Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[CH3:12])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)OC(C)(C)C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Cool a solution of 3-((S)-1-tert-butoxycarbonyl-ethoxy)-benzoic acid methyl ester (0.80 g, 2.85 mmol) in methylene chloride (10 mL) to 0° C. and add trifluoroacetic acid (0.98 g 8.60 mmol). Warm the mixture to room temperature and stir overnight. Dilute the mixture with water and extract with methylene chloride. Concentrate the combined organic phase under reduced pressure and purify the residue by trituration with hexanes and methylene chloride to provide 0.40 g of 3-((S)-1-carboxy-ethoxy)-benzoic acid methyl ester as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:47][C:43]3[NH:42][CH:46]=[CH:45][N:44]=3)[CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.8 %

Procedure:
The compound (242 mg) obtained in Example 87-4 and 2-imidazole carboxaldehyde (63.4 mg) were dissolved in anhydrous methanol (7.2 ml). Then, the solution was added with sodium cyanoborohydride (96.9 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. Subsequently, the extract was washed with saturated saline solution and the residue was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (282 mg) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:14](=O)[CH3:15])C.[CH3:18][NH2:19]>CO.[O-]S([O-])(=O)=O.[Mg+2].ClCCl>[CH3:18][N:19]1[C:14](=[CH2:15])[C:6]2[C:5](=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: C=C1c2cccc([N+](=O)[O-])c2C(=O)N1C
Reaction time: 0.25 h

Procedure:
Ethyl-2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture of MeOH (70 mL) and MgSO4. Methylamine (2 molar in THF, 28.13 mL) is added dropwise and the solution is stirred for 15 min at this temperature. Then it is preheated to 70° C. for 18 h. The solvent is eliminated in vacuo, the residue is taken up in dichloromethane (100 mL), washed with sodium chloride solution (10%) dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. For purification it is recrystallised from toluene (250 mL).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1cccc(CNC(=O)c2c(N)ncnc2Cl)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(CNC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Yield: 59.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (92 mg, 0.34 mmol), 4-amino-6-chloro-N-(3-methoxybenzyl)pyrimidine-5-carboxamide (100 mg, 0.34 mmol), DIEA (360 μl, 2.07 mmol) and cesium fluoride (157 mg, 1.03 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated to reflux for 48 h. The solvent was evaporated under reduced pressure and the crude was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 40%, dichloromethane-ethyl acetate) to obtain 106 mg (59% yield) of the title compound.
Reaction SMILES: ClC1C=C(OC2C=CC=CC2(N)F)N=CN=1.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:27][C:26]=2[F:45])[CH:19]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:59])[CH2:55][C:56]([OH:58])=O)=[CH:49][CH:48]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:56](=[O:58])[CH2:55][C:54]([NH:53][C:50]3[CH:49]=[CH:48][C:47]([F:46])=[CH:52][CH:51]=3)=[O:59])=[CH:27][C:26]=2[F:45])[CH:19]=1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1(F)C=CC=CC1Oc1cc(Cl)ncn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine (29 mg, 0.12 mmol, Compound B of Example 2), 3-(4-fluorophenylamino)-3-oxopropanoic acid (26 mg, 0.13 mmol, Compound B of Example 1) in DMF (1.5 mL) was treated with DIPEA (24 μl, 0.14 mmol) and TBTU (46 mg, 0.14 mmol). The reaction mixture was stirred at RT overnight, diluted with EtOAc (25 mL), and the organic phase was washed with brine (3×20 mL), dried (MgSO4) and concentrated. The product was purified by flash chromatography using 1-3% MeOH in CH2Cl2 as the eluent to give the title compound as a white solid (35 mg, 78%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.25 (s, 1H), 8.65 (s, 1H), 7.78 (d, 1H, J=12.1 Hz), 7.63-7.57 (m, 3H), 7.40-7.34 (m, 2H), 7.16 (t, 2H, J=8.8 Hz), 3.48 (s, 2H); MS (ESI+) m/z 419.21 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1>>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)[OH:8])[CH3:23]
Reactant: CCOC(CC(C(=O)c1ccccc1)c1ccccc1)OCC
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Product: CCOC(CC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)OCC

Procedure:
The compound is prepared from the evaporation residue obtained in Example 26 and 42.9 g of 1-bromo-4-(2-morpholinoethoxy)benzene according to the procedure described in Example 1(c).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4.09 g of azetidine are dissolved in a two-phase solvent system of 200 ml of dichloromethane and 130 ml of an aqueous potassium carbonate solution (strength 4.0 M). Subsequently, a solution of 15.25 g of commercially available 4-bromo-benzenesulfonyl chloride in 70 ml of dichloromethane is slowly added to the reaction mixture. Thereafter, the mixture is vigorously stirred for 17 hours at room temperature. For extraction, 200 ml of dichloromethane and 100 ml of water are added. The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo to yield 15.22 g of the title compound as a colorless, amorphous solid of m.p. 145° C. ESI-MS: 276.1/278.0 (MH+, 100%:95%). TLC: Rf=0.59 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[C:15]1([S:21]([CH2:24][CH2:25]I)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[C:28](=[S:30])=[S:29]>C1COCC1.C(OCC)(=O)C.O>[CH2:13]([O:12][C:10]([C:9]1[N:7]=[CH:8][S:29][C:28]=1[S:30][CH2:25][CH2:24][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[O:11])[CH3:14]
Reactant: S=C=S
Reactant: O=S(=O)(CCI)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncsc1SCCS(=O)(=O)c1ccccc1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
To a solution of potassium tert-butoxide (496 mg, 4.4 mmol) in 10 ml of THF was added a solution of ethyl isocyanoacetate (0.48 ml, 4.4 mmol) in 5 ml of THF at -40° C. and the reaction mixture was continued to stir for 10 min. After the reaction was cooled down to -60° C., a solution carbon disulfide in 5 ml of THF was added. The resulting mixture was allowed to warm up to 0° C. and 2-iodoethyl phenyl sulfone (4.4 mmol) was added. The mixture was then stirred at refluxed condition for 5 hours. After it was cooled down to room temperature, water and ethyl acetate were added. The aqueous layer was adjusted to acidic condition with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude residue was purified by chromatography to give the title compound (890 mg, 56%). 1H NMR (CDCl3) δ 1.40 (t, 3H, J=7), 3.3-3.5 (m, 4H), 4.40 (q, 2H, J=7), 7.6 (t, 2H, J=8), 7.70 (t, 1H, J=8), 7.93 (d, 2H, J=8), and 8.64 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].C[O:16][C:17]([C:19]1[N:20]=[CH:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:23]=2)=O.C[O-].[Na+].C[C:41]([N:43](C)C)=O>>[C:41]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:2][CH2:3][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:5]([OH:7])=[O:6])=[O:16])[N:20]=1)#[N:43]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(=O)N(C)C
Reactant: NCC(C(=O)O)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(C(=O)O)c2ccc(F)cc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 150 °C

Procedure:
A mixture of HCl salt of 3-amino-2-(4-fluoro-phenyl)-propionic acid (82 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg) and NaOMe (41 mg) in DMA (1 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column column-purified to give desired product (19 mg). LC-MS ESI+: 472 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[O:25])[O:16][C:15]2=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19][NH+:20]([O-:43])[C:21](=[O:33])[CH2:22][CH2:23][C:24]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[O:25])[O:16][C:15]2=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(CCC(=O)c1ccc(Cl)cc1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CCC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a cooled solution (0-5° C.) of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-4-(4-chlorophenyl)-4-oxobutanamide, (1.150 gm, 0.0023 moles) in dichloromethane (150 ml) was added 60% m-CPBA (0.725 gm, 0.0040 moles) and the resulting solution stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue chromatographed over silica gel (100-200 mesh, 40 g). The column was eluted with ethyl acetate (200 ml) followed by a mixture of chloroform:methanol (4:1, 600 ml). Concentration of the combined fractions gave the title N-oxide (0.950 g, 80%) as a white solid.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:30]3[C:29](=[O:31])[N:28]([CH2:32][CH3:33])[CH2:27][C:26]([CH3:35])([CH3:34])[O:25][C:24]=3[N:23]=[C:22]([N:36]3[CH2:42][CH:41]4[O:43][CH:38]([CH2:39][CH2:40]4)[CH2:37]3)[N:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[F:51][C:52]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:53]=1[NH2:54]>C(Cl)Cl>[F:51][C:52]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:53]=1[NH:54][C:5]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:30]3[C:29](=[O:31])[N:28]([CH2:32][CH3:33])[CH2:27][C:26]([CH3:35])([CH3:34])[O:25][C:24]=3[N:23]=[C:22]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:21]=2)=[CH:18][CH:19]=1)=[O:11]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)c2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of 350.35 mg (1.18 mmol) of triphosgene in 6 ml of DCM is added in a single portion a suspension of 500 mg (1.18 mmol) of 4-(4-aminophenyl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one and 987.33 μl (7.08 mmol) of triethylamine in 6 ml of DCM. The resulting mixture is stirred for 20 minutes at room temperature. 607.12 μl (5.90 mmol) of 2,4-difluoroaniline are added. The precipitate obtained is filtered off, rinsed twice with MeOH and dried under reduced pressure to give 575 mg of 1-(2,4-difluorophenyl)-3-{4-[6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}urea.
Reaction SMILES: [NH3:1].[H][H].[CH3:4][C:5]1([CH3:14])[CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]1=O>O1CCCC1.[Pt]>[NH2:1][CH:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:12][C:5]1([CH3:14])[CH3:4]
Reactant: [H][H]
Reactant: N
Reactant: CC1(C)Cc2sccc2C1=O
Agent: [Pt]
Solvent: C1CCOC1
Product: CC1(C)Cc2sccc2C1N

Procedure:
In a pressurised reactor, 7.0 g of 5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-one are dissolved in a mixture of 100 ml of tetrahydrofuran and 27 g of liquid ammonia. 1.4 g of a moist sulfided 5% platinum/carbon catalyst are added to this mixture. The reactor is filled with hydrogen gas up to a pressure of 100 bar and heated to from +175° C. to +180° C. When the hydrogenation has ceased, the catalyst is filtered off, the filtrate is concentrated and the residue distilled in a bulb tube, yielding 5.4 g of 4-amino-5,6-dihydro-5,5-dimethyl-4H-cyclopenta-[b]thiophene having a melting point of +80° C. at 0.08 mbar.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-fluoro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[CH3:14][O-:15].[Na+].CO>C(#N)C>[CH3:14][O:15][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)n2nc(N)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
5-Chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4; 100 mg, 0.50 mmol) was suspended in acetonitrile (5 mL) at room temperature and treated with 25% sodium methoxide in methanol (200 mg, 2 eq). The resulting slurry was stirred at room temperature for 1.5 hours and then filtered. The solids were washed with water and dried to afford the title compound as a chalk-colored solid (87 mg, 88%) that was identical in HPLC retention to authentic 5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5): mp 185-186° C.; 1H NMR (DMSO-d6) δ 7.48 (s, 1H), 6.38 (br s, 2H), 4.04 (s, 3H), 3.88 (s, 3H); EIMS m/z 195.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:37][C:38]([NH2:42])=[N:39]2)=[CH:34][CH:33]=1>>[NH2:42][C:38]1[CH:37]=[C:36]([N:43]2[CH2:48][CH2:47][N:46]([C:10]([NH:8][CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:11])[CH2:45][CH2:44]2)[C:35]2[C:40](=[CH:41][C:32]([Cl:31])=[CH:33][CH:34]=2)[N:39]=1
Reactant: NC1CCCCCC1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)NC3CCCCCC3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, cycloheptylamine, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 402 (M++1). 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.62 (s, 1H), 7.15 (d, 1H), 6.15 (s, 1H), 4.78 (s, 2H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 4H), 3.10 (m, 4H), 1.95 (m, 2H) 1.40–1.65 (m, 10H).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[C:3]1[C:16]([F:17])=[C:15]([F:18])[C:6]([CH2:7][O:8]C2CCCCO2)=[C:5]([F:19])[C:4]=1[F:20].C(OCC)(=O)C.C(OCC)C>CO.Cl>[CH3:1][Si:2]([CH3:22])([CH3:21])[C:3]1[C:16]([F:17])=[C:15]([F:18])[C:6]([CH2:7][OH:8])=[C:5]([F:19])[C:4]=1[F:20]
Reactant: C[Si](C)(C)c1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: C[Si](C)(C)c1c(F)c(F)c(CO)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude tetrahydropyranyl ether prepared in Stage (i) was dissolved in methanol (20 cm3), and to the stirred solution was added concentrated hydrochloric acid (3 drops). After stirring for 16 hours at the ambient temperature (ca. 25° C.), the reaction mixture was poured into ethyl acetate, washed with water and brine, and dried. Evaporation of the solvent under reduced pressure gave a yellow oil which was subjected to column chromatography on silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% gradually increased to 40% by volume) as eluent to give 4-trimethylsilyl-2,3,5,6-tetrafluorobenzyl alcohol (0.79 g).
Reaction SMILES: [OH:1][CH:2]([CH:7]=[CH2:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13](S(C)(=O)=O)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CO>C(C(C)=O)C.C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([O:1][C:2](=[CH:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:12]=1
Reactant: C=CC(O)C(=O)OC
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC=C(Oc1nc(OC)cc(OC)n1)C(=O)OC
Yield: 78.1 %

Procedure:
A mixture of methyl 2-hydroxybut-3-enoate (0.80g, 6.9mmol), 4,6-dimethoxy-2-methanesulphonylpyrimidine (1.50g, 6.9mmol) and potassium carbonate (1.04g, 7.6mmol) in methyl ethyl ketone (100ml) was refluxed for 12 hours. The reaction mixture was filtered and the filtrate evaporated in vacuo. Flash column chromatography (silica, 1.5% methanol in chloroform) of the residue gave the title compound (1.37g, 78% yield by weight).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:18].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:29])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Yield: 82.9 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (5.09 g; 19 mmole), methylene chloride (50 ml) and 4-methoxyphenyl isocyanate (2.83 g; 19 mmole). Recrystallization from methanol/methylene chloride provided the title compound (3.57 g; 45% yield) as orange-white crystals, m.p. 237°-238° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:13][C:14]([Cl:19])=[N:15][C:16]=1[CH2:17][CH3:18]>CN(C)C=O>[ClH:19].[CH3:10][C:11]1[C:12]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: Cc1cc(F)ccc1N
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Product: CCc1nc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 53.5 %

Procedure:
After 4-fluoro-2-methylaniline(0.5 ml, 3.6 mmol) was added to a mixture solution of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.7 g, 2.4 mmol) and dimethylformamide(5 ml), 0.53 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.