Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH:16]C(=O)C)[CH:9]=[CH:10][C:11]=2[CH3:15])[C:6]1=[O:20])(=[O:3])[CH3:2].C(NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:16])[CH:9]=[CH:10][C:11]=2[CH3:15])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CC2
Agent: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CCc2c(C)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 400 mg of the compound prepared in (7) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 265 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=1>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: BrCCCCCCBr
Product: Clc1ccc(CCOCCCCCCBr)cc1

Procedure:
(4.0 g), b.p. 169°/0.8 torr, from 1,6-dibromohexane (8.65 g) and 4-chlorobenzeneethanol (3.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:16][C:17](N(OC)C)=[O:18])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:16][C:17](=[O:18])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
At −78° C., to a solution of 4-methylpyridine (308 mg) in THF (7 mL) n-butyllithium (1.6M in hexane, 2.07 ml) was added. The reaction mixture was warmed slowly to rt, stirred for 1 h at that temperature, and cooled down again to −78° C. (R)-3-(4-Bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1; 400 mg) in THF (3 mL) was added slowly and the reaction mixture was warmed to rt and stirred for 3 h. The mixture was poured into a saturated aqueous solution of NaHCO3 (10 mL), the phases were separated, and the inorganic one was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (30% to 60% EtOAc in n-heptane to CH2Cl2/MeOH 9:1) to yield the title compound as a yellow oil (220 mg, 51%), MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: [CH2:1]([CH:4]([CH2:25][CH2:26][CH3:27])[C:5]([NH:7][C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH2:2][CH3:3]>C(O)C>[CH2:25]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH2:26][CH3:27]
Reactant: CCCC(CCC)C(=O)Nc1cccc(/C=C/CNC(=O)OC(C)(C)C)c1
Solvent: CCO
Product: CCCC(CCC)C(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
A solution of (E)-tert-butyl 3-(3-(2-propylpentanamido)phenyl)allylcarbamate (0.5 g, 1.32 mmol) in ethanol was degassed by bubbling argon for 2 min. Pd/C (10% wt, 0.5 g) was added and the reaction mixture atmosphere was changed to hydrogen by alternating between vacuum and hydrogen 2×. The reaction mixture was stirred under a H2-filled balloon for 16 h then filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 mesh silica, 10% to 15% EtOAc in hexane) gave compound tert-butyl 3-(3-(2-propylpentanamido)phenyl)propylcarbamate as a thick yellow oil. Yield (0.5 g, 99%); 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.08 (bs, 1H), 6.93 (d, J=7.6 Hz, 1H), 4.60 (bs, 1H), 3.15-3.14 (m, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.49-2.16 (m, 1H), 1.82-1.72 (m, 2H), 1.72-1.66 (m, 2H), 1.37 (s, 9H), 1.36-1.22 (m, 6H), 0.92 (t, J=7.2 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([NH:27][S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH:25]=2)[NH:20][C:19](=[O:37])[C:18]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=3)[C:19](=[O:37])[NH:20]2)=[CH:25][C:24]=1[NH:27][S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(thiophene-2-sulfonylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 5 mL methylene chloride was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 90:10) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([OH:30])=O)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[O:30])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNCCO
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.5 %

Procedure:
8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with 2-(methylamino)ethanol (0.028 mL, 0.35 mmol) using a procedure similar to the one described in Example 2.00 to afford 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (65.0 mg, 44.3%) as a white solid. Mass Spectrum: M+H+ 504. NMR Spectrum: (DMSOd6) 1.57 (d, 3H), 2.76 (s, 1.5H), 2.94 (s, 1.5H), 3.07 (bs, 1H), 3.27 (bs, 1H), 3.45 (bs, 1H), 3.51-3.64 (m, 5H), 3.70-3.78 (m, 4H), 4.69 (bs, 0.5H), 4.78 (ns, 0.5H), 5.08 (bs, 1H), 5.60 (s, 1H), 6.33-6.47 (bs, 2H), 6.65 (ddd, 1H), 6.83 (dd, 1H), 7.60 (bs, 0.5H), 7.61 (bs, 0.5H), 7.79 (bs, 0.5H), 7.81 (bs, 0.5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:6][C:5]2[C:7]([CH3:31])=[C:8]([N+:28]([O-])=O)[C:9]([CH3:27])=[C:10]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[O:3]1>C(O)C.[Pd]>[NH2:28][C:8]1[C:9]([CH3:27])=[C:10]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]2[O:3][C:2]([CH3:32])([CH3:1])[CH2:6][C:5]=2[C:7]=1[CH3:31]
Reactant: CCCCCCCCCCC(C)(C)C(=O)Nc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1c(C)c(N)c(C)c2c1OC(C)(C)C2
Reaction time: 24 h
Yield: 94 %

Procedure:
A 2.0 g amount of N-(2,2,4,6-tetramethyl-5-nitro-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide (485) was dissolved in 30 ml of ethanol, 600 mg of Pd-C (10%) was added thereto, and the mixture was subjected to hydrogenation at room temperature with vigorous stirring. After 24 hrs from the initiation of the hydrogenation, the reaction was completed. Pd-C was removed by filtration with Celite, and the solvent was removed by evaporation to provide 1.75 g of the intended title compound as a solid. The yield was 94%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@H:41]3[CH3:50])=[CH:36][N:35]=2)=[CH:29][C:28](C2C(C=O)=C(N3C=CN4C5CCCCC=5C=C4C3=O)N=CC=2)=[CH:27]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:28]5[CH:29]=[C:30]([NH:33][C:34]6[CH:39]=[CH:38][C:37]([N:40]7[CH2:45][CH2:44][N:43]([CH:46]8[CH2:47][O:48][CH2:49]8)[CH2:42][C@H:41]7[CH3:50])=[CH:36][N:35]=6)[C:31](=[O:32])[N:26]([CH3:25])[CH:27]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyri-dine-3-carbaldehyde 108a (105 mg, 0.30 mmol), 1-methyl-3-({5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(tetra-methyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 151g (216 mg, 0.45 mmol), PdCl2(dppf) (25 mg, 0.030 mmol), K3PO4 (126 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 153a as a red solid (82 mg, 41%). MS-ESI: [M+H]+ 663
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([OH:18])=O)(=[O:10])=[O:9])[CH:2]=1.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[S:8](=[O:9])(=[O:10])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)Nc1cccnc1
Product: O=C(NCCCc1ccccc1)[C@@H]1CCCN1S(=O)(=O)Nc1cccnc1

Procedure:
Compound 118 was prepared from the carboxylic acid (compound 116) and 3-phenyl-propylamine by a synthetic method analogous to the step 2 of compound 31 synthesis. A 21% yield was obtained for the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[C:21]([Cl:40])=[C:22]([C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]1=[O:35]>>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:22]([CH2:23][CH:24]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]3=[O:35])[C:21]=2[Cl:40])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Yield: 47.2 %

Procedure:
Using the procedure to synthesize Example 207 and using reagents 3-Chloro-2-methyl-benzenesulfonyl chloride (194 mg, 0.84 mmol), pyridine (0.07 mL, 0.84 mmol), and 3-(3-Amino-2,6-dichloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 192) (240 mg, 0.70 mmol) affords 175 mg (47%) of the title compound: Mass spectrum (apci) m/z=529.05 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:20]([C:17]2[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A 200 mL round-bottom flask was charged with 2-bromo-5-chloro-pyridin-3-ylamine (10.4 g, 50.0 mmol), 4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine (38 mL). The resultant solution was heated to 70° C. and stirred overnight. The following day, the pyridine was removed by removed in vacuo and 30 mL THF (tetrahydrofuran) and 100 mL 4.0 N NaOH were added and the reaction was stirred at 60° C. overnight. The organics were subsequently removed in vacuo and the residues were diluted with 400 mL water. The small quantity of insoluble solid was removed by filtration and the pH was adjusted to 6-7 with concentrated HCl. The resultant aqueous solution was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the desired sulfonamide (13.4 g) in 66% yield: MS (ES) M+H expected 403.0, found 403.1.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:18]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:18])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(=O)c1ccc2c(c1)N(C)c1ccccc1S2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
To a solution of 2-acetylphenothiazine (Aldrich) (2.41 g, 10 mmol) in dimethylformamide (25 mL) was added potassium t-butoxide (1.5 g, 13.4 mmol) and the mixture was stirred for 15 minutes. Methyl iodide (1.9 g, 13.4 mmol) was then added, dropwise, to the resulting solution and the mixture stirred for 30 minutes. Ice-water was added to the reaction mixture followed by ethyl acetate. The organic layer was decanted, washed with brine, dried over Na2SO4 and evaporated to dryness. The oily residue was chromatographed on flash silica gel eluting with 10% ethyl acetate/hexane to afford the pure title product (1.0 g, 39%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:30]3[C:31]([O:33][C:34](=O)[CH:29]3[CH:28]3[C:23]([CH2:24][CH2:25][N:26]([CH3:36])[CH2:27]3)=[CH:22]2)=[O:32])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:30]([CH2:31][OH:32])[CH:29]([CH2:34][OH:33])[CH:28]3[C:23]([CH2:24][CH2:25][N:26]([CH3:36])[CH2:27]3)=[CH:22]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C2C=C3CCN(C)CC3C3C(=O)OC(=O)C23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(C2C=C3CCN(C)CC3C(CO)C2CO)cc1
Yield: 60.7 %

Procedure:
To a slurry of 15 g lithium aluminum hydride in 800 ml. ether and 400 ml. dioxane is added 15 g (0.041 moles) 1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-2-methyl-7,8-isoquinoline-dicarboxylic acid anhydride hydrochloride slowly with stirring under nitrogen. This mixture is refluxed ovenight. Saturated potassium carbonate solution is added until the solution is white. This is filtered and washed with hot dioxane. The organics are combined and evaporated to yield 7.9 g (61%) crude 1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-2-methyl-7,8-isoquinolinedimethanol. The oil is crystallized from ethyl acetate, and recrystallization of 2 g from ethyl acetate gives an analytical sample, 1.7 g, mp 169°-171°C.
Reaction SMILES: [C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-water cooled solution of 1,1-dimethylethyl (2E)-3-{4-[cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (4) (0.28 g, 0.74 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (5 mL) with stirring under a nitrogen atmosphere. After 1 h, the reaction mixture was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane and the solution was concentrated in vacuo to give a pale tan solid. The solid was triturated with diethyl ether and filtered to give the acrylic acid as an off-white solid. The solid was dried overnight under vacuum at 70° C., however, 1H NMR indicated that solvent remained in the sample. The solid was dissolved in methanol and the solution was concentrated in vacuo to give an oil. The oil was dissolved in methanol and the solution was concentrated in vacuo under high vacuum at 60° C. to give an oil. Dichloromethane was added to the oil and crystallization was induced with the aid of a spatula. The suspension was filtered and the solid was dried in a vacuum oven overnight at 70° C. to give 0.072 g (30%) of compound 5 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 2.30 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 9.32 (s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C27H36Si2O3: 464.2203 (M+.). Found: 464.2210.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.Br.[C:22]1([CH2:28][N:29]2[CH2:34][CH:33]3[CH2:35][CH:30]2[CH2:31][NH:32]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:32]3[CH2:31][CH:30]4[CH2:35][CH:33]3[CH2:34][N:29]4[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CC3CN4Cc3ccccc3)c(F)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
A solution of 0.54 g (2.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.77 g (2.2 mmol) of 5-(phenylmethyl)-2,5-diazabicyclo(2.2.1)heptane dihydrobromide, (P. S. Portoghese and A. A. Mikhail, J. Org. Chem. 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene, and 20 ml of acetonitrile was heated under reflux for two hours and stirred at room temperature for two days. The mixture was filtered and the solid was washed with methanol to give 0.44 g of the title compound, mp 195°-198° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH2:8][CH3:9])[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:17][C:12]1[CH:11]=[C:10]([CH:7]([CH2:8][CH3:9])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CCC(CC[C@H](N)CO)c1cc(F)cc(F)c1
Reactant: N#CBr
Product: CCC(CC[C@H]1COC(N)=N1)c1cc(F)cc(F)c1

Procedure:
In analogy to example 1d (S)-2-amino-5-(3,5-difluoro-phenyl)-heptan-1-ol was reacted with cyanogen bromide to give (4S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow liquid. MS (ISP): 269.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOCCCCO
Reactant: BrCCCCCCBr
Product: CC(C)CCOCCCCOCCCCCCBr

Procedure:
Using 4-isopentyloxy butanol and 1,6-dibromo-hexane, the above compound is produced. B.P.: 142°-145°/0.7 mm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=4[CH3:29])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>CN(C=O)C>[CH3:29][C:23]1[CH:24]=[C:25]([NH:28][C:42]([C:38]2[O:37][CH:41]=[CH:40][CH:39]=2)=[O:43])[CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[CH:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(N)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2ccco2)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reaction time: 18 h

Procedure:
A solution of 4′-amino-2′-methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (40 mg) and triethylamine (0.4 ml) in dry DMF (3 ml) was treated with furan-2-carbonyl chloride (0.015 ml) and the mixture stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extract was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam (46 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)#[N:2].[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:15]([NH:14][CH2:13][CH2:12][Cl:11])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C=NCCCl
Product: N#Cc1ccc(CNC(=O)NCCCl)cc1

Procedure:
The 4-cyanobenzenemethanamine obtainable by modified Gabriel synthesis, when reacted with chloroethylisocyanate, yields 1-[(4-cyanophenyl)methyl]-3-(2-chloroethyl)urea which when treated with potassium tert.butoxide in dimethylformamide is easily cyclised into the 1-[(4-cyanophenyl)methyl]-2-imidazo-lidinone; catalytic hydrogenation then leads to the desired 4-[(2-oxo-1-imidazolidinyl)methyl]benzenemethanamine.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([F:16])=[C:6]([NH:5][CH2:4][C:3]3[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:2]=3[CH3:1])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1cccc(C)c1CNc1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C23H23FN6O2, 434.2