Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[OH:8][CH:7]1[CH:3]([CH2:2][NH:1][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC(O)C(CN)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(CNC(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate (3 g, 13.9 mmol) [Prepared according to Hong, C.-Y. J. Med. Chem. 1997, 40, 3584.] in DCM (100 mL) at 0° C. was added N-(benzyloxycarbonyloxy)succinimide (3.8 g, 15.3 mmol) portion-wise. After 1 h, the reaction was partitioned between H O-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na SO), concentrated and purified by column chromatography (silica, 3% MeOH in DCM (1% NH OH)) yielding the title compound (4.8 g, quant.) as a clear oil: LCMS (ES) m/e 351 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12].CC([O-])=O.[Na+].CC(OC(C)=O)=O>>[C:11]([NH:14][C:15](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=Cc1ccc(F)c(Br)c1)C(=O)O
Temperature: 130 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (50.0 g, 0.25 mol), N-acetylglycine (26.2 g, 0.22 mol), NaOAc (13.8 g, 0.56 mol), and Ac2O (52 mL) was heated at 130° C. for 10 h in a flask fitted with a reflux condenser. The resulting precipitate was collected by filtration, washed with water, and suspended in AcOH (250 mL). This mixture was heated at 100° C. for 1 h in a flask fitted with a reflux condenser, and then was cooled to 0° C. The solids were collected by filtration, washing with water, to give the product as a yellow solid (53.5 g, 76%). MS (ESI−): mass calcd. for C11H9BrFNO3, 301.0; m/z found, 299.9 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 12.80 (br s, 1H), 9.52 (br s, 1H), 7.93 (dd, J=6.9, 1.9, 1H), 7.66 (ddd, J=8.4, 4.8, 1.9, 1H), 7.42 (t, J=8.7, 1H), 7.19 (s, 1H), 1.98 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2.[Br:17]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)Cl>[Br:17][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:16])[CH:5]=[CH:4]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Yield: 103.6 %

Procedure:
A suspension of 5-hydroxy-8-methyl-6-(2-propenyl) carbostyril (64.57 g) in chloroform (2000 ml) was combined with N-bromosuccinimide (56.47 g) and refluxed with heat for 3 hours while stirring. The reaction mixture became yellow uniform solution. The reaction solution was washed with water, dried and condensed. n-Hexane was added to the concentrate, and crystallized. 91.40 g of the title compound was obtained as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.[Cl:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:21][CH2:20][Cl:19])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NCCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NCCCl
Yield: 41.8 %

Procedure:
2.54 g (10 mmol) of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (J. Med. Chem. 2001, 44, 1025) and 1.28 g (11 mmol) 2-chloroethylamine hydrochloride were added to 40 ml of anhydrous ethanol. Then 7 ml (50 mmol) of triethylamine were added. The mixture was heated at reflux until the reaction was completed (4 hours). The reaction mixture was concentrated under reduced pressure and 20 ml of saturated aqueous sodium carbonate solution was added. The mixture was extracted with 3×20 ml ethyl acetate. The combined organic layers were washed with 15 ml of water and 15 ml of brine, dried over Na2SO4 and evaporated in vacuo. The crude product (2.88 g) was first purified by flash chromatography on silica gel (petrol ether/ethyl acetate 5:1) and then crystallized from 20 ml of hexane/ethyl acetate=1/1 to afford 1.24 g (42%) of the desired product as a white crystalline solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[H-].[Na+:23]>CN(C)C=O>[CH:1]1([N:7]2[CH2:8][CH:9]([O:11][C:13]3[C:14]([C:15]([O-:17])=[O:16])=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:23]
Reactant: OC1CN(C2CCCCC2)C1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([O-])c1cccnc1OC1CN(C2CCCCC2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of 105 g (0.68 mole) of 1-cyclohexyl-3-azetidinol and 106 g (0.68 mole) of 2-chloronicotinic acid in 400 ml of dry dimethylformamide was added at a rapid drop to 52 g (1.35 mole) of 60% sodium hydride/mineral oil suspended in 400 ml of dry dimethylformamide at 60° C. Mild exothermic reaction was noted. After stirring for 2 hr at 60° C., the mixture was filtered. The filter cake was washed with ethylacetate and dried at 80° C./2 mm to give 174 g (86%) of crude title compound.
Reaction SMILES: C(C=C)=O.[H][H].C(O)C=C.[C]=O.[OH:13][CH2:14][CH2:15][CH2:16][CH:17]=[O:18]>[Cd].[Ag].[Ag].[Cd]>[OH:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:13].[CH2:17]([OH:18])[CH2:16][CH2:15][CH2:14][OH:13]
Reactant: [H][H]
Agent: [Ag]
Agent: C=CC=O
Agent: O=CCCCO
Solvent: C=CCO
Product: OCCCCO

Procedure:
One or more objects of the present invention are accomplished by the provision of a process for producing 1,4-butanediol which comprises (1) reacting acrolein with hydrogen in the vapor phase in the presence of a catalyst comprising a silver-cadmium alloy, wherein the atomic ratio of silver to cadmium in the alloy is in the range between about 0.1 and 3 to 1, to yield a hydrogenation product mixture containing allyl alcohol; (2) contacting the allyl alcohol product mixture with hydrogen and carbon monoxide under hydroformylation conditions to yield a product mixture containing 4-hydroxybutanal; (3) separating the 4-hydroxybutanal from the product mixture; and (4) hydrogenating the 4-hydroxybutanal to produce 1,4-butanediol.
Reaction SMILES: [C:1](=[O:18])([O:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])ON1C(=O)CCC1=O.[C:19]([NH:29][CH:30]([CH2:34][CH2:35][CH2:36][CH3:37])C(O)=O)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[CH2:13]1[C:12](=[O:17])[N:11]([O:10][C:1]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:30][NH:29][C:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])=[O:18])[C:15](=[O:16])[CH2:14]1
Reactant: CCCCC(NC(=O)CCc1ccccc1)C(=O)O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)NCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.7 %

Procedure:
Disuccinimidyl carbonate (155 mg, 604 μmoles) was added to a solution of 31 (159 mg, 604 μmoles) and pyridine (97.7 μL, 1.21 mmoles) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 2.5 h, during which the solution became clear and evolved gas. The solution was added to ethyl acetate (5 mL), washed with 1 N HCl (2×1 mL) and saturated aqueous NaHCO3 (2×1 mL), dried over MgSO4, and concentrated in vacuo to yield a colorless oil (156 mg, 433 μmoles, 72%). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22](=[O:24])[N:23]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:29]([NH2:31])[CH3:30]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25]([NH:31][O:29][CH3:30])=[O:26])[NH:21][C:22](=[O:24])[N:23]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)[nH]c(=O)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(=O)[nH]1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-oxo-2,3-dihydropyrimidine-4-carboxylic acid (Example 173) and methoxylamine hydrochloride.
Reaction SMILES: Cl.O.[O:3]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]3[C:14](=[CH:15][C:4]1=2)[C:13](=O)[CH2:12][CH2:11][CH2:10]3>[Zn].C1(C)C=CC=CC=1>[O:3]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]3[C:14](=[CH:15][C:4]1=2)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: O=C1CCCc2cc3c(cc21)OCC3
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: c1c2c(cc3c1CCO3)CCCC2

Procedure:
An amalgam of zinc and mercuric chloride (72 g Zn and 7.1 g HgCl2) is added to a mixture containing 120 ml of concentrated hydrochloric acid, 57 ml of water, 30 g of the compound of Example 1 and 71 ml of toluene, with stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][C:39](=[O:40])[CH2:38][Cl:37])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Yield: 55.6 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (0.5 g, 0.001 mol) and pyridine (2 mL) in DCM (20 mL) was added Chloroacetyl chloride (244 mg, 0.00215 mol) at 0° C. After few minutes, reaction mixture was diluted with water (10 ml). Organic layer was separated, dried and distilled out to get 300 mg of desired product in 52% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH:13][O:14]C)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC=CCc1ccc(CC(C)C)cc1
Agent: CC(C)Cc1ccc(C=O)cc1
Product: CC(C)Cc1ccc(CCC=O)cc1

Procedure:
4-Isobutyl 1-(3-methoxy-2-propen-1-yl)benzene was similarly prepared as described in Examples I and II. First, 4-isobutyl benzaldehyde (600 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-isobutyl-phenyl)-propionaldehyde (568 g) with a boiling point of 119° C. at a pressure of 5 mmHg. 3-(4-Isobutyl-phenyl)-propionaldehyde (345 g) was consequently used to provide 4-isobutyl 1-(3-methoxy-2-propen-1-yl)benzene (188 g) with a boiling point of 124° C. at a pressure of 4 mmHg.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][OH:68])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][OH:68])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: NC1CCN(CCO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(CCO)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-2.14 (m, 15 H) 2.38 (t, J=6.32 Hz, 3 H) 2.89 (d, J=11.62 Hz, 2 H) 3.28 (s, 3 H) 3.49 (q, J=6.23 Hz, 2 H) 3.67-3.85 (m, 3 H) 3.94 (s, 3 H) 4.37 (t, J=5.43 Hz, 1 H) 4.89 (d, J=8.34 Hz, 1 H) 5.28-5.48 (m, 2 H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1 H) 7.40-7.54 (m, 2 H) 7.82 (s, 1 H) 8.10 (d, J=7.58 Hz, 2 H) 8.30 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C30H40FN7O4, 582; found 582.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1>O1CCCC1>[N:1]1([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCCC2)nc1-c1ccc(C)cc1
Yield: 87.1 %

Procedure:
Methyl 2-(2-(azepan-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from azepane (0.152 mL; 1.32 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.110 g; 0.264 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 91 mg (87%) of the title compound as an oil. ESI/APCI(+): 396(M+H), 418 (M+Na). ESI/APCI(−): 394 (M−H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH2:14][CH2:13][CH2:12]1.CCN(S(F)(F)[F:24])CC>ClCCl>[F:24][C:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:17])([F:16])[F:1])[CH2:14][CH2:13][CH2:12]1
Reactant: OC1(c2cnccc2OCC(F)(F)F)CCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)COc1ccncc1C1(F)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1-[4-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-cyclobutanol (example 108b, 1.7 g, 6.88 mmol) in dry dichloromethane (25.0 ml) under an argon atmosphere cooled down to 0° C. was added DAST (1.36 ml, 10.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was quenched by addition of a 2M aqueous solution of sodium carbonate and the bi-phasic mixture was stirred for 20 minutes. The bi-phasic mixture was transferred into a separatory funnel and the organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness to yield the title compound (1.68 g, 98%); MS (ESI, m/z): 250.4 (M+H+). The crude material was used without any purification for the next step.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N+:8]1([O-])C(C)=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14]>>[C:5]([O:4][CH2:1][C:2]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[N:8]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)[n+]1[O-]
Product: CC(=O)OCc1cccc(C)n1
Temperature: 110 °C

Procedure:
Acetic anhydride (23 ml) was heated to 110° C. and 2,6-lutidine-N-oxide (20 g) was added dropwise over 1 hour. The solution was heated at 110° C. for five hours. After cooling, the crude mixture was distilled to yield 2-acetoxymethyl-6-methylpyridine (18.4 g, b.p. 110-120° C. @ 15 mmHg).
Reaction SMILES: [ClH:1].[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5]C=N1.NCC[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CC#N>[ClH:1].[C:7]([NH:2][CH2:6][CH2:5][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[NH:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=N)N
Reaction time: 24 h
Yield: 100 %

Procedure:
Portions of solid 1H -pyrazole-1-carboxamidine hydrochloride (91.10 g, 624 mmol)) are added to a stirred solution of N-(2-aminoethyl)(tert-butoxy)carboxamide (0.62 M) in CH3CN (1 L) at 80° C. After 24 hours, the reaction was stripped of solvent under reduced pressure. The residue was triturated with ether (3×100 ml), and dried in vacuo. The N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride was obtained in over 100% yield containing a small amount of pyrazole. The N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride was used without further purification.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][CH:14]1[C:23]2[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[CH:22]=2)[NH:17][C:16](=[O:33])[CH2:15]1>O1CCCC1>[CH3:13][CH:14]1[C:23]2[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([N:24]3[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH:31][C:1]3=[O:2])[CH:22]=2)[NH:17][C:16](=[O:33])[CH2:15]1
Reactant: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: Cc1cc(-n2c(=O)[nH]c3ccccc32)cc2c1NC(=O)CC2C

Procedure:
A solution of carbonyl diimidazole (0.33 g) in tetrahydrofuran (THF) (2 cm3) was added dropwise to a stirred solution of 3,4-dihydro-4,8-dimethyl-6-[(N-2-aminophenyl)amino]-2-(1H)-quinolone (0.24 g) in THF (2 cm3) at room temperature (20°). After 2 hours the solvent was evaporated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Collection and evaporation of appropriate fractions afforded a solid which was recrystallised from ethyl acetate to give the title compound, m.p. 250°-254° (0.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].C[CH2:16][N:17](C(C)C)[CH:18](C)C.CNC.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C(=O)N(C)C)cc1C
Yield: 5.6 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added a 2M solution of dimethylamine in THF (0.10 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-[(dimethylamino)carbonyl]-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (br. s., 1H) 6.37 (d, 1H) 4.22 (q, 2H) 3.10 (br. s., 3H) 2.97 (br. s., 3H) 2.26 (s, 3H) 1.28 (t, 3H). MS: m/z 225.5 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=O)[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[O:31][CH3:32].[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([C:4]1[C:5]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([OH:11])=[CH:8][C:9]=1[O:10][C:30]([O:31][CH3:32])=[O:33])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1c(C(C)=O)c(O)cc(O)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(OC(=O)OC)cc(O)c(-c2ccccc2)c1CC(=O)OC
Temperature: 4 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Compound 69 (0.12 g, 0.41 mmol) obtained in Example 69 was dissolved in tetrahydrofuran (10 mL), triethylamine (0.15 mL, 1.1 mmol) was added thereto, and the solution was cooled to 4° C. Then, methyl chlorocarbonate (0.081 mL, 1.1 mmol) was added thereto, and the mixture was stirred for 2 hours with heating up to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting methyl 2-acetyl-3,5-bis(methoxycarbonyloxy)-6-phenylphenylacetate was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL) and water (5.0 mL), then the solution was cooled to 4° C., and sodium borohydride (73 mg, 1.9 mmol) was added thereto, taking 5 minutes, and then stirred for 1 hour. Water (10 mL) was added to the reaction mixture, and stirred for 10 minutes, and then extracted twice with ethyl acetate (0.10 L). The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (ethyl acetate/n-hexane=1/2) to obtain methyl 6-ethyl-3-hydroxy-5-(methoxycarbonyloxy)-2-phenylphenylacetate (89 mg, 64%).