Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1.[CH2:35]([OH:38])[CH2:36][OH:37]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:37][CH2:36][CH2:35][O:38][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2NS(=O)(=O)CCc2ccccc2)c1
Reactant: OCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: COc1cccc(Oc2c(NS(=O)(=O)CCc3ccccc3)nc(N3CCOCC3)nc2OCCO)c1
Temperature: 100 °C
Reaction time: 288 h

Procedure:
A suspension of 2-phenyl-ethanesulfonic acid [6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.27 g) in ethylene glycol (12 ml) was treated with K-tert.-butylate (2.82 g). The resulting solution was stirred at 100° C. for 12 d. The solution was cooled to rt, diluted with 10% aq. citric acid (150 ml) and extracted twice with EA (150 ml). The organic phase was washed with water (50 ml) and evaporated. The crude product was purified by chromatography on silica gel eluting with heptane:EA 1:1 to 1:2 to furnish 2phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.1 g) as a white solid. LC-MS: tR=4.66 min, [M+1]+=531.20, [M−1]−=529.14.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[C:15]([CH3:18])([O-])[CH3:16].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].[Cl-]>CCCCCC.O.CN(C)C=O>[CH2:16]([C:12]1([CH2:22][CH:21]=[CH2:20])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:18]
Reactant: C=CCCl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(CC=C)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
There were put 10 g of fluorene manufactured by Wako Pure Chemical Industries, Ltd., and 10.1 g of potassium tert-butoxide manufactured by Aldrich Chemical Company in a 200 mL round-bottom flask. To the resultant mixture, 120 mL of dry N,N-dimethylformamide manufactured by Wako Pure Chemical Industries, Ltd. were added. While stirring the mixture at 50° C. under a nitrogen atmosphere, 5.86 mL of allyl chloride manufactured by Kanto Chemical Co., Inc. were added dropwise thereto over two hours. The mixture was stirred for 8 hours at 50° C., and 10.1 g of potassium tert-butoxide manufactured by Aldrich Chemical Company were added thereto, and then, 5.86 mL of ally chloride manufactured by Kanto Chemical Co., Inc. were added dropwise thereto over two hours. The mixture was stirred at 50° C. overnight. The reaction mixture was added to 900 mL of water, and 300 mL of hexane were added to the resultant mixture. The resultant organic layer was extracted with ether three times. The extract was washed with water four times, and was further washed with dilute hydrochloric acid and water, respectively. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried mixture was subjected to evaporation to remove the solvents contained therein. The obtained liquid was distilled in vacuo, thereby obtaining 12.8 g of 9,9-diallylfluorene as a yellow and oily fraction at 90° C. under a pressure of 4 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.CI.[C:29]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:29])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (73 mg, 0.178 mmol) in DMF (1.5 mL), followed by the addition of MeI (40 mg, 0.282 mmol) and K2CO3 (49 mg, 0.355 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc (20 mL), washed with water, brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (44 mg, 58%) as an off-white solid. LCMS (ESMS): m/z 424.58, 426.51 (M++1).
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[OH:18][S:19]([O-:22])(=O)=O.[K+].[CH3:24]O>O>[CH3:24][S:19]([C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])(=[O:22])=[O:18]
Reactant: O=S(=O)([O-])O
Reactant: C=CCOC(=O)c1cc(SC)cc([N+](=O)[O-])c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: C=CCOC(=O)c1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Reaction time: 4 h
Yield: 59 %

Procedure:
Allyl 3-methylthio-5-nitrobenzoate (1.12 g, 4.4 mM) was dissolved in methanol (30 ml), and cooled to 2°. A solution of “potassium peroxymonopersulfate” (2KHSO5.KHSO4.K2SO4, 8.13 g, 13.2 mM) in water (25 ml) was added slowly, and stirring continued for 4 hours. The mixture was diluted with water (60 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, and dried over Na2SO4. Crude product was purified by chromatography on silica using a gradient of petrol/ethyl acetate (3:1 to 2:1) to give allyl 3-methylsulphonyl-5-nitrobenzoate (0.74 g, 59%). Nmr (DMSO-d6): δ 3.44 (s, 3H); 4.94 (dt, 2H); 5.32-5.53 (m, 2H); 6.01-6.25 (m, 1H); 8.78 (t, 1H); 8.89 (t, 1H); 8.91 (t, 1H).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[NH:33][C:19]3[CH:20]=[N:21][N:22](COCC[Si](C)(C)C)[C:23](=[O:24])[C:18]=3[C:17]=2[CH3:34])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2.[Cl:36]C1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1>>[ClH:36].[F:35][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[NH:33][C:19]3[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=3[C:17]=2[CH3:34])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Reactant: Cc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: Cc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)[nH]c2cn[nH]c(=O)c12
Product: Cl
Yield: 84.6 %

Procedure:
Reaction was carried out in the same manner as in Example 6-(c) except for using 163 mg (0.323 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-3-methyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 53-(b) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the solid obtained from the reaction suspension by filtration was washed with diisopropyl ether and dried under reduced pressure to obtain 112 mg of the title compound as a white solid. (Yield: 84.6%)
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]([N:8]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=[N:4]1.C(=O)(O)[O-].[K+]>ClCCl>[Br:1][C:6]1[CH:5]=[N:4][S:3][C:7]=1[N:8]([C:18]([O:20][CH2:21][C:22]([Cl:23])([Cl:24])[Cl:25])=[O:19])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1ccns1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1sncc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
Bromine (85 μL, 1.7 mmol) was added to a solution of methyl N-isothiazol-5-yl-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (150 mg, 0.370 mmol) in dichloromethane (2.0 mL) over powdered potassium bicarbonate (370 mg, 3.7 mmol) with rapid stirring at rt for 5 h. Excess bromine was quenched by the addition of 1 M aqueous NaHSO3 solution and the mixture was partitioned between water and ether. The layers were separated and the aqueous phase was extracted with additional ether (2×). The extracts were combined, dried (Na2SO4) and concentrated to give 172 mg of methyl N-(4-bromoisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate as a yellow oil.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CCC1.[CH2:12]1[O:24][C:23]2[CH:22]=[C:21]3[C:16]([C:17](=[O:40])[CH2:18][CH:19]([C:37]([OH:39])=[O:38])[CH:20]3[C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=[CH:15][C:14]=2[O:13]1.[BH4-].[Na+]>>[CH2:12]1[O:24][C:23]2[CH:22]=[C:21]3[C:16]([CH:17]([OH:40])[CH2:18][CH:19]([C:37]([OH:39])=[O:38])[CH:20]3[C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)=[CH:15][C:14]=2[O:13]1
Reactant: COc1cc(C2c3cc4c(cc3C(=O)CC2C(=O)O)OCO4)cc(OC)c1OC
Agent: O=C1CCCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(C2c3cc4c(cc3C(O)CC2C(=O)O)OCO4)cc(OC)c1OC

Procedure:
The tetralone VIb prepared in Example 2 was hydrolyzed according to the procedure described by W. S. Murphy and S. Wattanasin, J. C. S. Perkin I, 271 (1982), and the resulting 1,2,3,4-tetrahydro-6,7-methylenedioxy-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalene-2-carboxylic acid (VId) was treated with sodium borohydride according to the general procedure described by W. J. Gensler et al., J. Am. Chem. Soc., 82, 1714 (1960) to give the title compound as a crystalline solid; m.p. 191.5°-193° C. (reported m.p. 181.4°-182° C.).
Reaction SMILES: [CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]3[C:9]4[CH:26]=[C:25]([CH3:27])[S:24][C:10]=4[N:11]=[C:12]([C:14]4[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]3[C:9]4[CH:26]=[C:25]([CH3:27])[S:24][C:10]=4[N:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-c3ccc(C(=O)O)cc3)nc2s1
Yield: 70.5 %

Procedure:
A solution of 1.1 g of methyl 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoate, 30 ml of 2N NaOH and 30 ml of tetrahydrofuran is heated at 100° for 6 hours. After cooling and acidification of the solution with 20% HCl, the mixture is further worked up in the customary manner. 0.75 g of 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid is obtained, m.p. >250°.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:28][CH2:29][C:30]1[O:31][CH2:32][CH2:33][CH2:34][CH:35]=1>ClCCl>[C:8]([NH:28][CH2:29][C:30]1[O:31][CH2:32][CH2:33][CH2:34][CH:35]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC1=CCCCO1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=C(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Triethylamine (37.7 mL, 270 mmol) and trityl chloride (41.4 g, 149 mmol) were sequentially added to a solution of the crude 2-aminomethyl-5,6-dihydro-4H-pyran (about 193 mmol) in dichloromethane (500 mL), and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with dichloromethane (500 mL), washed with water (2×500 mL) and brine (500 mL), and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90) to give 22.2 g (four steps, 32%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].Cl.C(N)=[NH:22].CC[O-].[Na+]>O.CCOC(C)=O>[CH3:17][C:6]([C:5]1[CH:4]=[CH:3][N:2]=[CH:19][N:22]=1)([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccncn1
Temperature: 150 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.5 g, 1.9 mmol.), formamidine HCl (0.305 g, 3.8 mmol.), and NaOEt (1.29 g, 4.0 mmol) was heated in Smith synthesizer under microwave for 10 min at 150° C. The resultant mixture was diluted with H2O and EtOAc. The organic layer was dried, and the residue was used without further purification. MS: 244 (M+1) Calc'd for C13H14N3O2—244.10.
Reaction SMILES: [F:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:1][C:2]1([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(F)(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (0.150 g, 0.643 mmol) was dissolved in dichloromethane (1.8 mL) and cooled to 0° C. The solution was treated with triethylamine (0.134 ml, 0.964 mmol) followed by methanesulfonyl chloride (0.0547 ml, 0.707 mmol). The reaction was stirred at 0° C. for 2 hours then diluted with methylene chloride and quenched with saturated NH4Cl and separated. The organic layer was washed with saturated NH4Cl, 6% NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to provide the desired product (200 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
3-methyl pyrazole 1-carboxylic acid tert-butyl ester (4.0 g, 21.95 mmol) was dissolved in 73 mL of CCl4. N-bromosuccinimide (5.47 g, 30.73 mmol) and benzoyl peroxide (744 mg, 3.07 mmol) were added. This solution was warmed to reflux for 5.5 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution. The phases were separated, and the organic phase was extracted with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (SiO2, ISCO chromatography system, elution with 5 to 10% ethyl acetate in hexanes) provided 3-bromomethyl pyrazole 1-carboxylic acid tert-butyl ester (53-2) as a pale yellow oil (2.94 g, 51% yield). 1H NMR was consistent with desired product.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([S:34]([C:36]([F:39])([F:37])[F:38])=[O:35])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 108 mg (0.50 mmol) 4-(4-Imidazol-1-yl-butyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued overnight. After addition of 10 ml water the resulting precipitate was washed with water, 10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) to yield 167 mg colorless powder that was further purified by HPLC-MS to give 75 mg (29%) colorless powder.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:18]1[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][N:3]([CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:18]3[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:30])[N:23]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: CN(C)c1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Yield: 46.1 %

Procedure:
A solution of (2S)-2-(4-(dimethylamino)phenyl)morpholine hydrochloride (0.20 g, 0.64 mmol), 2-chloro-1-methyl-6-oxo-4-(3-fluoropyridin-4-yl)-1,6-dihydropyrimidine (0.12 g, 0.53 mmol), and triethylamine (0.19 g, 1.92 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was evaporated off in vacuo and the residue treated with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford 2-((2S)-2-(4-(dimethylamino)phenyl)morpholin-4-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.10 g, 50%) as yellow crystals
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:22]([CH:26]([CH3:28])C)[CH:23]([CH3:25])C.ClC(OCC(C)C)=O.N1CCCC1>C(Cl)Cl>[O:19]=[C:17]([N:22]1[CH2:23][CH2:25][CH2:28][CH2:26]1)[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
N-Boc-(S)-3-(pyridin-4-yl)alanine (0.500 g, 1.88 mmol) was dissolved in CH2Cl2 (15 mL) and DIEA (361 μL, 2.07 mmol) was added. The mixture was cooled to 0° C. and isobutyl chloroformate (270 μL, 2.07 mmol) was added. The mixture was stirred for 10 min and pyrrolidine (267 mg, 3.76 mmol) in CH2Cl2 (5 mL) was added. This mixture was stirred for 15 min at 4° C., 12 h at 25° C., washed successively with NaH2PO4, saturated sodium hydrogen carbonate, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue obtained was purify by column chromatography (SiO2) using a gradient of MeOH 0-10% [v/v] in EtOAc to give tert-butyl (R)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06172 (146 mg, 24% yield) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=2)=[CH:25][N:24]=1)([O-])=O>C(O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:23]3[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]4[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=4)=[CH:25][N:24]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: CCO
Product: Cn1ccc(Cc2cnc(NCCCOc3cc(CN4CCCCC4)ccn3)[nH]c2=O)cc1=O

Procedure:
3-[4-(Piperidinomethyl)pyrid-2-yloxy]propylamine (1.12 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.11 g) were refluxed in ethanol (20 ml) for 40 hours. The reaction mixture was evaporated under reduced pressure and the residue was subjected to medium pressure chromatography on silica gel (eluting with 5% methanol/95% chloroform) to afford the title compound. This was dissolved in isopropanol and treated with a solution of maleic acid (0.51 g) in isopropanol to afford material which was recrystallised from isopropanol/methanol to afford 2-[3-[4-(piperidinomethyl)pyrid-2-yloxy]propylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one dimaleate (0.51 g), m.p. 115°-116.5° C.
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:21])[C:16]#[C:17][CH:18]([CH3:20])[CH3:19])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:16]1[N:1]([C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])[N:2]=[N:3][C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:21])[CH3:13]
Reactant: CCOC(=O)C#CC(C)C
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)C)nnn1-c1c(Cl)cccc1Cl

Procedure:
A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and 4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) is heated to 120° C. overnight. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction is concentrated under reduced pressure and the residue is purified by flash chromatography, eluting with 5% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H), 1.46 (d, 6H), 1.15 (t, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[OH:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:1]([N:3]=[C:4]1[N:8]([CH2:12][C:11]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:10]=2[OH:9])[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: N#CN=C1NCCS1
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#CN=C1SCCN1Cc1cc([N+](=O)[O-])ccc1O
Yield: 61.1 %

Procedure:
3.82 g (30 mmoles) of 2-cyanimino-thiazolidine, 5.63 g (30 moles) of 2-hydroxy-5-nitro-benzyl chloride and 4.3 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 6 hours. The mixture is cooled and the precipitate is filtered off. 9.85 g of a crude material are obtained, which is then dissolved in 600 ml of hot water, the impurities are filtered off, the pH is adjusted to 3, the mixture is cooled, filtered and the precipitate is dried. 5.1 g of 2-cyanimino-3-(2-hydroxy-5-nitro-benzyl)-thiazolidine are obtained, melting at 253° to 255° C. after crystallization from pyridine.