Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.O>CO.O>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(C=O)s1
Solvent: CO
Solvent: O
Product: O=Cc1ccc(CCCO)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
To a solution of crude 5-(3-((t-butyldimethylsilyl)oxy)propyl)thiophene-2-carbaldehyde (ca. 871 mg, 3.06 mmol) in 32 mL of 9:1 methanol/water was added p-tosic acid monohydrate (58 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 45 minutes and poured into 100 mL water. Organics were extracted with ethyl acetate (2×75 mL) and ether (75 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (20-50% ethyl acetate in hexanes) to give 5-(3-hydroxypropyl)thiophene-2-carbaldehyde (360 mg, 69%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCCCCCC>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1
Reactant: COc1cc2ncc(NC3CC4CCC3C4)nc2cc1OC
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCCC
Product: COc1cc2ncc(N[C@@H]3C[C@H]4CC[C@@H]3C4)nc2cc1OC

Procedure:
The (±)-bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 17 is resolved on a chiral HPLC column (Chiralpac AD, 25×2 cm, 60% heptane/40% ethanol with 10 mM (1S)-(+)-camphorsulfonic acid, 12 mL/minute) and the above titled product is obtained as the first eluent. The fractions collected are combined and washed with 50 mL of 1 N NaOH before drying (MgSO4). The solution after filtration is concentrated on a rotovap and then dried under a high vacuum. A yellow solid is obtained. [α]d20+19.50 (c=0.20, CH2Cl2) m.p. 184-186° C. Anal. calcd for C17H21N3O2×0.3 H2O: C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][OH:12])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: O=C1OCCO1
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc(Br)ccc1OCCO
Temperature: 125 °C
Yield: 82.1 %

Procedure:
To a solution of 2-ethyl-4-bromophenol (3.5 g, 17.4 mmol) and ethylene carbonate (3.22 g, 37 mmol) in NMP (60 mL) was added potassium carbonate (5.17 g, 37.4 mmol). The resulting mixture was heated to 125° C. and maintained for 3 h. The reaction was cooled and poured into water (250 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10-20% EtOAc in hexanes) to give the product (3.5 g, 82% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.19 (t, J=7.6 Hz, 3H), 1.89 (brs, 1H), 2.61 (q, J=7.6 Hz, 2H), 4.05 (m, 4H), 6.70 (d, J=8.7 Hz, 1H), 7.24 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][C:8](=[O:9])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCC(=O)Cl
Reactant: Nc1ccccn1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC(=O)Nc1ccccn1
Reaction time: 18 h

Procedure:
3-Chloro-3-oxopropyl acrylate, 1, (1 eq.), 2-aminopyridine (1 eq.) and triethylamine (3 eq.) are dissolved in toluene at 0° C. A few crystals of hydroquinone is added to inhibit any polymerization side reactions. The solution is allowed to stir approximately 18 hours at a temperature from about 0° C. to room temperature. The solvent is removed under reduced pressure and the crude material purified over silica. For a more detailed account of this procedure See M. A. Diab, A. Z. El-Sonbati, A. A. El-S anabori, F. I. Taha, Polymer Degrad. Stab. 1989, 24, 51, included herein by reference.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16](O)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].CN(C)C=O.S(Cl)([Cl:31])=O>ClCCl>[OH:19][C:5]1[C:6]([CH2:10][CH:11]=[C:12]([CH3:13])[CH2:14][CH2:15][C:16]([Cl:31])=[O:17])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[C:3]2[C:4]=1[C:20](=[O:21])[O:22][CH2:23]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)Cl)C(=O)OC2

Procedure:
A solution of mycophenolic acid (320 g, 1 mol) and dimethylformamide (0.1 g) in dichloromethane (3.2L) at reflux was treated dropwise with thionyl chloride (82 mL, 1.12 mol). After one hour additional heating at reflux, the volatiles were distilled at reduced pressure leaving a gray solid residue of (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride which was cooled and dissolved in anhydrous tetrahydrofuran (1L).
Reaction SMILES: I[C:2]1[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1.[CH3:26][NH:27][C:28]1[N:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:12][C:9]1[N:8]=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:6]2[C:11](=[C:2]([C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[N:29]=[C:28]([NH:27][CH3:26])[N:37]=[CH:36]4)[C:3]([CH3:25])=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1nc(Nc2cccc(OC(F)(F)F)c2)c2ccc(C)c(I)c2n1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(F)(F)F)c5)nc(C)nc34)ccc2n1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
8-Iodo-2,7-dimethyl-N-(3-(trifluoromethoxy)phenyl)quinazolin-4-amine (0.250 g, 0.544 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.186 g, 0.653 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0629 g, 0.0544 mmol) and 2 M aqueous sodium carbonate (0.544 mL, 1.09 mmol) were placed in a microwave vial and dioxane (3 mL) was added. The tube was capped and heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate and then purified by column chromatography on silica gel using a gradient of 20 to 80% EtOAc in hexanes. The clean fractions were combined and concentrated under vacuum to give a yellow film. The film was triturated with a 1:1 mixture of ether and hexanes. This resulted in the formation of an off-white solid which was collected by filtration and dried in a vacuum oven to give 6-(2,7-dimethyl-4-(3-(trifluoro-methoxy)phenylamino)quinazolin-8-yl)-N-methylquinazolin-2-amine (0.212 g, 79%). MS (M+H)+ 491.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]2[N:11]=[C:10]([CH3:13])[N:9]([CH3:14])[C:8]=2[CH:7]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=1.Cl[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23][CH2:22][CH2:21]1>CN(C)C=O>[O:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([O:3][C:4]2[C:12]3[N:11]=[C:10]([CH3:13])[N:9]([CH3:14])[C:8]=3[CH:7]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)[CH2:21][CH2:22]1
Reactant: ClC1CCOc2ccccc21
Reactant: COC(=O)c1cc(O)c2nc(C)n(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC2CCOc3ccccc32)c2nc(C)n(C)c2c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.71 g, 18 mmol) in N,N-dimethylformamide (40 mL) was added a suspension of methyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate (3.0 g, 14 mmol, WO 2004054984) in N,N-dimethylformamide (40 mL) dropwise under nitrogen atmosphere at room temperature. After stirring for 20 minutes, a solution of 4-chlorochromane (4.6 g, 27 mmol, WO 2000078751) in N,N-dimethylformamide (10 mL) was added at room temperature. The reaction mixture was warmed to 70° C. for 2.5 hours, cooled to room temperature, and stirred for 18 hours at the same temperature. The reaction mixture was quenched with water and extracted with ethyl acetate (250 mL×2). The combined extracts were washed with sodium hydrogencarbonate aqueous solution, ammonium chloride aqueous solution and brine, dried over sodium sulfate, and concentrated in vacuum. The resulting solid was suspended with ethyl acetate and diethyl ether, and collected by filtration to give the title compound as a white solid (2.95 g, 61%):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CC1(c2ccc(F)c(Br)c2)OCCO1

Procedure:
1-(3-bromo-4-fluorophenyl)ethanone (7.5 g, 34.5 mmol), ethylene glycol (10 mL) and a catalytic amount of tosyl acid was refluxed in toluene (100 mL) for 18 h with a Dean-Stark trap. The crude reaction mixture was quenched with H2O (100 mL) extracted with EtOAc (3×50 mL), washed organic layer with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 8.8 g of Intermediate 416.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.61 (s, 3H) 3.69-3.81 (m, 2H) 3.97-4.09 (m, 2H) 7.07 (t, J=8.35 Hz, 1H) 7.32-7.43 (m, 1H) 7.67 (dd, J=6.59, 2.20 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.Cl.O1CCOC[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Yield: 91.4 %

Procedure:
A suspension of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoic acid (preparation 38, 0.47 g, 1.5 mmol) and a 4M solution of hydrochloric acid in dioxane (2.00 mL, 8.0 mmol) in methanol (2 mL) was heated in a sealed tube at 80° C. with stirring. After stirring overnight the mixture was cooled and ethyl acetate and saturated aqueous potassium carbonate solution were added. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The resultant oil was taken up in a small amount of ethyl acetate and the suspension was filtered. The filtrate was evaporated to give the title compound (0.46 g, 86%) as a foam.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.[F:9][C:10]([CH3:41])([CH3:40])[CH2:11][CH2:12][CH:13]1[C:17](=O)[O:16][CH:15]([CH:19]([NH:27][C:28]([C:30]2[CH:39]=[N:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]1>C1(C)C=CC=CC=1>[CH2:20]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH:15]([OH:16])[CH2:14][CH:13]([C:17]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:12][CH2:11][C:10]([F:9])([CH3:41])[CH3:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCN1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
To a solution of ethylenediamine (0.040 mL, 0.598 mmol) in toluene (2 mL) at −10° C. was added trimethylaluminum (2.0 M in hexanes, 0.300 mL, 0.600 mmol) and stirred for 15 minutes. A solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (250 mg, 0.556 mmol) in toluene (3 mL) was then added and the reaction warmed to ambient temperature, then heated to reflux for 3 hours. The reaction was cooled to ambient temperature and quenched carefully with water (1 mL). The solution was diluted with methylene chloride and methanol and then filtered, washing the filtrate with methanol. The organics were concentrated and the crude product was purified by chromatography on silica gel to give the title compound (74 mg, 17%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[O:9]1CC[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C>O>[C:10]([NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3][O:2][CH3:1])(=[O:9])[CH3:11]
Reactant: C1CCOC1
Reactant: COCC(N)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCC(NC(C)=O)C(=O)O
Yield: 90 %

Procedure:
Into a vessel, equipped with a mechanical stirrer, was added O-methyl-D,L-serine (1.0 eq.) at 20° C. Tetrahydrofuran (6 volumes) and water (0.65 volume) were added. Acetic anhydride (1.2 eq.) was added dropwise over 5 minutes. The white suspension was stirred mechanically until complete conversion was observed by HPLC monitoring (approximately 16 h), by which time the reaction mixture had become homogeneous. The tetrahydrofuran and water were removed azeotropically. Toluene was added in order to effect complete removal of water and acetic acid (KF and GC control). The wet solid was dried at 40° C. under vacuum overnight. The title compound (90% yield) was obtained as a white solid with a chemical purity of >98% as measured by HPLC.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1cnc(N[N+](=O)[O-])[nH]c1=O
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.64 g) and 2-nitroamino-5-methoxypyrimidin-4-one (1.12 g) were stirred under reflux, for 40 hours, in ethanol (15 ml). The ethanol was replaced by pyridine (15 ml) and the solution stirred under reflux for a further 10 hours to complete the reaction. The reaction mixture was cooled and evaporated under reduced pressure to give a residue. This was partitioned between water (25 ml) and chloroform (25 ml), the aqueous layer being further extracted with chloroform (2×25 ml). The combined chloroform extracts were dried (MgSO4), evaporated under reduced pressure and subjected to medium pressure chromatography using chloroform: methanol (95 : 5) to give the title compound. The fractions containing the title compound were dissolved in isopropanol and treated with maleic acid (0.6 g) in isopropanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-5-methoxypyrimidin-4-one maleate (0.96 g), m.p. 148°-149.5° C (recrystallisation from ethanol).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14]
Reactant: NCCNC(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCNC(=O)c1ccccc1Cl

Procedure:
N-(2-Aminoethyl)-2-chlorobenzamide hydrochloride was suspended in dichloromethane and stirred with triethylamine and methanesulfonyl chloride to obtain 2-chloro-N-{2-[(methylsulfonyl)amino]ethyl}benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: CN1CCN(Cc2ccc(N)cn2)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)nc3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1), and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS: 566.0 [M+H]+; tR=3.64 min (System 1); TLC: Rf=0.24 (DCM/MeOH, 9:1).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH:15]([CH3:18])[CH:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC.C1COCC1>[CH:1]1([CH:16]([OH:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C=O)c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(c1ccccc1)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.4 %

Procedure:
To a solution of cyclohexylmagnesium chloride (50 mmol) in 25 mL of Et2O and 40 mL of THF at −5° C. was added a solution of 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. The reaction mixture exothermed to 5° C. After stirring at room temperature for 75 min, the solution was poured onto ice cold 1 N HCl, extracted with toluene, dried over MgSO4, and concentrated to give the title compound as a colorless oil (6.15 g, 70%): 1H NMR (d6-DMSO): δ 7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51 (brs, 1H, —OH), 3.23-3.33 (m, 1H, R2CHOH), 2.78 (dq, J=7.0 Hz, J=7.1 Hz, 1H, —CH(CH3)Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J=6.9 Hz, 3H, —CH(CH3)Ph), 0.88-1.18 (m, 5H, cyclohexyl CH).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)([O-:16])=[O:15]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: O=c1cc(N2CCN(Cc3ccccc3[N+](=O)[O-])CC2)nc[nH]1

Procedure:
6-[4-(2-Nitro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-nitrobenzaldehyde. Mass spectrum (ES) MH+=316.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[NH2:10].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1CCN2C(=NCCC2)CC1.[CH2:34]([O:36][C:37]([C:39]1([CH:42]=O)[CH2:41][CH2:40]1)=[O:38])[CH3:35]>C(O)C>[CH2:34]([O:36][C:37]([C:39]1([C:42]2[N:1]=[C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]3[N:10]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: COc1ccc[n+](N)c1N
Reactant: CCOC(=O)C1(C=O)CC1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a stirred solution of diamino-3-methoxy-pyridinium salt of 4-nitrobenzoic acid (1 g, 7.14 mmol) in ethanol (10 mL) at 0° C., DBU (2.1 mL) was added followed by 1-formyl-cyclopropanecarboxylic acid ethyl ester (1.5 g, 10.71 mmol). After addition the reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated, the obtained residue was diluted with EtOAc (100 mL), washed with water (20 mL×2), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (using 0 to 15% EtOAc in CH2Cl2 as eluent) to afford the title compound (800 mg, 53%, white solid). 1H NMR (400 MHz, CDCl3): δ=8.18-8.16 (d, J=6.4 Hz; 1H), 6.89 (t, J=7.2 Hz, 1H), 6.76 (d, J=8 Hz; 1H), 4.20-4.14 (m, 2H), 4.03 (s, 3H), 1.73-1.70 (m, 2H), 1.59-1.56 (m, 2H), 1.20 (t, J=6.8 Hz; 3H) ppm.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH:15]2[CH2:16][C:17](=[O:19])[CH2:18][CH:11]1[CH2:12][O:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:22])C>CO>[CH2:3]([N:10]1[CH:11]2[CH:18]([OH:22])[C:17](=[O:19])[CH2:16][CH:15]1[CH2:14][O:13][CH2:12]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: O=C1CC2COCC(C1)N2Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC2COCC(C1O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a stirred solution of potassium hydroxide (730 mg, 13 mmol) in dry MeOH (50 mL) at 0° C. under nitrogen was added a solution of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (CAS: 81514-40-1, 1 g, 4.3 mmol) in dry MeOH (20 mL) dropwise over 10 min. The reaction mixture was stirred at 0° C. for another 10 min, and PhI(OAc)2 (1.83 g, 5.5 mmol) was added portion wise over 10 min. The reaction mixture was warmed to room temperature, with stirring, overnight. After the starting material disappeared as monitored by TLC, MeOH was removed under reduced pressure and the residue was cooled to 0° C. and 10 ml of 6N HCl was added carefully. The mixture was stirred at room temperature for 2 hours, and then ethyl acetate and water (50 mL, 1:1) were added. The aqueous layer was separated and was added into K2CO3 till the solution was saturated. The mixture was extracted with ethyl acetate (20 mL) three times, dried and concentrated, the residue was purified by silica gel (EA/PE=1:2) to give 9-benzyl-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 106b as colorless oil, 270 mg, yield: 25%. MS: calc'd (MH+) 248, measured (MH+) 248.