Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.O.[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[F:18])([O-])=O.[H][H]>[Pt]=O.[Fe].C(O)C>[F:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[NH2:6]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 89.3 %

Procedure:
To a mixture of 40 ml of glacial acetic acid, 5 ml of water, and 8.32 g (0.0447 mole) of 2,4-dinitrofluorobenzene were added 0.10 g (0.00044 mole) of platinum oxide and 0.50 g (0.0090 mole) of powdered iron. Subsequently, 160 ml of ethanol was added to this mixture, and the entire reaction mixture was placed in a 500 ml Parr hydrogenation reactor. The reaction was stopped after 144 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was evaporated under reduced pressure, and the residue was passed through a pad of silica gel, eluting with methylene chloride. The solvent was evaporated from the eluate under reduced pressure, producing 6.23 g of crude 2-fluoro-5-nitroaniline, m.p. 90°-92° C. Analysis of the nmr spectrum of this material showed it to be at least 85% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2o1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.34 (bs, 2H), 8.10-8.07 (m, 2H), 7.78 (t, 1H, J=2.7 Hz), 7.66-7.53 (m, 4H), 7.12 (d, 1H, J=9.3 Hz), 3.87 (s, 3H), 3.85 (s, 3H); LCMS: purity: 99%; MS (m/e): 443 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=425.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.[S:28]([CH2:38][N+:39]#[C-:40])([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[C-]#N.[Na+].C1COCC1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]3[O:26][CH:40]=[N:39][CH:38]3[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2N=COC2c2cc3c(ncn3CCS(C)(=O)=O)c(F)c2Nc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.050 g, 0.107 mmol) is suspended in EtOH (0.5 mL) under N2 and tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added followed by catalytic NaCN (˜1 mg). After 2 hours, 2 mL THF is added to assist with solubility. After stirring for 16 hours at room temperature, a second equivalent of tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added. After 8 hours, the reaction mixture is concentrated under reduced pressure and used as is in the next reaction: LC/MS ESI (+) m/z 671, 669 (M+Br pattern) detected.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.N1([CH2:32][OH:33])C2C=CC=CC=2N=N1.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH2:32][OH:33])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: OCn1nnc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1cccc(Br)n1)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(6-bromopyridin-2-yl)methyl]morpholine (Example 2, Step 1) (500 mg, 1.945 mmol) in tetrahydrofuran at −78° C. was added a solution of LDA (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 3.24 ml, 5.83 mmol) over 15 minutes. The resulting red solution was stirred at −78° C. for one hour and then a solution of 1H-1,2,3-benzotriazol-1-ylmethanol (580 mg, 3.89 mmol) in 14 mL tetrahydrofuran was added. After 2.5 hours, a saturated aqueous ammonium chloride solution (5 mL) was added and the reaction mixture was allowed to warm to room temperature. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried with sodium sulfate, filtered, and concentrated. The resulting oil was dissolved in tetrahydrofuran (15 mL) and diethyl ether (30 mL), and this solution was washed with aqueous sodium hydroxide (5 M, 15 mL), brine (15 mL), saturated aqueous sodium carbonate (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting material was purified by silica gel chromatography (0.2-10% methanol/ethyl acetate) which afforded the title compound. LRMS (APCI) calc'd for C11H15BrN2O2 [M+H]+: 287, Found: 287.
Reaction SMILES: C[O-].[Na+:3].CO.[CH3:6][C:7]1[CH:8]=[N:9][C:10]([CH2:16][S+:17]([O-:29])[C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14]>C(C(C)=O)C(C)C>[CH3:6][C:7]1[CH:8]=[N:9][C:10]([CH2:16][S+:17]([O-:29])[C:18]2[N-:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14].[Na+:3]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 8 h

Procedure:
30% sodium methoxide in methanol (4.7 mL, 25.3 mmol) was added dropwise at room temperature to a solution of esomeprazole (8.5 g, 24.6 mmol; 2.2% sulfone) in methyl isobutyl ketone (60 mL). The resulting slurry was stirred overnight. The solid was collected by filtration, rinsed with methyl isobutyl ketone (2×10 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 6.3 g (70%). Sulfone content: 0.33%.
Reaction SMILES: N#N.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[O-:15]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].O>CS(C)=O>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:3]=[O:15])=[CH:5][NH:6]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1c[nH]c(=O)c2ccccc12
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c[nH]c(=O)c2ccccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In an apparatus equipped with a mechanical stirrer (N2 gas), 135 g (848 mmol) of 4-methyl-2H-isoquinolin-1-one in 2.0 l of DMSO are heated to 50° C. After removing the oil bath, 108 g (447 mmol) of Cu(NO3)2.3H2O are added. Then, whilst cooling, 432 g (1.81 mol) of Na2S2O8 are added in portions, and finally 162 g (1.91 mol) of NaNO3. After stirring for 2 h at 50° C., the mixture is cooled to 10° C., mixed with 4 l of water and stirred for 10 min. 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde can be filtered from the light green suspension and washed with water; m.p. 222-223° C. The filtrate is extracted 3 more times with EtOAc. The EtOAc phases are washed with water (3×) and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography of the residue (SiO2, methylene chloride/toluene/acetone 2:2:1) yields further 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:37])=[C:32](B(O)O)[CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:37])=[C:32]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:33]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(Cl)c(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(=O)c1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 7 %

Procedure:
5′-Acetyl-2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid was prepared in 7% yield (for two steps) from 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6) and 5-acetyl-2-chlorophenylboronic acid (available from Combi-Blocks Inc.) using General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.30-8.38 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.98 (dd, J=8.3, 2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[CH:10][C:9]2=[O:24])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][C:33](OC(C)=O)=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]([O:24][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:10]=1)(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12

Procedure:
A solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinolin-4(1H)-one 37 (707 mg, 2.11 mmol), triethylamine (1 mL), and Ac2O (0.7 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 16 h. Sat. aq NaHCO3 (10 mL) was added, and the reaction extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated to give 38.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
The compound obtained in Example 157 (1.0 g, 3.37 mmol) and sodium azide (1.9 g, 33.7 mmol) were suspended in dimethylformamide (20 ml). The suspension was stirred at 100° C. for 2 hours, followed by cooling. The reaction mixture was combined with water, and the precipitated crystals were collected by filtration and washed with water. 0.733 g of the title compound was obtained as pale brown crystals (89.4%, mp.: 194° C. (dec.)).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][CH:8]2[CH:9]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OC1CCC=CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 7.5 g of 6-acetoxy-2-cyclohexenone and 16.83 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 150 cm3 of dichloromethane are added, at a temperature of 10° C., 12 drops of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 7 hours, then 2 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (97.5-2.5 by volume) and collecting 60 cm3 fractions. Fractions 25 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.25 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:9]=[CH:8][C:7]=1[C:18]([OH:20])=O.[CH2:21]([O:23][C:24]([C:26]1([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][N:37]=2)[CH2:35][CH2:34][C:29]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:28][CH2:27]1)=[O:25])[CH3:22].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:18]([C:7]3[CH:8]=[N:9][N:10]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)[C:6]=3[CH3:5])=[O:20])=[CH:38][N:37]=2)[CH2:35][CH2:34][C:29]2([O:30][CH2:31][CH2:32][O:33]2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Reactant: CCOC(=O)C1(c2ccc(N)cn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 81.6 %

Procedure:
Thionyl chloride (185 mg) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 5-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carboxylic acid (210 mg) described in Reference Example 4 in toluene (3.0 ml) and stirred at 80° C. for an hour. The solvent and excess amounts of thionyl chloride were evaporated. The resulting reaction mixture of a pyridine solution (1.5 ml) was added to a solution of 8-(5-aminopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (312 mg) in pyridine (1.8 ml) and stirred at 40° C. for an hour. After the reaction, the reaction solution was cooled to room temperature, adjusted to pH 4-5 by the addition of 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid aqueous solution, dried over anhydrous sodium sulfate and concentrated to give the titled compound (400 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[C:37]([C:40]1[CH:49]=[CH:48][C:43]([O:44][CH2:45][CH2:46][OH:47])=[CH:42][CH:41]=1)(=[O:39])[CH3:38].[H-].[Na+].Cl>CC(N(C)C)=O>[C:37]([C:40]1[CH:49]=[CH:48][C:43]([O:44][CH2:45][CH2:46][O:47][C:2]2[N:7]=[C:6]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:5]=[C:4]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:3]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:42][CH:41]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(OCCO)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of N-{6-chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (1.05 g) and 2-(4-acetylphenoxy)ethanol (728 mg) in dimethylacetamide (12 ml) is added sodium hydride (240 mg) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/acetonitrile=2:1), and recrystallized from ethyl acetate/n-hexane to give N-[6-{2-(4-acetylphenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (482 mg) as crystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:24][CH:25]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(N2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 100 mg of 1-iodo-4-methylbenzene. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 23 mg of (8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: COCCN
Solvent: O
Product: C=CCNc1nc(NCCOC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 864 mg (11.50 mmol) of 2-methoxyethylamine was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 214 mg (yield: 74.7%) of the title compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:19][NH2:20]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:20][CH3:19])#[N:2]
Reactant: CN
Reactant: CSC(=NCCSCc1ncccc1O)NC#N
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1ncccc1O
Reaction time: 2.5 h

Procedure:
A mixture of N-cyano-N'-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]-S-methylisothiourea (4.8 g) and excess methylamine in ethanol was allowed to stand at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was chromatographed on a column of silica gel with ethyl acetate containing 15% isopropyl alcohol as eluant and recrystallisation from isopropyl alcohol-petroleum ether gave N-cyano-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-methylguanidine (2.4 g), m.p. 146°-148°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH2:60]>CN(C=O)C>[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH:60][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: COCCCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 3-methoxypropylamine (36 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)] afforded the title compound (101 mg, 82%) which was obtained as a white solid. MS: m/e=382.5 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[O:22])[CH2:17]2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 228, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.43 (d, 2H), 7.30 (d, 2H), 7.14 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 5.28 (d, 1H), 5.14 (d, 1H), 4.78 (d, 1H), 3.68 (dd, 1H), 3.26 (t, 1H), 3.04-2.91 (m, 1H), 2.88 (dd, 1H), 2.71-2.59 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C28H25ClFN5O3 found 534.2 (MH+).