (lH,s), 6.70 (lH,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].[Cl-].[Na+]>C1COCC1>[OH:49][CH2:48][C:47]([NH:46][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH2:24][OH:25])[CH:16]=1)=[O:22])([CH3:51])[CH3:50]
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) in THF (2.7 mL) was added 1-hydroxybenzotriazole hydrate (43.0 mg, 0.28 mmol), N-ethyldiisopropylamine (120 μL, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (43.0 mg, 0.28 mmol) and 2-amino-2-methyl-1-propanol (25.3 mg, 0.28 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (32 mg, 26%) as a white solid. MS: m/e=435.3 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].C[Si](C)(C)O[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31]>CC#N>[N:29]([CH:2]([O:1][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])=[N+:30]=[N-:31]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=CCCCNC(=O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc(COC(CCCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-oxobutyl)trifluoroacetamide (1.0 g; 5.5 mmol) and a catalytic amount of anhydrous ferric chloride (44 mg; 0.27 mmol) in anhydrous MeCN (6 mL) was cooled to −40° C. A solution of methyl 4-[(trimethylsilyloxy)methyl]benzoate (1.56 g; 6.6 mmol) and azidotrimethylsilane (0.94 g; 8.2 mmol) in MeCN (5 mL) was added dropwise to the cooled solution. The reaction mixture was stirred at −40° C. for 60 min and quenched with buffered phosphate saline (pH 7.2). The aqueous solution was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography (Hex:DCM:EtOAc 7:2:1) to provide methyl 4-[(1-azido-4-trifluoroacetamidobutoxy)methyl]benzoate in a yield of 0.95 g (46%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7](=[O:8])[CH:6]=[CH:5][S:4]1.[Cl:9]Cl>C(OCC)(=O)C>[Cl:1][C:6]1[C:7](=[O:8])[N:3]([CH3:2])[S:4][C:5]=1[Cl:9]
Reactant: Cl
Reactant: ClCl
Reactant: Cn1sccc1=O
Solvent: CCOC(C)=O
Product: Cn1sc(Cl)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 30.3 g (0.2 mole) of pure and dry 2-methyl-4-isothiazolin-3-one hydrochloride in 200 ml. of ethyl acetate is added over 1 hour, 71 g (1 mole) of chlorine. The reaction exotherms to 55° C. in 1/2 hour and all solid is dissolved after about 3/4 hour. The solution is degassed and evaporated under reduced pressure to give a cream color mush. The mush is shown by TLC (silica/toluene) to contain two major components. Crystallization of the mush from methanol gives 16.8 g of 4,5-dichloro-2-methyl-4-isothiazolin-3-one. Evaporation of the filtrate gives 23.4 of material which is chromatographed on a silica dry column with toluene. The fraction close to the solvent front is extracted and gives 8.8 g of crude product. Recrystallization from methanol gives 6.55 g (13% of white crystalline 2-methyl-4,4,5,5-tetrachloroisothiazolidin-3-one, m.p. 77°-80° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[O:25][CH3:24])=[CH:11][CH:12]=1)=[O:5]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COCC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COCC(=O)Nc1ccc(S(=O)(=O)NC(=O)c2ccccc2OC)cc1
Reaction time: 2 h

Procedure:
8 g (33 mmol) of 2-methoxy-N-(4-sulfamoylphenyl)acetamide are introduced into 160 ml of acetonitrile at 0° C., and 6.63 g (66 mmol) of triethylamine and a catalytic amount of DMAP are added. 5.6 g (33 mmol) of 2-methoxybenzoyl chloride—dissolved in 20 ml of acetonitrile—are subsequently added at 0° C., and stirring is continued for 2 hours at this temperature. After a further 2 hours at room temperature, the mixture is transferred into water and the precipitate is filtered off with suction;
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][C:17]2([CH2:20][OH:21])[CH2:19][CH2:18]2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:21][CH2:20][C:17]1([CH2:16][N:10]2[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:22])[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CC2(CO)CC2)c1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(COS(C)(=O)=O)CC2)c1=O

Procedure:
A mixture of 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethanol (1.95 g, 6.5 mmol), triethylamine (1.32 mL, 9.5 mmol) and methylene chloride (20 mL) was cooled to between 0° and 5° C. under argon and methanesulfonyl chloride (0.69 mL, 8.85 mmol) was added slowly. The mixture was stirred cooled 2 hours at 0° to 5° C., then diluted with water (20 mL) and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate, dried (MgSO4) and concentrated to give 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethyl methanesulfonate.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH3:9][C:10]([C:12]([CH3:14])=[CH2:13])=[CH2:11].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:9][C:10]1[CH2:11][C:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4](=[O:7])[C:5]=2[CH2:13][C:12]=1[CH3:14]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)C=C1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(C)CC2=C(C1)C(=O)C=CC2=O
Yield: 88 %

Procedure:
In toluene (60 ml) and acetic acid (10 ml), were dissolved 14.0 g (0.13 mol) of 1,4-benzoquinone, to which 20.0 g (0.24 mol) of 2,3-dimethyl-1,3-butadiene were added at -10° C. under stirring. Thereafter, the resultant mixture was gradually heated and stirred further for 3 hours at 40° C. The liquid reaction mixture was washed with water, and an organic layer was dried and concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) and ethanol (60 ml) were added to the residue, and the mixture was stirred for 1 hour at 40° C. After the liquid reaction mixture was concentrated under reduced pressure, the residue was dissolved in a liquid mixture of acetonitrile (100 ml) and water (30 ml). To the solution, were added 20.0 g (0.036 mol) of ceric ammonium nitrate at room temperature to stir the resultant mixture for 1 hour. The liquid reaction mixture was poured into water (200 ml) to make extraction with toluene (50 ml×2). The resulting organic layer was washed with water, dried and concentrated under reduced pressure to obtain 21.5 g of a crude product of the title compound (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.Br[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=CC(C)(C)Br
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 63, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-bromo-3-methyl-but-1-ene.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:34])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at 0° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3—CHCl3:MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10](=O)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(OCC)(=[O:22])C>C1COCC1>[OH:22][C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(/[CH:11]=[CH:10]/[CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CCCCC/C=C/C(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: C/C=C/C(O)(CCCCC)CC(=O)OCC
Yield: 99 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.70 g (5 mmol) of trans-3-nonen-2-one in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 8.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.13 g of the desired product (yield 99%).
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:24]([O:26]C)=O)=O.Cl.NC.[BH3-][C:32]#[N:33].[Na+]>CO>[CH3:32][N:33]1[C:24](=[O:26])[C:4]2[C:3](=[C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[CH2:1]1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Yield: 49.8 %

Procedure:
A sealed tube was charged with a solution of dimethyl 4-formyl-5-(4-(methylsulfonyl)phenoxy)-isophthalate (210 mg, 0.535 mmol) in MeOH and aminomethane hydrochloride (72.3 mg, 1.07 mmol). After stirring the reaction at room temperature for 2 hours, NaCNBH3 (84.1 mg, 1.34 mmol) was added. The mixture was then stirred at 65° C. for 14 hours. The solvent was evaporated and replaced with ethyl acetate. The organic layer was then washed with brine (3×), dried over MgSO4, and concentrated. The crude sample was introduced into a silica gel column chromatography and eluted with 5-10% MeOH/CHCl3 to provide the desired product (100 mg, 50% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.09 (s, 3 H) 3.21 (s, 3 H) 3.94 (s, 3 H) 4.36 (s, 2 H) 7.07-7.21 (m, 2 H) 7.84 (d, J=1.13 Hz, 1 H) 7.90-8.03 (m, 2 H) 8.37 (d, J=1.13 Hz, 1 H); LC-MS (ESI)+m/z=376.00 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[N:22]=1)([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:1][CH2:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=3)=[CH:32][CH:33]=2)[N:22]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: CC(C)c1nc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3noc(C(C)C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (1 g; 4.22 mmol) in dichloromethane (30 ml) was treated under nitrogen with 4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (0.96 g; 4.43 mmol), sodium triacetoxyborohydride (0.94 g; 4.43 mmol) and acetic acid (0.24 ml; 4.23 mmol). After stirring at rt overnight, the mixture was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using an ethyl acetate-hexane gradient (20–70%) followed by a methanol-dichloromethane gradient (1–10%) afforded the title compound (1.5 g; 81% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH2:45])[CH3:41]>C1COCC1>[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:14]([C@@H:13]1[CH2:12][S:11][C@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[N:9]1[C:7](=[O:8])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:16])[CH3:41]
Reactant: CCOC(=O)CN
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(C)=O
Yield: 81.6 %

Procedure:
The suspension is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the solution of 0.7 g of glycine ethyl ester hydrochloride and 0.51 g of N-methylmorpholine dissolved in aqueous THF is added, and treated in the same manner as Example 10 to give 1.8 g (82%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:4][OH:5].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:2][OH:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COCCOCOCCCCCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOCCCCCC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.06 g of 2-hydroxymethyl-7-(2-methoxyethoxy)methoxy-1-heptanol (prepared as described in Preparation 80) dissolved in 20 ml of dimethylformamide was added dropwise to 587 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) dispersed in 40 ml of dimethylformamide, whilst ice-cooling (at 5° to 7° C.). The mixture was then stirred at room temperature for 1 hour, after which 1.60 ml of benzyl bromide were added dropwise, whilst ice-cooling (at 5° to 7° C.) The reaction mixture was stirred at room temperature for 2 hours, after which it was poured into 300 ml of water and then extracted five times with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting oily residue was subjected to column chromatography through 60 g of silica gel, and 2.37 g of the title compound were obtained, as a colorless oil, from the fractions eluted with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:1 by volume.
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7]([Si:11]([CH3:14])([CH3:13])Cl)([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>CN(C=O)C>[Si:11]([O:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:14])[CH3:13]
Reactant: C[C@H](O)C(N)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O

Procedure:
A solution of (S)-2-hydroxypropanamide (13-1) (30 g, 337 mmol) and tert-butyldimethylchlorosilane (66.0 g, 438 mmol) in pyridine (101 ml, 1246 mmol) and DMF (90 ml) was stirred at room temperature for 16 h. The reaction mixture was filtered to remove insolubles and the filtrate was partitioned between saturated aqueous sodium bicarbonate solution (500 mL) and EtOAc (500 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), brine (3×100 mL) and water (3×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 13-2 as a viscous yellow oil. MS: m/z=204.0 (M+H).
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH2:25][N:26]([CH3:28])[CH3:27])=[C:20]=[S:21].N(C1C=CC(OCCN2CCCC2)=CC=1)=C=S.CN(CC1C=C(N)C=CC=1)C>C(Cl)Cl.CO>[CH3:27][N:26]([CH2:25][C:24]1[CH:23]=[C:22]([NH:19][C:20]([NH2:1])=[S:21])[CH:31]=[CH:30][CH:29]=1)[CH3:28].[N:19]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH2:25][N:26]([CH3:28])[CH3:27])=[C:20]=[S:21]
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Agent: CN(C)Cc1cccc(N)c1
Agent: CN(C)Cc1cccc(N=C=S)c1
Agent: S=C=Nc1ccc(OCCN2CCCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)Cc1cccc(NC(N)=S)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using (3-isothiocyanato-benzyl)-dimethyl-amine. Title compound: ES-MS: 210.0 [M+H]+; single peak at tR=3.38 min (System 1); Rf=0.63 (CH2Cl2/MeOH, 80/20). (3-Isothiocyanato-benzyl)-dimethyl-amine is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)ethyl]-pyrrolidine but using 3-dimethylaminomethyl-phenylamine. (3-Isothiocyanato-benzyl)dimethyl-amine is obtained and used as an impure crude material.
Reaction SMILES: Cl.[CH:2]([C:5](C(C)C)([CH:8]([CH3:10])C)[CH2:6][NH2:7])([CH3:4])[CH3:3].[N:14](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=C=O>CN(C)C=O.O1CCCC1>[CH2:6]1[C:5]2[CH:8]=[CH:10][N:14]=[CH:4][C:2]=2[CH2:3][NH:7]1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: CC(C)C(CN)(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cc2c(cn1)CNC2
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
HCl (1.55 g, 8.03 mmol) was suspended in dimethylformamide (30 ml) and treated with triisopropylethylamine (4.21 ml, 24.08 mmol). After stirring for 20 minutes, the mixture was cooled to −15° C. 2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.028 g, 8.03 mmol) was dissolved in 10 ml tetrahydrofuran and added via syringe over 10 minutes. The mixture was allowed to warm to room temperature, and it was stirred for 3 hours and concentrated under a stream of nitrogen to minimal volume. The residue was diluted with cold water to give a turbid mixture which was filtered with water washes to provide the title compound after drying.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH2:3]1.[F:15][C:16]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:17][NH:18][C:19](=[O:24])[CH2:20][C:21](O)=[O:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl>O1CCCC1>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH2:3][C@H:2]([NH:1][C:21](=[O:22])[CH2:20][C:19]([NH:18][CH2:17][C:16]([F:29])([F:15])[C:25]([F:26])([F:28])[F:27])=[O:24])[C:8]1=[O:9]
Reactant: CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)COc2ccccc21
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of 0.06 g (0.31 mmol) (S)-7-amino-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in 5 ml tetrahydrofurane were added 0.07 g (0.31 mmol) N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, 0.04 g (0.31 mmol) 1-hydroxybenzotriazole hydrate, 0.06 g (0.31 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride and 0.1 ml (0.62 mmol) diisopropylethylamine. After stirring at room temperature over night the mixture was added to 1N aqueous hydrochloric acid. Extraction with dichloromethane, followed by washing with saturated aqueous sodium bicarbonate solution and drying with sodium sulfate, and chromatography on silicagel with ethylacetate/heptane yielded 0.05 g (39%) N-((S)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid, MS m/e (%): 410.3 (M+H+, 100).