Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>CC(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 115 °C

Procedure:
61.8 g (0.4 mol) of 2-methylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 92 g (0.4 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin were added dropwise over the course of two to three hours while stirring. The temperature was then increased in steps to 115° C. When the reaction was complete, 50 ml of acetone were added at room temperature. After crystallization, 103 g (77% of theory) of the above-mentioned compound of melting point 102° to 104° C. were obtained.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C@@H:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.C(Cl)Cl.CS(C)=O.CO.O>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C@@H:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])=[CH:5][N:4]=1
Reactant: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cn1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1cnc(O)nc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A 25 mL round-bottomed flask containing a suspension of (S)-2-methoxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)pyrimidine-5-carboxamide (Example 44) (0.094 g, 0.206 mmol) and sodium iodide, anhydrous (0.129 g, 0.861 mmol) in anhydrous MeCN (3.5 mL) was treated with chlorotrimethylsilane, redistilled (0.130 mL, 1.028 mmol). The resulting suspension was stirred at rt for 17.5 h. The reaction was concentrated on the rotary evaporator resulting in a gummy residue which was taken up in DCM (55 mL), H2O (25 mL), and 10% aqueous sodium thiosulfate (20 mL). The resulting mixture was transferred to a separatory funnel and after vigorous extraction the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the product. The product thus obtained was dissolved in DMSO/MeOH (1/1) (3.5 mL) and loaded on a Gibson HPLC system for purification using a MeCN/H2O/0.1% TFA gradient and Phenomenex™ Gemini Axia-5μ C-18 column (150×30 mm). The solvent was removed from the pure fractions in the Genevac™ and the resulting product was dissolved in MeOH (3 mL), concentrated in the Genevac™, and dried under high vacuum to yield (S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)pyrimidine-5-carboxamide as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (d, J=7.6 Hz, 1H), 8.93 (d, J=3.9 Hz, 1H), 8.80 (s, 2H), 8.27 (dd, J=8.0, 1.2 Hz, 1H), 7.75-7.70 (m, 2H), 7.64 (dd, J=7.9, 5.0 Hz, 1H), 7.56-7.50 (m, 2H), 6.76 (d, J=7.6 Hz, 1H). MS (ESI pos. ion) m/z: 443.1 (M+H).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: Cl
Product: COc1ccc(CCC(=O)N2CCC(c3nc(CCc4ccccc4)cs3)CC2)cc1OC

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 3-(3,4-dimethoxyphenyl)propanoic acid (231 mg). After chromatographic purification, this gives 3-(3,4-dimethoxyphenyl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}propan-1-one (139 mg).
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccnn1C
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (172 mg, 0.272 mmol) prepared in Example 90a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (3.0 mL), to yield the title compound (131 mg, 99%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1.[C:16]([CH:20]([C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[O:21][C:22]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35])([O:18][CH3:19])=[O:17]>CN(C=O)C>[C:16]([CH:20]([C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[O:21][C:22]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:25]([CH2:26][N:9]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[N:7]=[CH:8]2)=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35])([O:18][CH3:19])=[O:17]
Reactant: c1cc2[nH]cnc2cn1
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
Cesium carbonate (156 mg, 0.48 mmol) was added to imidazo[4,5-c]pyridine (28.6 mg, 0.24 mmol) in DMF (3 mL) at room temperature under nitrogen. After stirring for 15 min, a solution of 4-(1-carbomethoxy-1-(3,4-methylenedioxyphenyl)-methoxy)-3,5-dipropylbenzyl bromide (121 mg, 0.26 mmol) in DMF (3 mL) was added and the mixture stirred at 50° C. for 18 h. The mixture was poured onto ice/water and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The crude material was purified by flash column chromatography (0 to 5% methanol/methylene chloride) to afford the less polar isomer of the titled compound (19 mg).
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][CH3:52])/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][CH3:52])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 71.9 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (994 mg: 2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetic acid (662 mg: 2.2 mMol.) in dichloromethane (16 ml) is added at -30° C. N-methylmorpholine (0.72 ml: 6.6 mMol.) and phenyl dichlorophosphate (0.33 ml: 2.2 mMol.), and the mixture is stirred at the same temperature for 2.5 hours. The reaction mixture is quenched by adding 10% hydrochloric acid (5 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1 containing 0.5% of acetic acid) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetyl]amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.07 g). Yield: 72%.
Reaction SMILES: [NH+]1[CH:5]=[CH:4]NC=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C1(N)CCC1>>[CH:10]1([NH:6][C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:24])(=[O:25])[N:12]=2)[CH2:9][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: c1c[nH+]c[nH]1
Agent: NC1CCC1
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(NC1CCC1)N2

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with cyclobutylamine according to the general procedure Method D to give the title compound; m.p. 298-301° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([O:23][CH3:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:27]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:13]1[C:22]([O:23][CH3:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(OC)nc(OC)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nc(OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
The product of Example 30 (0.444 g, 1.16 mmol) was dissolved in DMF (4 mL) and cooled to 0° C. Benzyl bromide (0.186 mL, 1.6 mmol) followed by NaH (56 mg, 1.39 mmol, 60% dispersion in mineral oil) were added and the reaction was allowed to warm to room temperature. After 1 h, the reaction was diluted with water and extracted 4× Et2O. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo to provide 0.545 g (100%) of pure methyl 3-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-2,6-dimethoxy-isonicotinate as an oil. Electrospray Mass Spec: 472.9 (M+H)+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](OC(OCC)C)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH2:1]([O:8][CH2:9][C:10]1([CH3:14])[CH2:11][O:12][CH:15]([CH3:16])[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CO)COCc1ccccc1
Reactant: CCOC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC1OCC(C)(COCc2ccccc2)O1

Procedure:
3-Benzyloxy-2-methylpropane-1,2-diol (5.0g), 1,1-diethoxyethane (3.0g) and p-toluenesulphonic acid were heated at 110°-115° C with stirring until no more alcohol was evolved. The mixture was then heated at 140°-145° C for 15 minutes. After cooling, the mixture was dissolved in ether and the resulting solution was then washed with 5% potassium carbonate solution followed by water. The solution was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure to yield a liquid which on distillation gave the desired product having a b.p. 81°-82° C at 0.3 mm Hg.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C@:5]1([CH2:16][CH:17]=[O:18])[CH2:7][C@H:6]1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].S(=O)(=O)(O)O>O1CCCC1>[CH3:4][C@:5]1([CH2:16][CH:17]([OH:18])[CH3:1])[CH2:7][C@H:6]1[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CC(c1ccccc1)[C@@H]1C[C@]1(C)CC=O
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(O)C[C@@]1(C)C[C@H]1C(C)c1ccccc1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L tetrahydrofuran solution, 3.0 ml, 2.9 mmol) was placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer. In the dropping funnel, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetaldehyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol) and tetrahydrofuran (1 ml) were placed, and added dropwise in 5 minutes, with the temperature kept at 20° C. At the same temperature, the mixture was stirred for 30 minutes. Next, a 5% aqueous sulfuric acid solution (2.9 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. The results of a GC analysis showed that the condensed residue was a mixture of four isomers. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2). Thus, a component (0.016 g, 0.07 mmol, 7% yield) with the longest retention time in the GC analysis was obtained. Results of evaluation based on gas chromatography-olfactometry (GC-O) showed that this component was a component having the lowest odor threshold, among the 4 isomers.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.B(F)(F)F.CCOCC>[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Reaction time: 48 h
Yield: 5 %

Procedure:
In 5 ml of dichloromethane were dissolved 155 mg of Compound (1) and 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added two drops of boron trifluoride etherate (47% ether solution) and 2 g of Molecular Sieves (3A). The mixture was allowed to stand at room temperature for 2 days. The reaction solution, after removing the Molecular Sieves, was washed with a cooled aqueous solution of sodium hydrogen carbonate, followed by drying (MgSO4). The solvent was evaporated off under reduced pressure, and the residue was purified by subjecting to a silica gel preparative thin-layer chromatography [developed with 1,2-dichloroethane-ethyl acetate (5:1)] to give 12.5 mg of the subject Compound (9).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]1([CH2:15][C:16]([NH2:18])=[NH:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:19]([O:23][C:24](=[O:39])/[C:25](/O)=[C:26](\[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)/[C:27](O)=[O:28])([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CO.CCCCCC>[C:19]([O:23][C:24]([C:25]1[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([OH:28])[N:18]=[C:16]([CH2:15][C:10]2([C:4]3[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=3[Cl:2])[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:17]=1)=[O:39])([CH3:22])([CH3:20])[CH3:21]
Reactant: N=C(N)CC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a stirred solution of 2-[1-(2,5-dichlorophenyl)-cyclopentyl]-acetamidine hydrochloride (2=3) (2.0, 7.407 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester (4) (3.422 g, 11.111 mmol) in methanol (50 mL) NaOMe (25% in methanol; 4.8 mL) was added dropwise at 0° C. and stirred at room temperature for 16 h. Silica thin layer chromatography was performed (40% ethyl acetate in hexane, Rf=0.6). The reaction mixture was quenched with HCl (1N; 5 mL), methanol was removed, the product was diluted with water and the mixture was extracted with ethyl acetate. The combined organic part was dried, the product was concentrated and the crude product was purified using a normal silica gel column using a gradient eluent of 10 to 40% ethyl acetate in hexane to get pure 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (204) (2.1 g, 53.55%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:16])C.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]2[CH2:11][O:16]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OO
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)Oc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-tert-butoxystyrene (17.6 g, 100 mmol) in methylene chloride (200 mL) cooled in an ice bath is added a solution of 32% peracetic acid in acetic acid (31.5 mL, 150 mmol). The mixture is stirred at rt overnight and quenched by addition of saturated sodium bicarbonate solution. The organic phase is separated, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. Chromatography on silica gel provides 2-(4-tert-butoxyphenyl)oxirane.
Reaction SMILES: [CH:1]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]4[CH3:31])[C:18]4[CH2:24][NH:23][CH2:22][CH2:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C[C@@H]1NCCOC1.[OH:39][C:40]([CH3:45])([CH3:44])[C:41](O)=[O:42]>>[CH:1]1([NH:5][C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[N:16]=[C:17]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]4[CH3:31])[C:18]4[CH2:24][N:23]([C:41](=[O:42])[C:40]([OH:39])([CH3:45])[CH3:44])[CH2:22][CH2:21][C:19]=4[N:20]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CNCC2
Reactant: CC(C)(O)C(=O)O
Agent: C[C@H]1COCCN1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CN(C(=O)C(C)(C)O)CC2

Procedure:
Compound hq was prepared generally following the procedures described in Examples 1, 27 and 30 and 147 except that (S)-1-cyclobutyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea was used instead of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and 3S-3-methylmorpholine was used instead of morpholine in step 1 of Example 1. Additionally, 2-hydroxyisobutyric acid was used instead of oxazole-5-carboxylic acid in Example 147: LC/MS-m/z+509 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[CH2:20]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCBr
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperidine-4-carboxamide (100 mg), potassium carbonate (41 mg) and ethyl bromide (0.022 mL) in dimethylformamide (4 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in dichloromethane to give the title compound as a white solid (80 mg, 74%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41](C=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56](OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:56][N:50]6[CH2:51][CH2:52][NH:53][CH2:54][CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 19 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL), 1,1-dimethylethyl 1-piperazinecarboxylate (44.6 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a beige colored solid [21 mg (19%)]. LC-MS m/z 729.6 (M+H)+.