Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][C:3](=[O:2])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN
Reactant: CCCCC(=O)CC(=O)OC
Solvent: CCO
Solvent: O
Product: CCCCC(=O)CC(=O)NC
Temperature: 90 °C

Procedure:
0.378 mol (60.2 ml) 3-oxo-heptanoic acid methylester, 400 ml 33% methylamine solution in ethanol and 40 ml water were stirred for 48 hours at 80° C. in a round-bottomed flask with a reflux condenser. After cooling off, the solvents were distilled off on a rotavap, the raw products were taken up in 200 ml water and 40 ml ethanol and set to about pH 3 with 40 ml 32% HCl. The reaction mixture was heated to 90° C. for 24 hours and then again concentrated to dryness in the rotavap. The raw product heated with 150 ml to reflux, filtrated hot and the filtrate was left to cool off. The product was filtrated off and dried in a vacuum drying cabinet at 50° C. 5.9 g of the title compound was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:42]=[CH:41][C:8]([CH2:9][C:10]2[CH:15]=[C:14]([C@:16]3([O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)[OH:17])[CH:13]=[CH:12][C:11]=2[CH3:40])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>CO.O1CCCC1>[OH:17][C@:16]1([C:14]2[CH:13]=[CH:12][C:11]([CH3:40])=[C:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:42][CH:41]=3)[CH:15]=2)[O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]1[OH:19]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(OC(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-acetoxybenzyl)-1-methyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene (1.8 g) in a mixture of methanol (30 mL) and tetrahydrofuran (15 mL) is treated with aqueous potassium hydroxide solution (4 mol/L, 3.8 mL). The reaction solution is stirred at ambient temperature for 30 min and then neutralized with hydrochloric acid (1 mol/L). The resulting mixture is concentrated under reduced pressure, diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried (sodium sulphate) and concentrated.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:16][C:14](=[O:15])[CH2:13][N:8]1[CH:5]([S:4][CH2:1][CH:2]=[CH2:3])[CH:6]([CH2:10][CH3:11])[C:7]1=[O:9]
Reactant: C=CCSC1NC(=O)C1CC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Reaction time: 8 h

Procedure:
To a solution of 2.34 g of 4-allylthio-3-ethylazetidinone in 20 ml of redistilled dimethylformamide were added 1.37 ml of methyl bromoacetate and 4.16 g of ground potassium carbonate. The solution was stirred overnight then filtered through a pad of Hyflo, (Hyflo being a Trade Mark), poured into 75 ml of water, and extracted five times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo to give the title compound. (Yield 3 g)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C@@H:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25]>>[CH2:24]([O:26][C@@H:27]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:22][CH2:21]/[CH:20]=[C:19](/[C:16]2[CH:15]=[CH:14][C:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:17]=2)\[CH3:23])=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(-c4ccccc4)c3)cc2)cc1)OCC
Yield: 78.7 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-en-1-ol (0.30 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 62 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (2-amino-ethyl)-carbamic acid tert-butyl ester according to the GPA affording 27 mg (62%) of a red powder. Rt=4.43 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:35]>>[CH3:34][N:30]([CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:11]([CH3:35])[CH:12]=1)=[N:18][CH:19]=[N:20]2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1ccccn1
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c12
Yield: 11 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide to give the title compound as a white solid in 11% yield; NMR spectrum (DMSO-d6 373K) 1.94 (s, 3H), 2.28 (s, 3H), 3.00 (s, 3H), 3.88 (t, 2H), 4.46 (m, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.34 (m, 2H), 7.51 (m, 2H), 7.55 (d, 1H), 7.68 (t, 1H), 7.83 (td, 1H), 8.41 (s, 1H), 8.58 (d, 1H), 9.63 (s, 1H); Mass spectrum MH+ 458.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of indole-5-carboxylic acid (2.63 g, 16.34 mmol) in N,N-dimethylformamide (50 mL) was added sodium bicarbonate (8.24 g, 98.04 mmol) and benzyl bromide (11.66 mL, 98.04 mmol). The reaction was stirred for 48 hours at ambient temperature under nitrogen. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted with a further portion of ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated in vacuo. The resultant crude product was purified by flash chromatography on SiO2, eluting with 20% ethyl acetate/hexane followed by 50% ethyl acetate/hexane to afford the title compound as an oil, 4.82 g, quantitative.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]=[O:11].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.Cl>C(#N)C>[OH:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C=O)c(O)c1
Yield: 84.5 %

Procedure:
A mixed solution of 3,5-dimethylphenol (20.0 g, 164 mmol), paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g, 246 mmol) and triethylamine (80 mL, 573 mmol) in acetonitrile (500 mL) was heated under reflux for 4 hours. The reaction solution was acidified with hydrochloric acid, which was extracted with diethyl ether. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 20.8 g (yield 84%) of the title compound. Melting point: 48-49° C. (hexane).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCC1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCCCC3)n2n1)c1cccnc1
Yield: 21.9 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclohexylamine (187 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (26 mg, 22%). HPLC, Rt: 3.48 min. (purity 98.5%). LC/MS, M+(ESI): 370.9, M−(ESI): 368.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[ClH:9].[NH2:10][N:11]1[CH2:15][CH:14]([CH3:16])[N:13]([CH3:17])[C:12]1=[O:18]>CO>[ClH:9].[CH3:17][N:13]1[CH:14]([CH3:16])[CH2:15][N:11]([N:10]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:12]1=[O:18]
Reactant: O=Cc1cccnc1
Reactant: CC1CN(N)C(=O)N1C
Agent: Cl
Solvent: CO
Product: CC1CN(N=Cc2cccnc2)C(=O)N1C
Yield: 84.1 %

Procedure:
2.3 g of pyridine-3-carbaldehyde are added at room temperature to a solution of 3.6 g of 1-amino-3,4-dimethylimidazolidin-2-one hydrochloride in 25 ml of methanol. The solution is concentrated by evaporation and the residue is stirred with tetrahydrofuran. 4.6 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride having a melting point of 232-236° are obtained. 2.3 g of triethylamine are added to a suspension of 4.4 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride in 100 ml of tetrahydrofuran and after 20 minutes under reflux the reaction mixture is filtered while hot. 300 ml of hexane are added to the filtrate. The crystals that have precipitated are filtered off with suction and dried. 2.5 g of the title compound having a melting point of 126-129° are obtained.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@:4]([CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[OH-].[Na+]>CO>[C:23]1([CH2:22][C@@:4]([C:3]([OH:33])=[O:2])([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@](Cc1cccc2ccccc12)(CC(C)C)NC(=O)CCC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@](Cc1cccc2ccccc12)(NC(=O)CCC(=O)N1CCOCC1)C(=O)O
Yield: 78.2 %

Procedure:
To a solution of 380 mg of the ester compound in 5 ml of methyl alcohol was added 0.92 ml of a 1Naqueous sodium hydroxide solution with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was washed with ethyl ether. The aqueous layer was adjusted to a pH of 2to 3 by adding a 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 288 mg of 2-(1-naphthylmethyl)-3-morpholinocarbonylpropionyl-L-leucine as a white powder.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][S:5][CH2:6][CH2:7][C:8]#[N:9].[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[NH:13])[NH2:12]>CC(C)=O>[C:8]([CH2:7][CH2:6][S:5][CH2:4][C:3]1[N:17]=[C:15]([N:14]=[C:11]([NH2:13])[NH2:12])[S:16][CH:2]=1)#[N:9]
Reactant: N#CCCSCC(=O)CCl
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: N#CCCSCc1csc(N=C(N)N)n1
Temperature: 50 °C
Reaction time: 9 h
Yield: 84.4 %

Procedure:
To a solution of 8.9 g of 1-chloro-3-(2-cyanoethylthio)propanone in 100 ml of acetone is added 6.3 g of amidinothiourea and the reaction mixture is stirred at 50° C. for 9 hours. Also, the reaction mixture is concentrated under reduced pressure, made basic with saturated sodium carbonate solution, and extracted with chloroformmethanol (10:1) solution (170 ml×2). The combined organic layer is dried over anhydrous magnesium sulfate, and is concentrated in vacuo to give a solid, which is crystallized from acetone-hexane to afford 10.2 g of the title compound, m.p.: 125°-128° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 27.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added at 10°-15° C. Successively 11.1 g (0.105 mole) of sodium carbonate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 75.3 g of water was added and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 29.9 g (69.9% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>C1COCC1.C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOCCCCOCCCN
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCOCCCCOCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-Butoxycarbonylamino)-4,9-dioxa-12-dodecanamine (5.0 g, 16.45 mmol) was dissolved in THF (30 mL), succinic anhydride (1.81 g, 18.1 mmol) in acetonitrile (10 mL) was added and the mixture was heated to 60 C for 4 h, and subsequently stirred at RT overnight.
Reaction SMILES: [C:1]1([S:7][CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:15]=3)[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.O1CCCC1>[C:1]1([S:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:15]=3)[O:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2cc(OCc3ccc4ccccc4n3)ccc2OCC1Sc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OC[C@H]1Sc1ccccc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a suspension of the title product of Example 63 (1.85 g, 0.00447 mol) in 70 ml of methanol at 0-5° C. was added in portions 208 mg (0.00538 mol) of sodium borohydride. The reaction was warmed with stirring to room temperature, then diluted with 20 ml of tetrahydrofuran to obtain a homogeneous mixture, which, after stirring for 1.2 hours was concentrated in vacuo and the residue taken up in 400 ml ethyl acetate, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to a yellow-white foam. Purification was carried out by silica gel column chromatography eluting with 20% ethyl acetate/CH2Cl2. The less polar cis-title product was isolated as a white solid (1.11 g, 60%). Recrystallization from isopropanol/hexanes gave 1.04 g of white crystals, m.p. 144-146° C. The more polar trans-title product was obtained as a mixture, contaminated with a small amount of the less polar product. It was re-chromatographed using the same eluant to yield 400 mg (22%) of trans-title product as a white foamy solid. Recrystallization from toluene-hexanes afforded 280 mg of white crystals, m.p. 100-102° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:15](Cl)[C:16]#[C:17][CH2:18][CH3:19]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]#[C:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCC#CCCl
Reactant: CCOC(=O)CSc1ccc(O)cc1
Product: CCC#CCOc1ccc(SCC(=O)OCC)cc1

Procedure:
(4-Pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4-hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol) 7.15 g of the product isolated. Yield 7.15 g (86%); brown oil; MS: 278 EI (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:50]2[CH:51]=[CH:52][C:53]([F:54])=[C:48]([F:47])[CH:49]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 55 °C
Yield: 39.6 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (0.239 g, 0.05 eq.), (R)-BINAP (0.575 g, 0.05 eq.) and 3,4-difluoro-phenylboronic acid (7.3 g, 2.5 eq.). 400 mL of MeOH and 40 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (3.72 g). The reaction mixture was heated at 55° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 2.31 g (40%) of the title product as a light yellow oil. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(NC2CCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of cyclopentylamine to give 12 mg (11% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: C[O-]
Reactant: N#Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of 3 g (11.49 mmol) 2,6-dinitro-4-trifluoromethyl-benzonitrile (CAS: 35213-02-6) in 30 ml methanol at 0° C. under nitrogen, was added 2.3 ml (11.49 mmol) of a 5M sodium methoxide in methanol. The reaction mixture was stirred at 0° C. for 1.5 hours then poured into ice water, stirred for 60 minutes and the product was collect by filtration. The crude solid was purified on silica (Eluent: heptane/ethyl acetate 0 to 30%) to provide 2.24 g (79%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (42.9 mmol)) 4-chloro-6-nitro-quinoline-3-carbonitrile, 260 ml ethanol, and 5.40 ml 3-chloroaniline was heated to reflux under N2. Removed heat at 4 hours, cooled to 25° C. and added saturated sodium bicarbonate until the pH was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solid, and air dried. Washed solids with water and dried in vacuo. Dissolved in boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried residue in vacuo, giving 6.5 g of yellow solid: mass spectrum (electrospray m/e): M+H=325.0, 327.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].O=[C:22]([CH2:28][CH3:29])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[NH2:20][C:19]1[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:4]=2[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])[N:1]=[C:22]([CH2:28][CH3:29])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: CCC(=O)CC(=O)OC
Product: CCCNC(=O)C(C)(C)COc1cccc2nc(CC)c(C(=O)OC)c(N)c12

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and methyl 3-oxopentanoate as a yellow solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 0.75 (t, J=8.0 Hz, 3H), 1.17 (t, J=8.0 Hz, 3H), 1.26 (s, 6H), 1.40 (m, 2H), 2.84 (q, J=8.0 Hz, 2H), 3.04 (q, J=8.0 Hz, 2H), 3.85 (s, 3H), 4.13 (s, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.27 (dd, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.81 (m, 3H). MS 388 (MH+).