Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9]4=[C:10]([C:19](=[O:23])[NH:20][C:21](=[O:22])[N:8]4[C:7]=2[CH:6]=1)[CH:11]=[CH:12][CH:13]=3.Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[OH:29][CH2:28][CH2:27][N:20]1[C:19](=[O:23])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[S:15][C:16]4[CH:17]=[CH:18][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][C:7]=4[N:8]([C:9]=23)[C:21]1=[O:22]
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3
Reaction time: 1 h

Procedure:
57% Sodium hydride in mineral oil (8.4 g., 0.200 mol.) was added to a stirred solution of 28.0 g (0.0834 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine -1,3(2H)-dione in 220 ml. of dry dimethylformamide. The mixture was stirred for 1 hour at 25°, then 54.0 g. (0.432 mol.) of 2-bromoethanol was added. The resulting mixture was stirred for 4.5 hours at 25°, then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel with chloroform and 90% chloroform-methanol as eluants to give the title compound, m.p. 90°-93° (methanol).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21][CH2:22][CH2:23][CH2:24]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:24][CH2:23][CH2:22][S:21][CH3:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (2.4 g) synthesized in Example A82(3) was dissolved in tetrahydrofuran (50 mL), and 3-(methylthio)propanol (1.0 mL), tributylphosphine (4.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (4.7 g) were added to the solution under ice-cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hr. Hexane (50 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.1 g, 95%) as a pale-yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[Mg].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C@@H:20]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@:21]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH2:4])([OH:25])[C@@H:20]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C=C(CBr)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A Grignard reagent was prepared from 3-bromo-2-phenylprop-1-ene (Description 93, 150 mg, 0.76 mmol) and magnesium metal (24 mg, 1 mmol) in THF (4 mL). The solution was cooled to -30° C. and a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1, 161 mg, 0.59 mmol) in THF (1 mL) was added. The mixture was stirred at ambient temperature for 16 h., then saturated aqueous ammonium chloride (10 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic fractions were dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (85:15) to give the title compound as an oil (52 mg). 1H NMR (360 MHz, CDCl3) δ7.44-7.20 (10 H, m), 5.43 (1 H, s), 5.25 (1 H, s), 5.12 (1 H, s), 4.06-4.03 (1 H, m), 3.34-3.30 (1 H, m), 3.08-2.94 (3 H, m), 2.47-2.43 (1 H, m), 1.93-1.86 (2 H, m), 1.70-1.64 (2 H, m), and 1.38 (9 H, s). m/z (ES+) 394 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si](CC)(CC)CC)[N:7]=[C:6]1[C:19](=[O:21])[CH3:20])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:6]1[C:19](=[O:21])[CH3:20])[CH3:2]
Reactant: CCOCn1cc(CO[Si](CC)(CC)CC)nc1C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOCn1cc(CO)nc1C(C)=O
Reaction time: 1 h

Procedure:
The compound (520 mg) obtained in (4) was dissolved in THF (10 mL), followed by addition of tetrabutylammonium fluoride (TBAF, 1.0 M THF solution, 3.32 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=25%→100%) using amino column (product name: SNAP Cartridge KP-NH 55 g, manufactured by Biotage, Ltd.) to afford the title compound (288 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[OH:33])=[CH:23][CH:22]=1
Reactant: O=C1CCCC1Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCC[C@@H]4O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(2-oxo-cyclopent-1-yloxy)-benzyl]-benzene (0.10 g) in dry tetrahydrofuran (3 mL) chilled to −78° C. is added L-selelctride (1 mol/l in tetrahydrofuran, 0.33 mL). The resulting solution is stirred at −78° C. for 2 h, then diluted with dichloromethane and quenched with aqueous hydrochloric acid (1 mol/l). The organic layer is separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are dried (Na2SO4), the solvent is removed in vacuo and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:24][CH3:25])[CH2:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:17][C:18]([CH:21]=[O:22])=[C:19]([CH3:20])[C:12]=2[C:11]1=[O:23])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([NH:7][CH2:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:17][C:18]([CH:21]=[O:22])=[C:19]([CH3:20])[C:12]=2[C:11]1=[O:23])[CH3:25]
Reactant: CCN(CCN1CCCc2[nH]c(C=O)c(C)c2C1=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCCN1CCCc2[nH]c(C=O)c(C)c2C1=O

Procedure:
Ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-5-yl)-ethyl]-carbamic acid tert-butyl ester 62f (43 mg, 0.118 mmol) was dissolved in 10 ml of dichloromethane under stirring, and added with trifluoroacetic acid (272 μl, 3.55 mmol) to the solution and stirred for 15 minutes in an ice-water bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5-(2-ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 62j to be used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2ccccc21
Product: CCC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A stirred solution of 3,4-dinitrophenol (1 g, 5.4 mmol) in 30 ml of anhydrous dimethylformamide was treated with 4-fluorobenzyl chloride (0.86 g, 6.0 mmol) and potassium carbonate (1.13 g, 8.2 mmol). The reaction mixture was stirred at room temperature for 24 hours and then poured into 200 ml of ice-water and this mixture was stirred overnight. The solid was filtered and washed with water to give 1.2 g (76%) of tilted compound as a yellow solid after drying in vacuo. 1H NMR (300 MHz, CDCl3) δ: 8.04 (d, J=9.0 Hz, 1H), 7.40 (dd, J=5.4 and 8.7 Hz, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.18 (dd, J=2.7 and 9.0 Hz, 1H), 7.12 (t, J=8.7 Hz, 2H), 5.16 (s, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([N:2]2[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[OH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][N:32]5[CH2:33][CH2:34][C@H:30]([OH:29])[CH2:31]5)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2cc3cc(-c4c5c(nc6ccnn46)CCC5)ccc3o2)C1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 3-(S)-hydroxypyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give 1-{2-[5-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethyl}-pyrrol idin-3-(S)-ol.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[O:10][C:11]3[C:16]([C:17]4([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Br.[C:24](=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:24][N:20]1[CH2:19][CH2:18][C:17]2([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:3])[C:9]=3[O:10][C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Reactant: O=C([O-])O
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
1'-Methyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (1.0 g.) in a solution of 45% w/v hydrobromic acid in glacial acetic acid (10 ml.) is heated under reflux for 2 hours. The solution is basified with sodium bicarbonate, diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over MgSO4, and evaporated to dryness. The residue is recrystallised from toluene-petroleum ether (b.p. 60°-80° C.) to give 1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 171°-173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=[N:11]1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Then, 3.2 g of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 50 ml of DMF, to which 2.0 g of potassium carbonate was added at room temperature. Furthermore, 1.3 g of propargyl bromide was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with 100 m of water, and the precipitated crystals were collected by filtration and washed with hexane. The resulting crystals were recrystallized from isopropanol to give 3.4 g of 2-[2-fluoro-4-chloro-5-(2-propynyloxy)phenyl]-4-methyl-5-trifluoromethylpyridazin-3-one (hereinafter referred to as compound A) (m.p., 140.7° C.; decomposition).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:45](=[O:46])[CH2:44][C:39]1[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:38]=1
Reactant: COCCOc1ccccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCCOc1ccccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 303 mg of 2-(2-methoxyethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 223 mg of N-[2-(2-methoxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]=[C:7]=[O:8])=[O:4].[CH2:9]([O:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12]([NH:14][NH:15][C:7]([NH:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:8])=[O:13])[CH3:10]
Reactant: CCOC(=O)NN
Reactant: COC(=O)CN=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of 19.72 g (0.17 mol) of methoxycarbonylmethyl isocyanate in 70 ml of dry toluene was added dropwise at room temperature to a stirred solution of 18.00 g (0.17 mol) of ethoxycarbonylhydrazine in 400 ml of dry toluene. The mixture was stirred at room temperature overnight and filtered. The colourless solid was washed with toluene, dried and recrystallized from ethyl acetate to give 28.54 g (76%) of 1-ethoxycarbonyl-4-methoxycarbonylmethyl-semicarbazide of melting point 116°-121° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH:25]1([CH2:24][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:22])[F:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94–95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C=O)C>[CH:25]1([NH:28][C:7]2[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC1CC1
Yield: 95.1 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 27, 1.83 ml (0.026 mol) of cyclopropylamine in 30 ml of DMF were reacted at room temperature affording 4.95 g of dark oil which was purified by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent to give 3.87 g (74.4%) of product as a yellow oil, nD25 1.4708.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1.[F:15][C:16]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:15][C:16]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:17]=1[C:18]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1)=[O:19]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Mg]
Product: COc1cc(C(=O)c2cc(I)ccc2F)cc(OC)c1OC

Procedure:
First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 2-fluoro-5-iodobenzoyl chloride was added thereto to obtain a Compound 21 derivative [(2-fluoro-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone]. Using NaOMe, the fluoro group of thus obtained compound was substituted with a methoxy group to obtain (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone (320 mg, 0.75 mmol) was dissolved in tetrahydrofuran (50 ml), and 2-(tributylstannyl)thiazole (475 mg, 1.27 mmol) and Pd(PPh3)2Cl2 (26 mg, 0.04 mmol) were slowly added thereto at room temperature. The mixture was heat refluxed for 8 hours. After completion of the reaction, the reaction mixture was extracted with water and EtOAc. The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance was filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/2) to obtain Compound 583 (140 mg, 49%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[CH3:30][C:31](=[CH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:30][CH:31]([CH3:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]1
Reactant: C=C(C)Cc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(Cc1ccccc1)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (2-methylallyl)-benzene analogous to Example 51: (M−1)−=359. HPLC retention time=1.65 min (Method A).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.C[O-].[Na+].CS(O[CH2:15][CH:16]1[CH2:18][CH2:17]1)(=O)=O>CO>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:2]1
Reactant: Sc1nc[nH]n1
Reactant: CS(=O)(=O)OCC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CC2)n[nH]1
Temperature: 40 °C
Yield: 63.5 %

Procedure:
1,2,4-Triazole-3-thiol (20.2 g; 0.20 mol) and sodium methoxide (11.8 g; 0.22 mol) were dissolved in methanol (250 ml) and cyclopropylmethyl methanesulfonate (32.3 g; 0.215 mol) added. The mixture was refluxed for 25 min under dry nitrogen, allowed to cool to 40° C. and filtered. The solid was washed with ethyl acetate and the organic solutions combined and evaporated. The residue was dissolved in water (250 ml) and the solution extracted with ethyl acetate (2×250 ml). The extracts were combined, washed with saturated brine (200 ml), dried (Na2SO4), filtered and evaporated, giving cyclopropylmethyl 1,2,4-triazol-3-yl sulfide (19.7 g; 64%) as a pale yellow pasty solid. NMR - d(CDCl3 +CD3SOCD3 ; 90 MHz) 0.1-0.7 (4H, m), 0.9-1.4 (1H, m), 3.1 (2H, d, J=7 Hz), 8.1 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Temperature: 25 °C

Procedure:
To a solution of (1R,6S)-tert-butyl 8-(6-methylpyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (80 mg, 0.26 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 h the mixture was concentrated under reduced pressure. The resulting trifluoroacetic acid salt of the title compound (80 mg) was used without further purification. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.