Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18]C)[N:3]=1.B(Br)(Br)Br.[NH4+].[Cl-]>ClCCl>[F:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1ccc(Oc2cccc(F)n2)c(OC)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCc1ccc(Oc2cccc(F)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine (1.7 mmol; 449 mg) under argon, in dichloromethane (1.5 mL), cooled to −78° C., was added BBr3 (17 mmol; 1M in CH2Cl2; 17 mL). The reaction mixture was allowed to stir overnight, with gradual heating to room temperature. At −20° C., the reaction was hydrolysed with saturated NH4Cl (3 mL), extracted with ethyl acetate (3*10 mL). Combined organic phases were dried over MgSO4, concentrated in vacuo. The residue was chromatographed on silica gel (gradient cyclohexane/dichloromethane) to give the desired product as a white solid (160 mg; 0.65 mmol; 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 56.6 %

Procedure:
Using preparation method 2, 4-bromobenzenesulfonamide (472 mg, 2 mmol) was reacted with phenylboronic acid (268 mg, 2.2 mmol). Purification by washing with hot toluene followed by filtration gave 4-phenylbenzenesulfonamide as an off-white crystalline solid (264 mg, 55%). NMR 1H (ppm, CDCl3): 7.87 (d, J3=8.6 Hz, 2H), 7.83 (d, J3=8.7 Hz, 2H), 7.70 (d, J3=7.2 Hz, 2H), 7.48 (t, J3=7.3 Hz), 7.40 (t, J3=7.1 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:9][C@H:10]1[CH2:15][N:14]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[N:21]=1
Reactant: C[C@H]1CNCCN1c1ccc2nnc(C(F)(F)F)n2n1
Reactant: O=Cc1ccncc1
Product: C[C@H]1CN(Cc2ccncc2)CCN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 53 %

Procedure:
A mixture of pyridine-4-carboxaldehyde and 6-[(2S)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2S)-2-methyl-4-(pyridin-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 53% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.O[C:23]1[CH:27]=[CH:26][O:25][N:24]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:25]1[CH:26]=[CH:27][C:23]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:11]([F:21])[CH:10]=3)[CH2:4]2)=[N:24]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Yield: 69.2 %

Procedure:
Prepared by the general method of Example 1 using as starting material 5(R)-hydroxymethyl-3-(4-morpholino-3-fluoro-phenyl)oxazolidin-2-one (WO95/07271; 300 mg, 1.01 mmol), 3-hydroxyisoxazole (95 mg, 1.12 mmol), diisopropylazodicarboxylate (225 mg, 1.11 mmol) and triphenylphosphine (305 mg, 1.16 mmol) in THF (5 ml). Purified by flash chromatography (Merck 9385 silica. EtOAc/isohexane (7/3)) to give the title compound (254 mg, 69%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:14])=[N-]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dibromobenzoic acid (1 eq.) in ether was added dropwise a solution of diazomethane in ether until gas evolution had ceased. The reaction was stirred for 20 min and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[OH:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: CCNCc1ccccc1F
Reactant: O=C(O)COc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.248 g, 0.993) was dissolved in DMF (10 ml), (4-hydroxyphenoxy)acetic acid (0.150 g, 0.903 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.319 g, 0.993 mmol) and N-ethyl-N,N-diisopropylamine (0.245 g, 1.896 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.177 g of N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenoxy)acetamide (yield 64.6%).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[C:16]([F:33])[CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:4]1=[O:40])[CH3:2].[ClH:41]>C(OCC)(=O)C.C(OCC)C>[ClH:41].[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:16]([F:33])[CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:4]1=[O:40])[CH3:2]
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)nc21
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCNCC4)c(F)c3)nc21
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(8-ethyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)-2-fluorophenyl)piperazine-1-carboxylate (45 mg, 0.08 mmol) in ethyl acetate (5 mL) was added a 4M solution of hydrochloric acid in diethyl ether (5 mL) and the reaction was stirred for 18 h. The precipitate was filtered off to give 8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride as an off-white solid (36 mg, 0.07 mmol, 87%). ESMS m/z 445 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (br. S., 1H), 9.22 (br. S., 2H), 8.85 (s, 1H), 8.02 (s, 1H), 7.84 (d, J=15. e.g., 1 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.11 (t, J=8.5 Hz, 1H), 4.41 (q, J=6.7 Hz, 2H), 3.22 (br. S., 8H), 1.31 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[N:24]=1>>[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2([NH:32][C:12]([C:10]3[CH:9]=[N:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:31][CH2:30][CH2:29]2)[N:24]=1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc(C2(N)CCC2)no1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(N4CC(F)(F)C4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine (CAN 1170897-128-5, 64.42 mg, 0.42 mmol) as starting materials, and isolated (25 mg, 16.95%) as off white solid; LC-MS (UV peak area, ESI) 99.10%, 421.4 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[Li].O>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(ccn4C)c3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2cc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(1-methyl-1H-indol-5-yl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (51 mg, 0.13 mmol) (Example 48) in THF (1.8 mL) was added LiOH.H2O (6 mg, 0.15 mmol) in water (0.6 mL). The mixture was stirred for 12 h at rt, then the reaction mixture was concentrated under reduced pressure and the residue suspended in a small volume of water. The pH was adjusted to below 3 with HCl (1 N aqueous solution), and the aqueous layer was extracted with EtOAc. The organic layer was dried, filtered, and concentrated under reduced pressure to give 44 mg (93%) of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 7.10 (d, 1H), 7.05-6.96 (m, 2H), 6.93 (d, 1H), 6.81 (dd, 1H), 6.72 (s, 1H), 6.65 (dd, 1H), 6.32 (d, 1H), 4.18-4.00 (m, 4H), 3.69 (s, 3H), 3.52-3.40 (m, 1H), 2.92-2.65 (m, 3H), 2.42-2.24 (m, 2H), 2.22-2.10 (m, 2H), 1.78-1.62 (m, 1H); LC-MS RT=3.45 min, (M+H)+ 380.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][C:4]=1[N+:11]([O-])=O.C(O)(=O)C>ClCCl.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][C:4]=1[NH2:11]
Reactant: C=Cc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=Cc1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 1-methoxy-2-nitro-4-vinyl-benzene (100 mg) in dichloromethane (2 mL) was added zinc dust (large excess), followed by acetic acid (0.5 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with dichloromethane and discarded. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 50 mg of 2-methoxy-5-vinyl-phenylamine.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(-c2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: ClCc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 50 mg of 3-hydroxymethylbiphenyl in 1.5 mL thionyl chloride was heated at reflux temperature for 4 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 45 mg of 3-chloromethylbiphenyl which was used in the next step without further purification or characterization.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([F:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: O[C@@H]1CCNC1
Reactant: CC(=O)c1cc(F)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C
Yield: 12.1 %

Procedure:
A stirred mixture of 7-acetyl-5-fluoroquinolin-8-yl trifluoromethanesulfonate (0.101 g, 0.301 mmol), (3R)-pyrrolidin-3-ol (0.0315 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.147 g, 0.451 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (10 mg, 10%). LCMS calculated for C15H16FN2O2 (M+H)±: m/z=275.1; Found: 275.1.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br.C(N(CC)CC)C>C(Cl)(Cl)Cl.O1CCCC1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([Br:14])[C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=C1C=CC(=O)N1c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1C=C(Br)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To N-phenylmaleimide (2 g, 11.50 mmol) in chloroform (15 mL) was added bromine (0.65 mL, 12.70 mmol) dropwise in chloroform (5 mL). The reaction mixture was refluxed for 1 hour, and then allowed to cool to room temperature. The precipitate was filtered off and washed with chloroform (50 mL). This solid (2.70 g, 8.10 mmol) was dissolved in tetrahydrofuran (50 mL) and to this was added dropwise dropwise a solution of triethylamine (1.2 mL, 8.9 mmol) in tetrahydrofuran (10 mL) at 0° C. and the mixture was stirred for 2 hours. The mixture was allowed to warm to room temperature and solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with H2O (50 mL) brine (50 mL) and dried (Na2SO4). Solvent was removed in vacuo to afford the desired compound as a pale yellow solid (1.80 g, 7.14 mmol) in 62% yield. Data matched literature: Sahoo et al., Synthesis, 2003, 346
Reaction SMILES: [CH3:1]/[C:2](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][CH2:5][C:6](=[CH2:9])[CH:7]=[CH2:8].CO>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][CH2:7][C:6]([CH2:5][CH2:4]/[CH:3]=[C:2](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])\[CH3:1])=[CH2:9]
Reactant: C=CC(=C)CC/C=C(\C)CCC=C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C=C(CC)CC/C=C(\C)CCC=C(C)C
Temperature: 90 °C
Reaction time: 64 h
Yield: 115.9 %

Procedure:
In a 75 mL Keim autoclave, containing a stirring bar, were placed (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene (1.00 g, 4.89 mmol) in THF (20 ml). Methanol (200 μl, 4.94 mmol) and PdCl2(PPh3)2 (80 mg, 0.114 mmol) were added. Then the reactor was sealed and the mixture purged with 3×10 bar of carbon monoxide (CO). While stiffing, the autoclave was pressurized to 40 bar with CO and then heated in an oil bath at 90° C. Once the temperature equilibrated to the set point, the autoclave was pressurized to 67 bar with CO and the reaction allowed to proceed under these conditions for 64 h. Then the reaction mixture was concentrated on a rotary evaporator to give a crude residue which was subsequently distilled on a Kugelrohr apparatus (0.3 mbar/170° C.) to afford a colorless liquid (1.17 g) containing (3E,7E)-homofarnesic acid methyl ester and (3Z,7E)-homofarnesic acid methyl ester (61%, 2/1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:27])[N:10]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:7][CH2:8][C:9]([N:10]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH2:11]1)=[O:27]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of {2-oxo-2-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (preparation #10) (3.25 g, 8.39 mmol) in DCM (200 mL) was added TFA (15 mL). The reaction mixture was stirred at ambient temperature for about 5 h. Toluene (100 mL) was added and the solvents were removed in vacuo. The residue was dissolved in DCM (400 mL) and the organic was washed with saturated NaHCO3, 1.0N NaOH, brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-amino-1-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethanone (2.34 g, 97%) as a light tan solid; RP-HPLC (Table 1, Method a) Rt 1.09 min; m/z: (M+H)+ 288.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[N:7]=1.ClC(Cl)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:18][CH3:19])=[O:17])[N:7]=2)=[CH:49][CH:48]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CNC(=O)c1cccc(Nc2ncnc(NCCCO)n2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Product: CNC(=O)c1cccc(Nc2ncnc(NCCCOc3ccc(Cl)cc3)n2)c1
Yield: 19.6 %

Procedure:
To a microwave vial charged 3-(4-(3-hydroxypropylamino)-1,3,5-triazin-2-ylamino)-N-methylbenzamide (0.112 g, 0.370 mmol) was added dichloroethane (4 mL), triphenylphosphine (0.146 g, 0.556 mmol), p-chlorophenol (0.095 g, 0.741 mmol)) and DEAD (0.129 g, 0.741 mmol) respectively. The reaction mixture was irradiated in the microwave at 130° C. for 30 min. The reaction mixture was concentrated under reduced pressure and purified with flash chromatography using CH2Cl2:MeOH:NH4OH (90:10:1) in CH2Cl2 to afford 3-(4-(3-(4-chlorophenoxy)propylamino)-1,3,5-triazin-2-ylamino)-N-methylbenzamide (30 mg, 20%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1.Cl>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:18][C:17]([CH3:25])([CH3:16])[CH2:22][CH:21]([CH3:23])[CH:20]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCCCCC
Product: CC1C=C(c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)CC(C)(C)C1
Reaction time: 24 h
Yield: 43 %

Procedure:
A mixture consisting of 30.9 g (0.15 mol) of 2,4-di-tert-butylphenol and 10.5 g (0.075 mol) of 3,3,5-trimethylcyclohexanone is melted together and is then saturated, with stirring, with hydrochloric acid gas at 35° C. After 24 hours, the reaction mixture is again saturated with hydrochloric acid gas and is then stirred for 20 hours. Subsequently, the green reaction mixture is diluted with hexane and washed with water and sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=49:1, giving 10.6 g (43%) of 2,4-di-tert-butyl-6-(3,5,5-trimethylcyclohexen-1-yl)phenol as a thick yellowish oil (compound (106), Table 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CC(C)N=C=O
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)NC(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and isopropyl isocyanate (0.012 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 24 h. Isopropyl isocyanate (0.006 mL, 0.06 mmol) was added. The solution was stirred at 50° C. for 24 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.4, 160.9 (dd), 157.8 (dd), 157.4, 151.1, 140.9, 138.7, 136.1, 134.9, 132.6, 131.9, 128.7, 127.3 (dd), 125.9 (dd), 122.4, 120.7, 116.6, 112.9, 112.6 (dd), 105.7 (dd), 42.8, 23.4, 19.6
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:27](=[O:31])[NH:26][C:25]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][C:23]2=3)[C:10]1=[O:41])C1C=CC=CC=1.[H][H]>[Ni].CO>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:27](=[O:31])[NH:26][C:25]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][C:23]2=3)[C:10]1=[O:41]
Reactant: [H][H]
Reactant: O=C(Nc1nc2c(ncn2C2C(=O)N(OCc3ccccc3)C2COCc2ccccc2)c(=O)[nH]1)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1nc2c(ncn2C2C(=O)N(O)C2CO)c(=O)[nH]1)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoylguanin-9-yl)-4-benzyloxymethyl-2-azetidinone (10 mmole) and methanol (50 ml) is hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined methanol fractions are concentrated to give the title compound as a solid.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[CH3:22][NH:23][C:24](=[O:27])[NH:25][NH2:26].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[CH3:22][NH:23][C:24](=[O:27])[NH:25]/[N:26]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: CNC(=O)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=O)N/N=C1/C(=O)N(CCN(C(C)C)C(C)C)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 1.00 g of 1-(2-diisopropylaminoethyl)-5-methylisatin and 0.34 g of 4-methylsemicarbazide in 15 ml of a mixture of ethanol and water (2:1) was added 3.8 ml of a 1N-hydrochloric acid. The mixture was stirred for 16 hours at room temperature. To the reaction mixture was added an aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 0.77 g of (E)-1-(2-diisopropylaminoethyl)-5-methylisatin 3-(4-methylsemicarbazone) having a melting point of 157.5°-158.5° C.