Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[NH2:24])=[O:5])[CH3:2].[CH3:25]C[O-].[Na+].CI>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH3:25])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[N:8]=[C:7]1[NH2:24])=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C1=C(C)N=C(N)C(C)(C(=O)OCC)C1c1ccccc1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 33.0 g of 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 15 g of methyl iodide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gives 18.6 g (54% of theory) of 2-amino-3,6-dimethyl-4-phenyl-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 139°C.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClC(Cl)C>[CH:1]1([NH:5][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]3)=[CH:16][C:17]=2[F:23])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
To a solution of cyclobutanamine (1.26 mL, 14.7 mmol) and 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 14.7 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (4.39 g, 20.6 mmol) followed by acetic acid (0.84 mL, 14.7 mmol) and the reaction was stirred at ambient temperature for 16 hours. 1 N aqueous NaOH was then added to basify the reaction and the product was extracted with Et2O (x3), washed with brine, dried with MgSO4, concentrated and dried in vacuo to give 1-[4-[4[(cyclobutylamino)methyl]-3-fluoro-phenyl]piperazin-1-yl]ethanone (4.76 g, 99% yield). The product was used without purification. LCMS (m/z) ES+ 306 [M+1]+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[O:6][N:5]=1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=7[F:25])=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6F)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (272 mg; compound B88) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (237 mg; compound C10) and HBTU (249 mg) in DCM (7 ml) in the presence of DIPEA (0.42 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]=[C:8]([NH2:14])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.N(OC(C)(C)C)=O.C[Si]([N:28]=[N+:29]=[N-])(C)C>C(#N)C>[N:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=3[C:6]=2[N:7]=1)=[N+:28]=[N-:29]
Reactant: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine (2.38 g, 8 mmol) in acetonitrile at 0° C. was added tert-butyl nitrite (1.43 mL, 12 mmol) followed by trimethylsilyl azide (1.26 mL, 9.6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 90 mins, allowed to warm up to RT and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to yield the title compound as a red oil which solidified upon standing (956 mg, 37%). 1H NMR (CDCl3): 8.21 (1H, d, J=8.6 Hz), 7.24 (1H, dd, J=8.6, 2.1 Hz), 7.20 (1H, d, J=2.1 Hz), 4.34 (2H, t, J=5.1 Hz), 3.21 (2H, t, J=5.1 Hz).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[CH:46]([C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:46]([C:49]1[CH:50]=[C:51]([NH:57][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[N:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]3)[CH3:35])=[CH:4][N:3]=2)[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47]
Reactant: COc1ncc(N)cc1C(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(C(C)C)c3)n2)cc1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a solution of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Examples 145 and 146) 0.380 g, 0.598 mmol) and 5-isopropyl-6-methoxypyridin-3-amine (0.149 g, 0.897 mmol) in 3 mL THF at 0° C. was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.69 mL, 2.69 mmol) dropwise via syringe over 1 min. The dark red reaction was allowed to stir 30 min and was quenched by addition of saturated aq. NH4Cl. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 20-100% EtOAc/hexane followed by 10% MeOH/EtOAc to elute the desired product. The product-containing fractions were concentrated to afford (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.097 g, 0.124 mmol, 21% yield) as a red oil. m/z (ESI, +ve ion) 782 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.15-8.29 (m, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.15-7.25 (m, 4H), 6.77-6.96 (m, 4H), 4.71-4.97 (m, 4H), 3.95 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.53 (q, J=6.8 Hz, 1H), 3.11-3.20 (m, 5H), 2.69 (s, 3H), 2.47-2.63 (m, 7H), 1.38 (d, J=6.7 Hz, 3H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)#[N:15]
Reactant: O=Cc1cc2[nH]c(C(=O)O)cc2o1
Reactant: NO
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)O)cc2o1

Procedure:
2-Formyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (see, for example, Krutosikova, A.; Dandarova, M.; Alfoldi, J., Chem. Pap., 48: 268-73 (1994)) was treated with hydroxylamine hydrochloride according to Procedure G.
Reaction SMILES: [C:1]1([CH2:6][SH:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N1C(=O)C2=CC=C[CH:20]=[C:13]2[C:12]1=[S:21])CC>>[CH2:12]([S:21][S:7][CH2:6][C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH3:20]
Reactant: SCc1cccs1
Reactant: CCCN1C(=O)c2ccccc2C1=S
Product: CCCSSCc1cccs1

Procedure:
Starting from thenylmercaptan and N-propylthiophthalimide there is obtained propyl-thenyl-disulphide. IR (liq.): bands inter alia at 2990, 1455, 1220, 1030, 850, 700 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[CH:23]=O)([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1/[CH:23]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 92.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.37 g, 12.7 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde prepared in Example 18 (4 g, 12.7 mmol) and piperidine (1.25 mL, 12.7 mmol) in methanol to give E/Z-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzylidene}-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.46 g, 92%).
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][N:11]=[C:10]([C:13]([N:26]3[CH2:27][CH2:28][N:23]([C:19]4[S:18][CH:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:15])[CH2:9]2)[CH2:16][CH2:17]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1csc(N2CCNCC2)n1
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)N1CCN(c3nccs3)CC1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), 1-thiazol-2-ylpiperazine (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were washed with sat. aq. NaCl solution, dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 3:1), the desired product (8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-(4-thiazol-2-ylpiperazin-1-yl)methanone was obtained as a trans isomer (50 mg, 26% of the theoretical amount) and as a cis isomer (100 mg, 51% of the theoretical amount).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]2=[O:17].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:66][N:67]1[CH2:73][CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:17])[CH:8]=1)=[CH:5][C:4]([O:18][CH3:19])=[CH:3][C:2]=2[N:70]1[CH2:71][CH2:72][CH2:73][N:67]([CH3:66])[CH2:68][CH2:69]1)=[O:13])[CH3:16]
Reactant: CN1CCCNCC1
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a 250 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5 g (4.59 mmol, 1.0 equiv.) of 8-Bromo-6-methoxy-4-oxo-4H-chromene acid ethyl ester (Reference Example 2c), 84 mg (0.092 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 2 g of 4 A molecular sieves. To this suspension is added 150 mL of dry toluene. To the stirred suspension is then added 628 mg, 684 μL, (5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05 g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 20% methanol in methylene chloride as eluent, yielded 1.0 g, (60%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)C(F)(F)F
Reaction time: 14 h

Procedure:
DMF (3 drops) was added to a solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid [889940-13-0] (179 mmol) in CH2Cl2 (160 mL) at rt. Slowly added a solution of oxalyl chloride (197 mmol) in CH2Cl2 (20 mL). After stirring for 14 h, the reaction mixture was carefully evaporated (500 mbar, 33° C.) to afford the title compound (volatile!) as a yellow solution.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:10]=[CH:11][CH:12]=[CH2:13]>>[CH2:8]=[C:7]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:9]
Reactant: C=CCCCC=CCO
Reactant: C=CC=C
Product: C=C(CC=CC)CCCC=CCO

Procedure:
Additional examples of reactions according to the invention are of 2,7-octadiene-1-ol with 1,3-butadiene to yield 7-methylene-2,9-undecadiene-1-ol and the reaction of 1-methoxy-2,7-octadiene with 1,3-butadiene to yield 1-methoxy-7-methylene-2,9-undecadiene. Additional examples of suitable compounds of Formula (II) are 1-acetoxy-2,6-dimethyl-2,7-octadiene, 1-methoxy-2,6-dimethyl-2,7-octadiene, 2-acetoxy-3,8-decadiene, 2-methoxy-3,8-decadiene and 3,8-decadiene-2-ol. Additional examples of suitable compounds of Formula (III) are isoprene and piperylene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].Br.Br.[CH:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]3[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[C:15]4[CH3:20])=[O:8])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(C3CCCCC3)CC2)c2nccc(C)c2c1
Yield: 75.1 %

Procedure:
A mixture of 3.7 g (0.01 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 3.4 g (0.0105 mole) of 1-cyclo-hexylpiperazine, dihydrobromide, and 4.2 ml (0.03 mole) of triethylamine in 100 ml of benzene was heated under reflux for 40 hr, allowed to cool, filtered and concentrated. The residue was chromatographed over 150 g of silica gel first with dichloromethane and then with 500 ml each of the following solutions of methanol in dichloromethane: 2%, 4%, 6%, 10% and 15%. The fractions containing the product [Rf(silica--75 ethyl acetate:25 methanol:1 triethylamine)=0.6] were concentrated to provide 3.4 g (75%) of clean material and 0.8 g (18%) which was slightly contaminated according to TLC. The contaminated material was combined with 0.8 g of the purer material and recrystallized first from 2-propanol and then from 2-propanol-water to afford 0.7 g (44% recovery) of analytical material, mp 109°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[O:26][CH3:27].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[O:26][CH3:27]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 5.34 mmol) in CH2Cl2 (50 ml) was added TFA (20 ml) at room temperature. After 2 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (1.50 g, 76%) as a colorless powder. mp 246–249° C. (dec.); 1H-NMR (DMSO-d6) δ 3.49 (s, 2H), 3.88 (s, 3H), 6.75 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.97 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 8.86 (s, 1H), 12.23 (br, 1H); MS (ESI) m/z 369 (M++1), 371 (M++3), 373 (M++5).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH:18]([CH3:23])[C:19](OC)=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>COCCO>[CH3:23][CH:18]1[C:10]2[CH:11]=[C:12]3[O:17][CH2:16][O:15][C:13]3=[CH:14][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:26][NH:25][C:19]1=[O:20]
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: NN
Solvent: O
Solvent: COCCO
Product: CC1C(=O)NN=C(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 18 %

Procedure:
A mixture of methyl 2-(2-benzoyl-4,5-methylenedioxyphenyl)propionate, hydrazine hydrate (0.45 mL), and 2-methoxyethanol (6 mL) was heated to reflux for 20 h. The solvent was then removed in vacuo and the residue was purified by a flash chromatography (EtOAc:Hex=1:1.5) to yield the product as a white solid (62 mg, 18%), mp, 206°-209° C. 1H NMR (CDCl3) 8.45 (s, 1H), 7.62 (m, 2H), 7.45 (m, 3H), 6.88 (s, 1H), 6.63 (s, 1H), 6.05 (s, 1H), 6.00 (s, 1H), 3.29 (q,J=6.7, 1H), 1.62 (d,J=6.7, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[CH3:11][NH:12][CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([CH3:1])[N:12]([CH3:13])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: CC(=O)c1cccc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(c1cccc(Br)c1)N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
60 g (0.30 mols) of 3-bromoacetophenone are dissolved in 800 ml of ethanol and mixed with 250 ml of dimethylamine. The pH of the solution is adjusted to 6.5 with acetic acid. The reaction mixture is then cooled to 0° and mixed with 19 g of sodium cyanoborohydride. After stirring for 2 days at room temperature, the reaction mixture is concentrated. The residue is mixed with 800 ml of water and acidified. The solution is then extracted twice with 400 ml of ether, the aqueous phase is rendered basic and extraction follows 3× with 400 ml of ether. The combined organic extracts are dried and concentrated. After distillation of the residue, the 3-bromo-N,N,α-trimethylbenzenemethanamine is obtained; b.p.: 98°-100°/10 mmHg.
Reaction SMILES: [C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:3])[NH2:2].Br[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)C>[C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])[CH:8]=1)=[O:6])(=[O:3])[NH2:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2c[nH]c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A solution of 0.10 g (0.223 mmol) of the product from step d), 0.15 g (0.56 mmol) of N-(3-bromopropyl)phthalimide, 0.10 g (0.72 mmol) of K2CO3 and 1.5 ml of DMF. The flask was sealed and heated to 65° C. for 5 hours. The reaction mixture was partitioned between 10 ml of EtOAc and 10 ml of water. The organic phase was collected and the aqueous phase was extracted with an additional 10 ml of EtOAc. The combined organic phases were washed with water and brine. The organic phase was evaporated to give a yellowish solid. The solid was suspended in 20 ml of diethyl ether and stirred for 30 minutes. The precipitate was allowed to settle and the ethereal phase was removed. The residual precipitate was dried in vacuum to give 100 mg (70%) of the sub-title product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][O:28][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=1[C:25](=[O:27])[CH3:26]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), morpholine (49 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (60 mg, 68%).