Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([CH2:11][F:12])=[O:10])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[BH4-].[Na+].Cl>O1CCCC1.CO>[F:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]2[C:4]1=[O:13]
Reactant: O=C(CF)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCC(O)CF
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimidopropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20° C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20° C. The reaction mixture is stirred for 15 minutes at -20° C and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford 1-fluoro-5-phthalimido-2-pentanol, m.p. 85° C. A mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-2-pentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25° C. The solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give 1-fluoromethyl-1,4-butanediyl-bis-phthalimide, m.p. 112° C. A suspension of 3.1 g of 1-fluoromethyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4° C is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4° C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-1,4-butanediamine dihydrochloride, m.p. 154° C.
Reaction SMILES: C(N[C:9](=[O:37])[CH:10]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C@@H:22]([O:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O:42]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.O.[OH-].[Li+].Cl>C(#N)C.O>[CH:31]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]([OH:42])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-benzyl-2-cyclohexyl-2-[5,6-difluoro-2-((S)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide (2.16 g, 4 mmol, 1.0 equiv) in acetonitrile (25 ml) were added di-tert.-butyl-dicarbonate (1.123 g, 5 mmol, 1.2 equiv., [CAS RN 24424-99-5]) and N,N-dimethylaminopyridine ((0.051 g, 0.1 equiv., [CAS RN 1122-58-3]). The mixture was stirred 48 h at room temperature. A solution of lithium hydroxide monohydrate (0.54 g, 3.0 equiv., [CAS RN 1310-66-3]) in water (4 ml) was added, and the mixture vigorously stirred overnight at room temperature, and 2 h at 70° C. The mixture was allowed to cool to room temperature and poured into 1M aqueous hydrochloric acid (25 ml). The product was extracted with ethyl acetate (3×50 ml) and the combined organic phases washed with brine and dried over magnesium sulfate. The brown residue was purified by column chromatography on silica gel (75 g, 1:0 to 98:2 EtOAc/AcOH eluant) to afford the product as an off-white mixture of diastereomers. MS (ISN): 413.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:29])[C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(C(=O)C(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(O)C(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (4.16 g, 30.5 mmol) in diethyl ether (50 ml), sodium borohydride (2.31 g, 61.1 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-3-oxopropionate (6.540 g, 15.27 mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1−1/1) to give the objective substance.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Ni].C(O)(C)C>[CH:1]1([CH2:7][CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(CCO)CC1=CCCCC1
Agent: [Ni]
Solvent: CC(C)O
Product: CC(CCO)CC1CCCCC1
Yield: 93 %

Procedure:
A solution of 4-(cyclohex-1-en-1-yl)-3-methylbutan-1-ol (1.68 kg, 10.0 mols), isopropyl alcohol (100 ml) and Raney nickel (100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-(Cyclohex-1-yl)-3-methylbutan-1-ol (1.58 kg, yield: 93%, purity: 99% sum of the isomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[Cl:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol S was followed using 1-(4-chloro-phenyl) piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)=[O:4].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([OH:1])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(N[C@@H]1CNc2ccccc2C1)[C@@H](O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-hydroxy-2-phenyl-N—((S)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (355 mg, 1.26 mmol) in 1,2-dichloroethane (20 mL) was added 4-fluorobenzaldehyde (160 μL, 1.51 mmol) followed by glacial acetic acid (86 μL) and sodium triacetoxyborohydride (533 mg, 2.51 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM (20 mL) and quenched by addition of water (20 mL). The organic layer was separated and the aqueous layer was once again extracted with DCM (20 mL). The combined organic extracts were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography using a gradient (20-40% EtOAc in hexanes). The desired product (S)—N—((S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylacetamide was obtained as a beige solid (351 mg, 72% yield). 1H NMR (DMSO-d6) 400 MHz δ 7.67 (d, J=7.8 Hz, 1H), 7.39-7.34 (m, 2H), 7.33-7.22 (m, 5H), 7.12-7.07 (m, 2H), 6.96-6.90 (m, 2H), 6.58-6.52 (m, 2H), 6.07 (d, J=5.1 Hz, 1H), 4.91 (d, J=4.7 Hz, 1H), 4.45 (d, J=16.8 Hz, 1H for AB system), 4.41 (d, J=16.4 Hz, 1H for AB system), 4.24-4.15 (m, 1H), 3.34 (ddd, J=11.3, 3.5, 1.2 Hz, 1H), 3.22 (dd, J=11.0, 7.0 Hz, 1H), 2.95 (dd, J=15.7, 4.7 Hz, 1H), 2.80 (dd, J=16.0, 7.8 Hz, 1H). LCMS m/e 391 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)c1ccccn1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2ccccn2)no1

Procedure:
Method same as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (210 mg, 057 mmol) and 2-pyridinesulphonylchloride (J. Med. Chem; 1997, 40, 1149) (170 mg, 0.96 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10].C(N(CC)CC)C.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 59.2 %

Procedure:
To a solution of 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazole (597 mg) and triethylamine (243 mg) in methylene chloride (10 ml) was added triphenylmethyl chloride (669 mg), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate to give 4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methyl-5-triphenylmethylaminopyrazole (640 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([CH:5]1[CH2:8][C:7](=[O:9])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]([CH2:3][CH:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)[CH3:10]
Reactant: CN(C)C(=O)C1CC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC(O)C1
Yield: 57.3 %

Procedure:
To a solution of N,N-dimethyl-3-oxocyclobutanecarboxamide (700 mg, 5 mmol) in 20 mL of THF was added LAH (370 mg, 10 mmol, 2 eq) at 0° C. The mixture was heated at reflux for 2 h and cooled down. The reaction was quenched with 1 mL of water carefully and filtered. The filtrated was concentrated to afford the desired product as a brown oil (370 mg, 56%), which was used in the next step without further purification. MS: m/z 130.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1ccco1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccco2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-furyl)pentanoate (1.5 eq., prepared in Synthetic Example 18) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(2-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 166 to 167° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]2[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=12)=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.C(OCC)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:1]([OH:2])[C:3]2[CH:8]=[N:7][CH:6]=[C:5]3[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=23)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(C=O)cncc2s1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1cc2c(C(O)c3ccc(Cl)cc3)cncc2s1

Procedure:
To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) at −5° C. was slowly added a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (2.85 mL, 2.85 mmol). The reaction was quench after 10 minutes with dropwise addition of water (1 mL) and partitioned between dichloromethane (25 mL) and 50% sat. aq NaHCO3 (50 mL). The aqueous phase was extracted with dichloromethane (25 mL) and the organic extracts combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc/hexane as eluent to provide the title compound as a foam, which was crushed and dried in a desiccator to yield a powder (0.36 g, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:15]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.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.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:15]1([C:21](=[O:22])[CH2:23][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCCCC1
Temperature: 90 °C
Yield: 29.7 %

Procedure:
A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (3.92 mmol, 1.0 g), cyclohexylmethylketone (5.92 mmol, 0.83 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.88 mmol, 1.17 g), tris(dibenzylideneacetone)dipalladium(0) (0.78 mmol, 0.72 g), and potassium t-butoxide (7.84 mmol, 0.88 g) were heated to 90° C. for 12 h in a sealed vial. The reaction was cooled and partitioned in water (50 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (3×20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on a 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 1-cyclohexyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.35 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F-].[Cs+]>O1CCOCC1>[CH3:2][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 131.7 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 102 mg (0.15 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 7), 1.27 g (10.0 mmol) of 4-chlorotoluene, 2.04 g (15.0 mmol) of MeC6H4B(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 20 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of hexane. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.2 g (66% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9](O)[C:8]([O:12][CH2:13][CH3:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][OH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[C:7]([O:15][CH2:16][CH3:17])[C:8]([O:12][CH2:13][CH3:14])=[C:9]([O:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)c(OCC)c(OCC)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCC)c(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (3.93 mmol) of 3,4-Diethoxy-5-hydroxy-benzoic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 0.83 g (4.33 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 3.93 g (equivalent to 11.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.05 g (11.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:15].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]([I:15])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ncc(Br)cn1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ncc(I)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
5-Bromo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 1) (950 mg, 3.68 mmol) was dissolved in dioxane (10 ml). Sodium iodide (2.2 g, 14.7 mmol, 4 equiv.), copper(I)iodide (66 mg, 0.74 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (CAS 67579-81-1) (105 mg, 0.74 mmol, 0.2 equiv.) were added and the mixture was stirred for 16 hours at 100° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (870 mg, 78% yield) was obtained as a yellow solid, MS: m/e=306.0 (M+H+).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[N+](C(C)C)([O-])=O.ClC[C:13]1[CH:18]=[CH:17][CH:16]=C[C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)=[O:24])(=[O:21])=[O:20]>C(O)C>[CH:2]([C:3]1[CH:16]=[CH:17][CH:18]=[CH:13][C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[N:31]=1)=[O:24])(=[O:21])=[O:20])=[O:1]
Reactant: CC[O-]
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCl)n1
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)[N+](=O)[O-]
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1

Procedure:
To a solution of 6.26 mmol of sodium ethoxide in 10 ml of absolute ethanol under an argon atmosphere was added 0.80 ml of 2-nitropropane. Next 0.74 g (2.09 mmol) of 2-chloromethyl-N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide was added and the solution was heated to reflux. The mixture became pasty shortly after heating was begun and an additional 3 ml of ethanol was added to facilitate stirring. After heating for 4 hours, the solvent was removed under reduced pressure and the residue was dissolved in 12 ml of water. The crude product was precipitated by neutralization of the solution with 3N hydrochloric acid. The crude product was purified by preparative thin layer chromatography on silica gel and subsequent recrystallization from acetone to provide the title compound, m.p. 157° C. (decomp.). The infrared spectrum showed a new carbonyl band at 1675 cm-1, indicative of the formation of an aldehyde, in addition to the urea carbonyl band at 1710 cm-1. The nuclear magnetic resonance spectrum showed peaks at 10.57 ppm and 10.67 ppm which are consistent with an aromatic aldehyde with restricted rotation.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=1)=[O:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (1.054 g, 6.50 mmol) was added to a solution of 5-bromo-2-fluorobenzoic acid (1.129 g, 5.0 mmol) in DMF (10 mL) and the RM was stirred for 2 h at 0° C. 4-(trifluoromethoxy)aniline (1.129 g, 5.0 mmol) was added and the RM was allowed to warm up RT and stirred for 2 days. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3, stirred and filtered. The filtered material was washed with water, dissolved in EtOAc, washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 100 g, n-hexane/EtOAc 2:1) to afford the title compound as a white crystalline solid. UPLC-MS (Condition 2) tR=1.27 min, m/z=378.0/380.0 [M+H]+.