Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5])#[N:2].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CC(C)=O>[CH:14]1([NH:20][C:4](=[O:5])[C:3]([C:1]#[N:2])([CH3:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C#N)(C(=O)Cl)c1ccccc1
Reactant: NC1CCCCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C#N)(C(=O)NC1CCCCC1)c1ccccc1
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A solution of 9.75 g (0.05 mole) of 2-cyano-2-methyl-2-phenylacetyl chloride in 20 ml of acetone is cooled to 5° C., and a mixture of 5 g (0.05 mole) of cyclohexylamine, 5.2 g of triethyl amine and 10 ml of acetone is added to the solution under maintaining the temperature of the mixture below 10° C. The reaction mixture is poured into ice water, the separated solid is filtered off, and dried in vacuo. 12.12 g of N-cyclohexyl-2-cyano-2-methyl-2-phenylacetic acid amide are obtained; m.p.: 76°-78° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22]
Reactant: COCCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCN(C)c1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of {3-chloro-2-fluoro-5-[(2-methoxy-ethyl)-methyl-amino]-benzyl}-carbamic acid tert-butyl ester (60 mg, 0.17 mmol) in MeOH (2 mL) was added a solution of 4N HCl in dioxane (2 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 247.0 [M]+. tR (HPLC conditions c): 3.15 min.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:32][CH2:33][CH3:34])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:25]([N:17]([C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]([CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[CH:16]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccs3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccs3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(thiophene-2-carbonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.58 (d, 1H), 7.40 (d, 1H), 7.28 (m, 6H), 6.92 (m, 1H), 6.83 (m, 1H), 6.61 (d, 1H), 5.04 (s, 2H), 4.82 (s, 2H), 2.71 (t, 2H), 1.78 (m, 2H), 0.98 (t, 3H). MS calculated for C24H23N3O3S+H: 434, observed: 434.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine, prepared in Example 153) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure E to give, after purification by reverse HPLC, 4 mg of 5-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine. MS (Q1) 475 (M+)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:27])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:20]>>[CH3:18][C:19]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:20]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1cnc(C(C)(C)N)s1
Product: Cc1cnc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)s1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and 1-methyl-1-(5-methyl-thiazol-2-yl)-ethylamine (100 mg, 0.64 mmol) as starting materials and isolated (29 mg, 18.3%) as white solid; LC-MS (UV peak area, ESI) 94.85%, 372.8 (M+H)+.
Reaction SMILES: O1[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)([CH2:8][CH:9]([O:12]C)OC)[CH:2]1[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([C:7]2[CH:8]=[CH:9][O:12][C:2]=2[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:18]=1
Reactant: COC(=O)C1OC1(CC(OC)OC)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1occc1-c1ccc(C)cc1
Yield: 50.4 %

Procedure:
A solution of 10.8 g of methyl 2,3-epoxy-3-(4-methylphenyl)-5,5-dimethoxypentanoate and 1.1 g of p-toluenesulfonic acid in 60 ml of anhydrous benzene is refluxed over molecular sieves for 3 h. 60 ml of ethyl acetate are added, the mixture is washed 2 times with 50 ml of a NaHCO3 saturated aqueous solution, dried over Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by F.C. to obtain 4.2 g of a yellow oil (50% yield). 1H NMR (CDCl3), δ: 2.39 (s, 3 H), 3.85 (s, 3 H), 6.62 (d, 1 H), 7.24 (d, 2 H), 7.48 (d, 2 H), 7.56 (d, 1 H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].S(=O)(=O)(O)O.[CH2:13]1[CH:18]2CC3[O:22][C:23](=O)[CH:16]([CH2:17]2)[CH2:15][CH:14]1[CH2:21]3>C1CCCCC1>[C:5]([O:4][CH:1]1[CH:18]2[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:21][CH:2]1[C:23]3=[O:22])[CH2:13]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Product: CC(=O)OC1C2CC3CC(C2)C(=O)C1C3
Reaction time: 6 h

Procedure:
A mixture containing 4-Oxahomoadamantane-5-one (12.5 grams, 75.3 mmol), 40 mL acetic anhydride, and 100 mL cyclohexane was charged to a 250-mL round-bottom flask and heated to reflux with a heating mantle. Concentrated sulfuric acid (0.52 grams, 5.4 mmol) was added dropwise from the top of the condenser with magnetic stirring. After 40 hours of reflux, about 5% of the 4-Oxahomoadamantan-5-one was converted to the products. More concentrated H2SO4 was added (15.8 grams, 158 mmol) in the same fashion. This separated the reaction mixture into a top grayish layer of mostly cyclohexane and a black bottom layer. Refluxing was continued for additional 6 hrs, when GC analysis of the top layer showed that the reaction was complete. After cooling, the reaction mixture was transferred into a separatory funnel and the layers were separated. The dark bottom layer was extracted with 3×50 mL cyclohexane. The combined cyclohexane solutions was washed with 100 mL each of 1N NaOH and saturated brine. GC analysis of the solution showed >99% pure two isomers of 4-Acetoxyadamantanones. After drying over anhydrous Na2SO4, removal of solvent gave 4.03 gram of 4-Acetoxyadamantanone as a yellowish oil. Crushed ice was added to the conc. H2SO4 layer separated from the reaction mixture. The resulting solution was diluted with water to ≈500 mL and extracted with 4×100 mL CH2Cl2. The combined yellow CH2Cl2 solutions was washed with 1N NaOH (2 ×200 mL), water (100 mL), and saturated brine (100 mL). GC analysis of the solution showed that it was predominantly 4-Acetoxyadamantanone with small amounts of 4-Hydroxyadamantanones. Removal of solvent by rotary evaporation gave 7.24 grams of a red oil.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:24]=[CH:23][C:8](/[CH:9]=[C:10]2\[O:11][C:12](=O)[C:13]3[C:18]\2=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26].CN(C)C=O>O>[F:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:19]([O-:21])=[O:20])[C:12](=[O:11])[NH:3][N:2]=2)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]
Reactant: NN
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cccc([N+](=O)[O-])c43)ccc2F)CC1
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc([N+](=O)[O-])c34)ccc2F)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
Hydrazine hydrate (0.046 mL, 0.94 mmol) was added in one portion to (Z)-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)-4-nitroisobenzofuran-1(3H)-one (44) (50 mg, 0.12 mmol) and N,N-Dimethylformamide (0.045 mL, 0.59 mmol) in water (2 mL) at 25° C. under air. The resulting mixture was stirred at 100° C. for 18 hours. The mixture was cooled to ambient temperature and the solvent evaporated to give crude desired product as a pale brown solid (40.0 mg, 77% yield); 1H NMR: (400.132 MHz, DMSO) δ 1.23-1.33 (1H, m), 1.36-1.50 (1H, m), 1.65-1.72 (1H, m), 1.79-1.92 (1H, m), 3.25-3.27 (4H, m), 3.33 (3H, s), 3.82-3.97 (1H, m), 4.10 (2H, s), 7.10-7.21 (3H, m), 7.99-8.03 (1H, m), 8.27 (1H, d), 8.59 (1H, d); m/z (LC-MS, ESI+), RT=1.85 (M+H 441.3).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[N:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: c1cc(N2CCNCC2)ccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 66 %

Procedure:
3.4 g of methyl chloronicotinate, 5.5 g of potassium carbonate, 3.3 g of 4-pyridylpiperazine and a spatula tipful of 18-crown-6 were heated at 100° C. for 5 h in 75 ml of DMF and then stirred at room temperature for 60 h. The excess potassium carbonate was filtered off, the filtrate was concentrated and the residue was partitioned between water and ethyl acetate. After drying the organic phase over magnesium sulfate and concentrating the solvent, 3.9 g (82%) of the product were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.Cl.[CH3:40][N:41]1[C:45]([C:46](Cl)=[O:47])=[CH:44][N:43]=[CH:42]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:46]([C:45]1[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=1)=[O:47])[CH:29]=3
Reactant: Cn1cncc1C(=O)Cl
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23H21ClN7O (M+H)+: m/z=446.2.
Reaction SMILES: [Mg].BrBr.C([O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:13]=1[CH:14]=[O:15])C1C=CC=CC=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:12]([OH:11])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: BrBr
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
To a mixed suspension of magnesium (305 mg, 12.6 mmol) in diethyl ether (7.5 mL) and toluene (7.5 mL) was added bromine (354 μL, 6.91 mmol) at 0° C., which was stirred at room temperature for 5 minutes under nitrogen atmosphere and was refluxed while heating for 5 minutes. After the reaction mixture was cooled to room temperature, a toluene (20 mL) solution of 2,5-bis-benzyloxy-benzaldehyde (2.00 g, 6.28 mmol) described in Production Example 7-1-1 were added followed by stirring at room temperature for 24 hours under nitrogen atmosphere. Moreover, after stirring for 6 hours while refluxing while heating, the reaction mixture was cooled to room temperature. The precipitated solid was filtered out and washed with toluene. 1 N aqueous hydrochloric acid solution (20 mL) was added to the filtered solid followed by stirring for 1 hour while refluxing and heating. The reaction solution was allowed to cool to room temperature followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (830 mg, 58%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31].O>C1C=CC=CC=1>[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][NH:22][CH:21]([C:30]([O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])=[O:31])[CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Solvent: O
Solvent: c1ccccc1
Product: C=CCC1(C2=CC(C(=O)OCC(Cl)(Cl)Cl)NCC2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (3.3 g, 10.0 mmol) in 50 mL of benzene, and added 2,2,2-trichloroethylchloroformate (3.0 mL, 4.6 g, 21.8 mmol). Refluxed for 20 hours under a nitrogen atmosphere. Cooled to room temperature, and added water. Extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 3.7 g (75% yield) of 2,2,2-trichloroethyl 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1,2,5,6-tetrahydro-pyridinecarboxylate as an oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]1[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=1.CN1CCOCC1>C(Cl)Cl>[CH:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:14][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[N:17]=1)([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1nc(CO)cs1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)c1nc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.12 g (5.56 mmol) of 4-nitrophenyl chloroformate in 20 ml of CH2Cl2 was cooled to 0° C. and treated sequentially with 0.8 g (5.1 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole and 0.6 ml (5.6 mmol) of 4-methylmorpholine. The resulting solution was stirred at 0° C. for 1 h, diluted with CH2Cl2, washed with three portions of aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to give crude 2-isopropyl-4-(p-nitrophenyloxycarbonyloxymethyl)thiazole. A portion (0.53 g, 1.65 mmol) of the residue was taken up in 20 ml of chloroform, treated with 0.23 g (1.67 mmol) of L-alanine methyl ester hydrochloride and 0.36 ml (3.3 mmol) of 4-methylmorpholine, and heated at reflux for 16 h. After being allowed to cool, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.45 g (94%) of the desired compound, Rf 0.43 (5% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ1.26 (d, J=8 Hz, 3H), 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H), 4.10 (p, J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.81 (d, J=8 Hz, 1H). Mass spectrum: (M+H)+ =287.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: C1COCCN1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 9 and morpholine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>>[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: OCCCNc1ccc2ccccc2n1
Product: Cc1cccc(COCCCNc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 362 (M+H)+. Prepared from 3-(quinolin-2-ylamino)-propan-1-ol and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([C:30]([OH:46])([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([CH3:45])([O:38]C3CCCCO3)[CH3:37])[CH3:31])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:46][C:30]([C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1)([CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])([CH3:45])[CH3:37]
Reactant: CCOCOc1cc(C=Cc2cccc(C(C)(O)CCCCC(C)(C)OC3CCCCO3)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CCCCC(C)(O)c1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.6 ml of concentrated sulphuric acid in 7.5 ml of methanol with 369 mg (0.65 mmol) of 2-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl}phenyl}-7-methyl-7-(tetrahydropyran-2-yloxy)octan-2-ol in 7.4 ml of THF, after purification on a silica column (ethyl acetate 70-heptane 30), a yellowish paste (m=220 mg; Y=92%) is obtained.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])C1C=CC=CC=1.[ClH:37]>CCO.[Pd]>[ClH:37].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)(=[NH:10])[NH2:12]
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(O)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(O)cc1F
Yield: 88 %

Procedure:
(RS)-[(4-{[2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester (100 mg) was dissolved in EtOH (2 ml). 1.25 M HCl in EtOH (0.1 ml) was added and the mixture was hydrogenated 1.5 h at 1 atm H2 in the presence of a catalytic amount of 10% Pd/C. After filtration of the catalyst the solvent was removed to obtain 71 mg (88%) of (RS)-N-(4-carbamimidoyl-benzyl)-2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetamide hydrochloride. White powder. MS 364.3 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[C:31]([NH:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCN)C(=O)c2cccc(Cl)c2)CC1=O
Solvent: C1CCOC1
Product: CC(=O)NCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(2-Amino-ethyl)-3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-benzamide (80 mg, 0.16 mmol, 1 eq), Acetyl chloride (0.014 ml, 0.19 mmol, 1.2 eq), TEA (0.07 ml) in THF (1 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 491.2
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:18][O:19][CH3:20])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.Cl>C1COCC1.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:18][O:19][CH3:20])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(=NOC)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
Lithium hydroxide (0.632 g, 26.40 mmol) was added in one portion at 20° C. to a solution of ethyl 4-(4-chlorophenyl)-4-(methoxyimino)butanoate (Intermediate 14) (1.78 g, 6.60 mmol) in THF (30 ml) and water (20 ml). The resulting solution was stirred at room temperature for 6 hours then acidified with dilute HCl and extracted with TBME (2×). The combined extracts were washed with brine, dried over MgSO4 and evaporated to give 4-(4-chlorophenyl)-4-(methoxyimino)butanoic acid (1.520 g, 95%) as a colourless solid.
Reaction SMILES: [CH2:1]([N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[O:8][C:7]1=[O:20])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH3:21][C:12]1([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:14][CH2:15][C:9]2([O:8][C:7](=[O:20])[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:10]2)[CH2:11]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 78° C. solution of methyl 3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (15.0 g, 52.9 mmol) in THF (41.0 mL) under N2 was added sodium bis(trimethylsilyl)amide, 1 M in THF (238 mL, 238 mmol) over 1 h using an addition funnel. The reaction mixture was stirred at −78° C. for 3 h. Iodomethane (14.9 mL, 238 mmol) was added, and the reaction was stirred at −78° C. for an additional 2 h. The reaction was quenched at −78° C. with water (5 mL) and diluted with brine (200 mL). The product was extracted into EtOAc (3×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to a light yellow solid. The solid was suspended in Et2O (75 mL) and collected in a frit. The collected solids were washed with cold Et2O (4×10 mL) and dried to afford the title compound (13.4 g, 81% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.40 (d, J=8.78 Hz, 1H), 3.29 (d, J=8.78 Hz, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.16 (d, J=14.05 Hz, 1H), 1.77-1.93 (m, 4H), 1.43-1.69 (m, 3H), 1.35 (s, 3H), 0.96 (s, 9H). MS (m/z) 298.1 (M+H+).