Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH3:1][CH:2]([CH3:5])[CH2:3][S:4][CH2:8][CH2:7][C:6]#[N:9]
Reactant: C=CC#N
Reactant: CC(C)CS
Agent: C[O-]
Agent: [Na+]
Product: CC(C)CSCCC#N

Procedure:
β-(2-Methyl-1-propylmercapto)propionitrile was prepared according to the procedure of Example 1 using 2-methyl-1-propanethiol (25.0 g; 0.28 moles), acrylonitrile (14.9 g; 0.28 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[CH2:26][C:27]#[N:28].O>O1CCCC1>[C:27]([CH2:26][CH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:16])#[N:28]
Reactant: O=C1CC(c2ccccc2)(c2ccccc2)c2ccccc21
Reactant: N#CCBr
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC1C(=O)c2ccccc2C1(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3,-2'-cyanooxirane] (Compound 5) and 2-cyanomethyl-3,3-diphenylindanone (Compound 9) were synthesized as follows: 3,3-diphenylindanone (Compound 2), 5.0 g (0.0176 mole) and 2.62 g (0.0229 mole) of potassium hydride were stirred at room temperature in 40 mL of tetrahydrofuran. After the gas evolution subsided (approx. 45 min), 1.5 mL (0.0215 mole) of bromoacetonitrile was added. The dark red mixture was stirred for 1 hour and then 50 mL of water was added. The mixture was extracted three times with 75 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo, loaded onto a silica gel column and eluted with 10% ethyl acetate in hexane. Three fractions were collected. After evaporation of the solvent, the first fraction yielded unreacted starting material (3.5 g). The second fraction yielded 0.49 g (9% yield) of spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3'-2'-cyanooxirane] (Compound 5) as a white solid. The third fraction yielded 1.05 g (18% yield) of 2-cyanomethyl-3,3-diphenylindanone (Compound 9) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[CH:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[CH:23]2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30])[CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:12])[CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[CH:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[CH:23]2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30]
Reactant: CN(CCCNC(=O)OC(C)(C)C)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCN)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of [3-[[3-(1,3-dioxo-3a,9b-dihydro-1H,3H-benzo[de]isoquinolin-2-yl)propyl]methylamino]propyl]carbamic acid tert-butyl ester (0.34 g, 0.81 mmol) in CH2Cl2 (24 ml) was added trifluoroacetic acid (6 ml). The reaction mixture was stirred at room temperature for 16 h at which point the reaction was completed by TLC. All solvents were removed under reduced pressure to give 2-[3-[(3-aminopropyl)methylamino]propyl]-3a,9b-dihydro-benzo[de]isoquinoline-1,3-dione (0.24 g, 92%) as an oil, which was used directly in the next reaction. 1H-NMR [MeOD, _, ppm]: 8.64 (m, 2H), 8.54 (m, 2H), 7.92 (m, 2H), 4.45 (m, 2H, 2CH2NO), 3.55 (m, 4H, 2CH2), 3.33 (m, 2H, CH2), 3.22 (s, 3H, N(CH3)), 2.44 (m, 4H, 2(CH2)).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])[CH3:4].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[OH:29])(=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 4.2 mmol), 2-hydroxybenzoic acid (0.57 g, 4.2 mmol) and imidazole (0.29 g, 4.2 mmol) in EtOAc (40 mL) at 0° C. was added a solution of DCC (0.87 g, 4.2 mmol) in EtOAc (40 mL). The mixture was allowed to warm to RT, stirred (16 h) and filtered. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel, eluting with EtOAc-PE (0-50%) to afford N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (1.07 g, 50.5%) as a light yellow oil. Mass calculated for C32H44N2O3=504.70; found: [M+H]+=505.5.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[N+:1]([CH:4]=[C:5]([NH:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: NCCCSc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCCSc1ccccn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene with 2-(3-aminopropylthio)pyridine according to the procedure of Example 1 (a) (ii) yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:46]1[CH2:51][CH2:50][C:49]2([C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][O:52]2)[CH2:48][CH2:47]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:46]3[CH2:51][CH2:50][C:49]4([C:59]5[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=5[CH2:53][O:52]4)[CH2:48][CH2:47]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2cc(Cl)ccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.036 g (0.19 mmol) spiro[isobenzofuran-1(3H),4′-piperidine] at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.036 g, 49%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([CH3:21])=[C:8]([C:18](O)=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:32]1[CH2:36]CC[CH2:33]1.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[CH3:33][N:32]([CH3:36])[C:18]([C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5]([C:6](=[O:22])[C:7]=1[CH3:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:19]
Reactant: Cc1c(C(=O)O)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N(C)C)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
In a 50 mL round bottom flask, 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid (0.5 g, 1.60 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 1.11 g, 2.39 mmol) and N,N-diisopropylethylamine (1.11 mL, 6.37 mmol) were added to anhydrous DMF (5.0 mL). The mixture was stirred at room temperature for 30 min. Dimethylamine (2M in THF, 1.6 mL, 3.2 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was concentrated to dryness and the crude was purified by flash chromatography using 3:2 hexane-ethyl acetate to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (600 mg, >100% yield). MS calcd for C19H17ClN2O2 [(M+H)+] 341, obsd 341.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[CH2:20][CH2:19]1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCC1CC1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CC1CC1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and cyclopropylmethyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+:11].Br>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O-:9].[Na+:11]
Reactant: Cc1ccc(O)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc([O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium 3,4-dimethylphenoxide was prepared by adding slowly with stirring and under nitrogen a solution of 3,4-dimethylphenol (48.86, 0.4 mole) in 250 ml of tetrahydrofuran (distilled from lithium aluminum hydride) to a suspension of 50% sodium hydride (18.2 g, 0.4 mole) previously washed with hexane and in 250 ml of tetrahydrofuran. After stirring for 30 minutes at room temperature, all evolution of hydrogen ceased and 1-(2'-pyridyl)-2-bromoethanol* hydrobromide (28.3 g, 0.1 mole) was added all at once in solid form. The reaction mixture was refluxed under nitrogen overnight. The tetrahydrofuran was removed on the rotary evaporator, and the resulting oil was partitioned between water and methylene chloride. The methylene chloride layer was extracted with three 200 ml portions of 10% sodium hydroxide and dried over sodium sulfate. Removal of solvent gave a brown oil (23.82 g). This oil was dissolved in methanol and converted to the hydrochloride salt with ethereal hydrogen chloride. This salt was recrystallized from methanoldiethyl ether to give 16.20 g (57.9%) of an off-white crystalline solid, m.p. softens 161°-162° C., melts 163°-164° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ncc1C(=O)OCC1CC1
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of 6-fluoro-4-methylpyridine-3-carboxylic acid (4.94 g, 31.8 mmol), cyclopropylmethanol (3.78 mL, 47.8 mmol) and N,N-dimethylpyridin-4-amine (778 mg, 6.37 mmol) in DMF (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.71 g, 35.0 mmol), and the mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:1) to give the title compound (3.86 g, yield 58%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[SH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cccc(SCC(=O)c2ccccc2)c1
Yield: 120.3 %

Procedure:
To bromoacetophenone (250 mg, 1.16 mmole) and anhydrous K2CO3 (694 mg, 5.02 mmole) in ethanol, 193.6 mg (1.25 mmole) 3-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The basic aqueous solution was extracted with ethyl acetate to remove unreacted bromoacetophenone. The aqueous layer was acidified and extracted with ethyl acetate, dried, evaporated and the residue purified by flash chromatography using chloroform:methanol 95:5. Evaporation of the fractions resulted in a yellow powder (380 mg). M.S. m/s 271 (M−1)+. 1H NMR (DMSO) δ4.75 (2H, s, —CH2-), 7.39-7.7 (4H, m, 4×ArH), 7.75 (1H, d, ArH, J==5.61 Hz), 7.86 (1H, s, ArH), 8.02 (3H, d, ArH).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[S:23]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (8.8 ml) was added to a stirred mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (European Patent Application No. 0 495 750, Chem. Abstracts, Vol. 117, Abstract 191869g, 6.38 g), methanesulphonyl chloride (3.7 ml) and methylene chloride (70 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and a concentrated aqueous citric acid solution. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent to give tert-butyl 4-mesyloxypiperidine-1-carboxylate (7.82 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH2:25])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[S:42][C:41]([S:43](Cl)(=[O:45])=[O:44])=[CH:40][CH:39]=1.O>CC(C)=O>[CH2:1]([C@H:8]([NH:25][S:43]([C:41]1[S:42][C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:39][CH:40]=1)(=[O:44])=[O:45])[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(N[C@@H](Cc1ccccc1)CN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
The product of Example 6, Step (a) (0.091 g) was dissolved in acetone (2 ml). Potassium carbonate [0.066 g dissolved in H2O (0.5 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.067 g) and the reaction left to stir for 10 mins. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by flash silica column chromatography with 1% MeOH/98.9% CH2Cl2/0.1% aq NH3 as eluent, and then reverse phase HPLC {with a gradient eluent system [50% MeCN/NH4OAcaq (0.1%) to 70% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.057 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[NH:28][C:29](=[O:37])[C:30]2[CH2:36][O:35][CH2:34][CH2:33][C:31]=2[N:32]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH2:26][C:27]3[NH:28][C:29](=[O:37])[C:30]4[CH2:36][O:35][CH2:34][CH2:33][C:31]=4[N:32]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: COCCNCc1nc2c(c(=O)[nH]1)COCC2
Solvent: CC#N
Product: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Yield: 23.4 %

Procedure:
The title compound (22 mg, 0.044 mmol) was prepared following the general procedure of Example 1 from [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (65 mg, 0.188 mmol, 1.0 eq) and 2-[(2-methoxy-ethylamino)-methyl]-3,5,7,8tetrahydro-pyrano[4,3-d]pyrimidin-4-one (51.7 mg, 0.188 mmol, 1.0 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88-8.02 (m, 2H) 6.98-7.10 (m, 2H) 4.52 (br s, 1H) 4.36 (d, J=16.67 Hz, 3H) 3.75-3.92 (m, 5H) 3.52-3.58 (m, 3H) 3.42-3.45 (m, 3H) 3.27 (d, J=5.05 Hz, 15H) 3.17 (br s, 2H). HR-MS (m/z, MH+): 499.2580, 500.2607, 501.2628. HPLC retention time: 2.62 min (Ascentis column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=1)[CH3:58]>CN(C)C=O>[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:65][N:64]=1)[CH3:58]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CCc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.7 g, Reference Example 31) in anhydrous dimethylformamide (25 ml) was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.85 g), diisopropylethylamine (0.54 g) and a solution of 3-(5-amino-pyrid-2-yl)propanoic acid ethyl ester [0.42 g, Reference Example 4(a)] in dimethylformamide (5 ml). After stirring at room temperature for 5 hours and standing over night the reaction mixture was evaporated. The residue was treated with ethyl acetate and the resulting solution was washed three times with water, then with brine and then evaporated. The residue was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97:3, v/v) to give the title compound (0.68 g) as a white foam.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1
Product: Nc1ncc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C4CC4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example E.14) (0.30 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.093 g, 37%). MS (ISP) 390.3 [(M+H)+]; mp 238-240° C.
Reaction SMILES: [CH2:1]([SH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[CH2:14][CH:15]=[C:16]=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C(OCC)C>[C:20]([O:22][CH3:23])(=[O:21])[CH2:19][CH2:18][CH:17]=[C:16]=[CH:15][CH2:14][S:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)CCC=C=CCBr
Reactant: CCCCCCCCCCCS
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCSCC=C=CCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A mixture of 376 mg of undecylmercaptan, 438 mg of methyl 7-bromohepta-4,5-dienoate and 0.278 ml of triethyl amine in 2 ml of diethyl ether were stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with hexane and toluene to give 210 mg of methyl 8-thianonadeca-4,5-dienoate having the following NMR spectrum which was run in deutochloroform solution with TMS as the internal standard.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CS(C)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: Brc1nccs1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (100 mg, 0.41 mmol), potassium carbonate (114 mg, 0.83 mmol), 2-bromothiazole (0.38 mL, 4.2 mmol), and dimethyl sulfoxide (2.5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound.