Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2OC(=O)[S:22][N:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(OCC)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[S:22][N:21]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2ccc([N+](=O)[O-])cc2)ns1
Solvent: CCOC(C)=O
Product: COC(=O)c1snc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)OC
Yield: 25.2 %

Procedure:
Dimethyl acetylenedicarboxylate (85.26 g, 0.6 mol) and 5-(p-nitrophenyl)-1,3,4-oxathiazol-2-one (33.63 g, 0.15 mol) were heated as given above for 15 hours. Crystallization of the brown solid from methanol (2×) gave little improvement in purity. The brown solid was decolorized in ethyl acetate solution and recrystallized (3×) to give 12.2 g (0.0378 mol, 25.2%) of dark gold solid, m.p. 142°-143°.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][OH:12].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:15]([O:14][CH2:13][C@@H:10]([NH:9][C:24](=[O:25])[CH2:23][Cl:22])[CH2:11][OH:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)COCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H](CO)COCc1ccccc1
Temperature: 0 °C

Procedure:
Add triethylamine (7.0 mL, 50.6 mmol) to a RT slurry of (S)-2-amino-3-benzyloxy-propan-1-ol hydrochloride (5 g, 23.0 mmol) in CH2Cl2 (75 mL). Stir until all the solid dissolves and then cool to 0° C. Add chloroacetylchloride (2.0 mL, 25.3 mmol). Stir 1 h and add more TEA (960 μL, 6.9 mmol) and chloroacetylchloride (549 μL, 6.9 mmol) to consume all the starting amine with continued stirring for 2 h. Pour into a separatory funnel containing 1 N HCl (200 mL) and extract with CH2Cl2 (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, and concentrate to give crude N—((S)-1-benzyloxymethyl-2-hydroxy-ethyl)-2-chloro-acetamide. Dissolve this intermediate in THF (75 mL), cool to 0° C., and treat with NaH (1.1 g, 27.6 mmol). Stir 6 h at 0° C. to form the NH morpholinone. Add additional NaH 1.1 g (27.6 mmol) followed by MeI (3.6 mL, 57.5 mmol). Stir at 0° C. for 30 min and then pour into a separatory funnel containing 0.1 M HCl (200 mL). Extract with EtOAc (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, filter, and concentrate to give the crude methylated product. Purify via silica gel chromatography using a gradient of 0-100% EtOAc/hexanes to yield 1.3 g (24%, 3 steps) of the title compound. MS/ES m/z 236.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[N:21][N:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([C:19]4[N:18]([CH3:17])[CH:22]=[N:21][N:20]=4)=[CH:29][CH:28]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc(-c4nncn4C)cc3)n2)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-(2-chloropyrimidin-4-yl)-N,N-dimethylaniline (50 mg, 0.2 mmol) [obtained from 4-(dimethylamino)phenylboronic acid and 2,4-dicholorpyrimidine by following procedure B], 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (45 mg, 0.25 mmol), Davephos (3 mg, 0.006 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), NaOtBu (30 mg, 0.28 mmol) and DME (1.0 mL) was placed in a sealed tube and heated to 140° C. in a microwave for 30 min. The reaction mixture was cooled, filtered through a pad of Celite, washed with ethyl acetate and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 4-(4-(dimethylamino)phenyl)-N-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-2-amine. 1H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 9.06 (s, 1H), 8.47 (d, 1H), 8.12-8.08 (m, 4H), 8.78 (d, 2H), 7.38 (d, 1H), 6.84 (d, 2H), 3.88 (s, 3H), 3.03 (s, 6H). MS (ESI) 372 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([F:17])[C:11]([C:12](O)=[O:13])=[C:10]([C:18]#[N:19])[CH:9]=2)=[CH:6][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([F:17])[C:11]([C:12]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:13])=[C:10]([C:18]#[N:19])[CH:9]=2)=[CH:6][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: N#Cc1cc(-c2cc(C3CCOCC3)cnc2N)cc(F)c1C(=O)O
Reactant: NCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(-c2cc(C3CCOCC3)cnc2N)cc(F)c1C(=O)NCc1ccccc1

Procedure:
To 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-cyano-6-fluorobenzoic acid were added DCM (1 mL), followed by benzylamine (0.017 mL, 0.153 mmol), triethylamine (0.053 mL, 0.383 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol). After 1 h more benzylamine (0.017 mL, 0.153 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol) were added and at 2 h the reaction was completed. Saturated NaHCO3 solution was added and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 0:1) to give the product as a colorless solid (17 mg). LCMS (m/z) 431.1 (MH+), 0.65 min. 1H NMR (400 MHz, CDCl3)) δ ppm 8.03 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H, J 12 Hz), 7.43-7.30 (m, 4H) 7.26 (s, 1H), 7.23 (s, 1H) 6.57 (br s, 1H), 4.74 (d, J 5.53 Hz, 2H), 4.10-4.06 (m, 2H), 3.55-3.46 (m, 2H), 2.77-2.67 (m, 1H), 1.80-1.70 (m, 4H).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22].N12CCN(CC1)CC2.CO>CN(C)C=O>[C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])[C:20]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:25]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1N
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
was prepared as described in Example II of U.S. Pat. No. 6,590,082, which is hereby incorporated by reference herein in its entirety. A mixture of octadecanol (270 grams, 1.0 mol; obtained from Sigma-Aldrich Co., Milwaukee, Wis.), isatoic anhydride (24 grams, 1.5 mol; obtained from Sigma-Aldrich Co.), and 1,4-diazabicyclo[2.2.2]octane (56 grams, 0.50 mol; obtained from Sigma-Aldrich Co.) in 1,000 milliliters of dimethylformamide was stirred and heated to 100° C. in a 4 liter beaker. Vigorous gas evolution occurred. After 10 minutes, the resultant brown solution was heated to 150° C. for 15 minutes. The reaction mixture was then cooled to 50° C. and vigorously stirred while 3,000 milliliters of methanol was added. The resultant suspension was stirred for 0.5 hour followed by vacuum filtration. The solid thus obtained was washed in the filter funnel with 4×300 milliliter portions of methanol and then dried in air to give the product stearyl anthranilate as white power (330.5 grams, 85 percent yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][C:3]=1[F:13].[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=1[C:6]([OH:12])=[O:14]
Reactant: O=C1Nc2cc(Br)c(F)cc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a 100 mL round bottom flask, 6-bromo-5-fluoro-1H-indole-2,3-dione (3 g, 0.0121 mol) and 2N NaOH (15 mL) were added and cooled the reaction vessel to 0° C. To this reaction mixture, 30% hydrogen peroxide (10.5 mL) was slowly added. The reaction mixture was stirred at 0° C. for 3 hours. Subsequently, the reaction mixture was acidified with 2N HCl at 0° C. (pH 5) to afford solid compound. The solid material was collected by filtration and dried to obtain the title compound (700 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 7.52 (d, J=9.6 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[C:42](=[O:54])[CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:23][NH:22][CH2:21][CH:20]2[C:42](=[O:54])[CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(COCCN2CCOCC2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(C(=O)Cc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C(Cc1ccc2ccccc2c1)C1CNCC(COCCN2CCOCC2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 73(d), from tert-butyl (3RS,4SR, 5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(2-morpholin-4-yl-ethoxymethyl)-3-(naphthalen-2-yl-acetyl)-piperidine-1-carboxylate by cleavage of BOC protecting group by means of anhydrous zinc bromide in methylene chloride there was obtained 1-[(3RS,4SR,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(2-morpholin-4-yl-ethoxymethyl)-piperidin-3-yl]-2-naphthalen-2-yl-ethanone as a yellow oil MS: 637 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a solution of ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (for a preparation see Intermediate 22) (270 mg, 0.597 mmol) in methanol (6 mL) and water (2.0 mL) was added aqueous sodium hydroxide (2N, 0.597 mL, 1.193 mmol) at room temperature and the resulting mixture was stirred for 6 h. Aqueous sodium hydroxide (2N, 0.5 mL) was added and the mixture was left standing overnight. The bulk of methanol was removed in vacuo and the resulting residue was partitioned between water and Et2O and the layers were separated. The aqueous layer was acidified with hydrochloric acid (2N, 2 mL) and extracted twice with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetic acid (200 mg, 0.471 mmol, 79% yield) as a brown foam. This compound was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.65, MH+=425.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](C(O)=O)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1C(O)=O.NCCO>O>[CH3:1][N:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]1[CH3:7]
Reactant: Cc1c(C(=O)O)c(-c2ccccc2)c(C(=O)O)n1C
Solvent: O
Solvent: NCCO
Product: Cc1cc(-c2ccccc2)cn1C
Temperature: 175 °C
Yield: 77.4 %

Procedure:
A suspension of 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60 g, 0.23 mol) and 2-aminoethanol (300 mL) was heated to 175° C. under a nitrogen atmosphere for 30 min. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed successively with water (3×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo at a temperature below 40° C. to afford the crude product. Flash column chromatography over neutral alumina using 5% ethyl acetate in petroleum ether as eluent afforded 1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 78%) as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[C:24]([F:30])=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=1)[CH3:22])[CH:2]=C.C(=O)(O)[O-:32].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:29][C:27]1[CH:28]=[C:23]([C@:5]2([CH3:22])[CH:4]([CH2:1][CH2:2][OH:32])[S:9](=[O:11])(=[O:10])[C:8]([CH3:12])([CH3:13])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:6]2)[C:24]([F:30])=[N:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: C=CCC1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C(CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
To a solution of tert-butyl ((5R)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.988 g, 1.96 mmol) in MeOH (5 mL) and DCM (15 mL) at room temperature was added sodium bicarbonate (0.333 g, 3.96 mmol). The reaction mixture was cooled to −78° C. and ozone was bubbled through the solution. After 15 min, the solution turned blue and oxygen was bubbled through the mixture for 5 min. Sodium borohydride (0.154 g, 4.07 mmol) was added and the reaction mixture was removed from the −78° C. bath. The solution was warmed to room temperature, stirred for 1 h, and quenched with saturated NH4Cl, and diluted with EtOAc water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated. Purification by flash column chromatography on silica gel (40 g, 20% to 60% EtOAc in hexanes) gave tert-butyl ((5R)-5-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.913 g, 1.80 mmol, 92% yield) as a mixture of isomers that was used in the next step without separation. LC/MS (ESI+) m/z=508 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]([O:12]C)=[O:11])=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]([OH:12])=[O:11])=[N:3]1
Reactant: COC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1cc(C(CC2CCOCC2)C(=O)O)nn1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate (2.52 g), 2N aqueous sodium hydroxide solution (6.3 ml), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 50° C. for 3 hr. To the reaction mixture was added 1N hydrochloric acid (13 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.47 g, quantitatively) as a colorless oil from the fraction eluted with ethyl acetate. MS: 285 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=[C:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:35][C:33]([CH3:36])([O:32][C:31]([NH:30][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH:3]([O:2][CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[N:22][C:23]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:29])=[O:37])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCCCN)NC(=O)OC(C)(C)C
Reactant: COC(=O)C(OC)C(=O)[O-]
Product: COC(=O)C(OC)C(=O)NCCCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 91.9 %

Procedure:
By following a procedure analogous to the method of Preparation 18, using 3.5 g (23.65.10-3 mol) of methyl 2-methoxypropanedioate and 7 g (18.1.10-3 mol) of bis(1,1-dimethylethyl) [[(8-aminooctyl)imino]methylene]biscarbamate as the starting materials, 8.6 g (yield=95%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].[CH:19](N1CCCCC1)=[O:20].Cl>CCCCCC.O1CCCC1>[CH:16]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:13]([CH3:15])[CH3:14])[C:7]=1[CH:19]=[O:20])([CH3:18])[CH3:17]
Reactant: O=CN1CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
6.8 ml of a 1.6M solution of butyllithium in hexane was added dropwise at -78° C. while stirring to a solution of 2.6 g of 2-bromo-1,3-diisopropylbenzene in 16 ml of tetrahydrofuran. The mixture was stirred at the same temperature for 30 minutes and thereafter treated with a solution of 1.3 g of N-formylpiperdine in 1.5 ml of tetrahydrofuran. Thereafter, the mixture was left to warm to room temperature over a period of 6 hours. The mixture was cooled to 0° C. and treated with 12 ml of 3N hydrochloric acid. The aqueous solution was extracted four times with diethyl ether and the combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel with dichloromethane as the eluent and yielded 1.07 g of 2,6-diisopropylbenzaldehyde as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>C(OCC)(=O)C.CO>[C:24]([NH:26][C:27]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)#[N:25]
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=597 ([M+H]+ 1), 214 (100); IR (KBr): 2162 cm-1 (C≡N).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([C:5]1([OH:12])[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2)[CH:14]=[CH2:13]
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: C=CCBr
Product: C=CCC1(O)C2CC3CC1CC(O)(C3)C2

Procedure:
The title compound is prepared from 5-hydroxy-adamantan-2-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=226 [M+NH4]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=3[O:38][CH3:39])[CH2:37][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(Cl)ccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-2-methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.02 (s, 1H), 6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s, 3H), 3.60 (m, 4H), 3.03 (m, 2H), 2.95 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=451.1, found=451.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].N1C=CN=C1>>[Br:1][CH2:2][CH2:3][CH2:4][O:5][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCBr
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), tert.-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, extracted with diethylether, the organic layer dried over MgSO4, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93%). 1H NMR (300 MHz, CDCl3) 3.73 (t; 3J=5.7 Hz; 2H; CH2O); 3.51 (t; 3J=6.4 Hz; 2H; CH2Br); 2.02 (q; 3J=5.7 Hz; 3J=6.4 Hz; 2H; CH2CH2CH2); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2×CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=2[F:9])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(O)c(F)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated to 70° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, =6.0 Hz, 1H), 7.05 (s, 1H), 6.95 (m, 1H), 6.92 (m, 1H), 6.62 (m, 1H), 5.60 (s, 2H); MS (ESI) m/z: 257.1 [M+H]+.