Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[C:11](/[C:17]#[N:18])\C(OCC)=O)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:11][C:17]#[N:18])[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2ccc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCc2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
A solution of (E)-ethyl 2-cyano-2-(6-chloro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep38, 15.00 g, 0.06 mol) in ethanol (300 ml) was treated with a solution of KCN (9.75 g, 0.15 mol) in water (90 ml). The mixture was warmed to 65° C., and stirred for 16 h. The mixture was concentrated in vacuo to remove solvent. The residue was extracted with EA (100 ml×3). The organic layers were combined and washed with a saturated solution of NaHCO3, brine and dried over Na2SO4. The crude was purified by FC (P:E=10/1) to obtain the title compound (4.60 g, y=37.1%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]1[CH2:11][CH2:10][C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][C:14]([OH:16])=[O:15])=[N:8]1.Br[CH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]2([CH3:39])[CH3:38].CCOC(C)=O>CS(C)=O.[Cl-].[Na+].O>[O:7]1[CH2:11][CH2:10][C:9]([CH:12]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=4[CH:27]=3)=[CH:21][CH:22]=2)[CH2:13][C:14]([OH:16])=[O:15])=[N:8]1
Reactant: O=C(O)CC(C1=NOCC1)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(COc3ccc(C(CC(=O)O)C4=NOCC4)cc3)ccc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
Cesium carbonate (108 mg, 0.33 mmol) was added into a mixture of 15.2 (25 mg, 0.11 mmol) and 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (76 mg, 0.27 mmol) in DMSO (1 mL). The mixture was stirred at 45° C. for 3 hours. After cooling, the mixture was treated with EtOAc (5 mL) and brine (5 mL). The organic layer was separated, washed with brine twice, dried and concentrated. The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10N). The mixture was stirred at room temperature for 4 hours. The organic solvent was blown away by nitrogen, and the aqueous layer was acidified by HCl (0.18 mL, 3N). The aqueous layer was extracted with DCM. The organic layer was dried, concentrated and purified by flash chromatography to give 15 (15 mg). MS ESI (pos.) m/e: 436 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[F:29][C:28]([F:31])([F:30])[C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3cc(C(F)(F)F)ncn3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (72 mg, 0.4 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in dimethylacetamide (1.3 ml) and stirred at 80° C. overnight. For work-up water was added, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, 20 to 40% ethyl acetate in heptane) to yield a white solid (135 mg, 89%). MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][C:9](=[N:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].Cl>CO.O1CCCC1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH:9]([NH:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:23][CH:22]=2)=[O:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OCC(=NNC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(OCC(NNC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccccc2)cc1
Yield: 106.2 %

Procedure:
In a mixed solvent of 15 ml of methanol and 15 ml of tetrahydrofuran was dissolved 0.30 g (0.66 mmole) of 2-[2-(4-cyanophenoxy)-1-phenylethylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, after which 0.20 g (3.2 mmoles) of sodium cyanoborohydride (NaBH3CN) was added to the resulting solution. The resulting mixture was maintained at pH 4 to 6 with hydrogen chloride (a methanolic solution) with stirring. After confirming the completion of the reaction by a thinlayer chromatography, the solvent was distilled off under reduced pressure and water was added to the residue, followed by neutralization with sodium hydrogencarbonate. The desired compound was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 0.32 g of the desired compound was obtained.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:26][C:27]1([CH3:46])[C:31](=[CH2:32])[S:30][C:29]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])=[N:28]1>>[CH3:6][N:4]([CH3:5])[CH:3]=[C:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][S:33][C:29]1[S:30][C:31](=[CH2:32])[C:27]([CH3:26])([CH3:46])[N:28]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: C=C1SC(SCc2ccccc2CC(=O)OC)=NC1(C)C
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C=C1SC(SCc2ccccc2C(=CN(C)C)C(=O)OC)=NC1(C)C

Procedure:
This product (5.21 g), dimethylformamide dimethyl acetal (4.8 g) and pyridinium tosylate were heated together in a flask equipped with a Vigreaux column topped by a distillation head. The mixture was heated by an oil bath at 95° for 6 hours, causing the methanol produced by reaction to slowly distil off. The reaction mixture was then cooled, diluted with an aqueous solution of sodium hydrogen carbonate and extracted into ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated to give an oil which was purified by column chromatography (stationary phase: silica, eluent: 4:1 hexane:ethyl acetate) to give methyl 3-dimethylamino-2-[α-(4,4-dimethyl-5-methylene-2-thiazolin-2-ylthio)-o-tolyl]prop-2-enoate. (Compound 13A)
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[CH:11][C:9](N)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.NC(N)=O.[I-:20].[K+]>Cl>[N+:13]([C:8]1[CH:7]=[C:6]([Cl:5])[CH:12]=[CH:11][C:9]=1[I:20])([O-:15])=[O:14]
Reactant: [I-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Product: O=[N+]([O-])c1cc(Cl)ccc1I
Reaction time: 0.75 h

Procedure:
A 1M aqueous solution of sodium nitrite (50 milliliters (mL)) was added dropwise to a cold (3° C.) stirred mixture of 4-chloro-2-nitroaniline (8.63 grams (g), 50 millimoles (mmol)) in 6M HCl (150 mL) over a 45 minute (min) period with subsequent addition of about 5 g of urea during 30 min. An aqueous solution of potassium iodide (60 mL, 1M) was dripped into the resulting orange solution over a period of 35 min at 5° C. After an additional 45 min, the desired product, which had separated from solution, was isolated by filtration and then dried in air; yield, 13.73 g (brown powder): m.p. 50°-60° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[S:6][CH:7]=4)[CH2:22][CH2:21]3)[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2nc(CCl)cs2)cc(OC)c1OC
Product: COc1cc(-c2nc(CN3CCCN(Cc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)thiazole (198 mg) and homopiperazine (30 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH:13]=[O:14])[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]=1)=[O:4].[OH-].[Na+]>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:7]2[C:8]([CH:13]=[O:14])=[C:9]([CH:10]([CH3:12])[CH3:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1nn(-c2ccc(F)cc2)c(C=O)c1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Temperature: 60 °C
Yield: 79.2 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (11.34 g, 39.1 mmol) in MeOH (150 mL) was added NaOH (156 mL of 1 N solution, 156 mmol). The reaction was heated to 60° C. for 4 hr. The solvent was then removed under reduced pressure and water (150 mL) and Et2O (100 mL) were added. The organic layer was discarded and the aqueous layer was acidified with 10% HCl to pH 1 and then extracted with EtOAc (200 mL×2). The combined organic extracts were dried over Na2SO4 and concentrated to give 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (8.55 g, 79%) as a white solid that required no purification: MS(APCI+): m/z 277.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(OCC)(=O)C>[CH2:18]([O:17][C:15]([NH:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred refluxing mixture of 2-aminoindan-2-carboxylic acid (1.90 g, 10.7 mmol, Pinder, R. M.; Butcher, B. H.; Buxton, D. A.; and Howells, O. J. J. Med. Chem. 1971, 14, 892) in ethyl acetate (200 ml) ws added ethyl chloroformate (1.16 g, 10.7 mmol). After 15 hours, the mixture was cooled, filtered, evaporated, and vacuum dried to give 1.17 g (44%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]4[CH:25]=[CH:26][S:22][CH:23]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccsc1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and 3-thiophene carboxylic acid using method D. NMR; δH [2H6]—DMSO 10.05,(1H, s), 8.62,(1H, t), 8.32,(1H, m), 7.93,(2H, d), 7.69,(1H, dd), 7.65-7.61,(3H, m), 7.44,(2H, d), 7.28,(1H, d), 3.16,(2H, t), 2.20,(3H, s), 1.04,(1H, m), 0.44,(2H, m), 0.24,(2H, m). LCMS: retention time 3.41 min, MH+391.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: C=CCOCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOCCCCOc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
2-Acetyl-7-hydroxyfluorene 22.4 g, allyl(4-chlorobutyl) ether 18 g and potassium carbonate 20 g were added to dimethylformamide 150 ml and stirred at 90° C. for 8 hours. The reaction mixture was poured into 6N hydrochloric acid 300 ml to obtain a solid matter. The solid matter was filtered and dried, and then it was recrystallized from ethanol to obtain 22 g of 2-acetyl-7-(allyloxybutyloxy)fluorene. The melting point was 77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1.[CH3:41][NH2:42].C1COCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15]([NH:42][CH3:41])[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccc(Cl)nn12
Reactant: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ccc2nc(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)c(Cc3cc(Br)ccc3OC)n2n1
Temperature: 150 °C
Yield: 24 %

Procedure:
A solution of 130 mg (0.2 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl]-6-chloro(imidazolo[1,2-b]pyridazin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in DMSO (3 mL) is treated with 2M methyl amine in THF 1.5 mL (3.0 mmol). The reaction mixture is heated to 150° C. in a sealed tube for 18 hr and following cooling partitioned between ethyl acetate and water. The organic extract is washed with 5×10 mL water, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 31 mg (24%) of the title compound. Mass Spec m/z (M++1) 646.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.ClCl.O.[Cl-].[NH4+]>O1CCCC1.[Ni](Cl)Cl>[CH2:9]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH3:12])=[C:3]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:8]=1)[CH3:10]
Reactant: COc1ccc(Br)cc1
Reactant: CCc1ccc(OC)c(Br)c1
Agent: Cl[Ni]Cl
Agent: ClCl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(OC)c(-c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture was prepared by suspending 7.2 g of metallic magnesium into 40 ml of tetrahydrofuran (THF). The mixture, wherein 1 ml of 2-bromo-4-ethylanisole was added, was stirred at room temperature. After an exothermic reaction occurred, the reaction mixture was diluted with 100 ml of THF, followed by dropwise addition of the solution which was prepared by dissolving 63.5 g of 2-bromo-4-ethylanisole into 160 ml of THF. The addition was took 2 hours. The reaction mixture was stirred for 1 hour, reflexed by heating for further 1 hour and cooled down to 0° C. in internal temperature, wherein 59 g of p-bromoanisole was added thereinto, 0.5 g power of the complex compound of nickel chloride and 1,3-diphenylphosphynopropane (Nidppp Cl2) was added in the reaction mixture, and stirred overnight. The reactant was transferred into ammonium chloride water solution and extracted with diethylether. The extract was washed with an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was distilled under reduced pressure to yield 51.6 g of 5-ethyl-2,4'-dimethoxy-biphenyl having a b.p. of 135°-148° C. (0.5 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH3:22][C:23]([C:25]#[CH:26])=[CH2:24].O.CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:26]#[C:25][C:23]([CH3:24])=[CH2:22])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#CC(=C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Yield: 53 %

Procedure:
To a solution of ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in U.S. Pat. No. 6,271,253 B1 Example 73, Step 2 (0.342 g, 0.790 mmole) in degassed anhydrous toluene was added Pd(PPh3)4 (54 mg, 0.47 mmole), CuI (15 mg, 0.079 mmole), TEA (0.275 mg, 2.72 mmole) and 2-methylbut-1-en-3-yne (0.247 g, 3.74 mmole) and the mixture was stirred under a N2 atmosphere. After the reaction was determined to be complete by GCMS, H2O and EtOAc were added and the layers were separated. The EtOAc layer was washed with 10% HCl, twice with H2O, twice with aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo. Purification of the crude product by silica chromatography (95:5 hexanes:EtOAc) gave 155 mg (53% yield) of the product as a white crystalline solid: 1H NMR (CDCl3/300 MHz) 7.62 (s, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.14 (d, 1H, J=2.4 Hz), 5.80 (q, 1H, J=6.6 Hz), 5.44 (m, 1H), 5.35-5.36 (m, 1H), 4.31-4.34 (m, 2H), 1.99 (s, 3H), 1.36 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:28])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(C1C=CC(C)=CC=1)(O[C:33]#[C:34][CH3:35])(=O)=O.C[O-].[Na+].[Cl-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:28])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:35][C:34]#[CH:33])=[C:21]([O:26][CH3:27])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Reactant: CC#COS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
A solution of 0.6 g (1.4 mmol) of 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(4-hydroxy-3-methoxy-phenyl)-cyclohexyl]-acetamide and 0.4 g (1.9 mmol) of propynyl tosylate and 2.7 ml of 1 M solution of sodium methoxide in 10 ml methanol is heated to reflux for 3 hours. The reaction mixture is cooled and poured into 30 ml of aqueous saturated sodium chloride solution and finally extracted with two 100 ml portions of ethyl acetate. The combined organic extract is concentrated under reduced pressure to a residue, which is subjected to column chromatography on silica gel, with 1:1 ethyl acetate/isohexane as the eluant to obtain 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-cyclohexyl]-acetamide.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH:25]=[C:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]1)[CH3:30]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 9.1 g of 60% oily sodium hydride in 200 ml of tetrahydrofuran, 38.0 ml of ethyl diethylphosphonoacetate was added dropwise under cooling with ice, stirred for 20 minutes, and thereafter a solution of 31.4 g of 1-t-butoxycarbonyl-4-piperidone in 500 ml of tetrahydrofuran was added dropwise, followed by 40 minutes' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was recrystallized from methanol to provide 33.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>N1C=CC=CC=1.O>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1OC

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzenamine (16d, 5g, 27.2 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.5g, 29.9 mmol) is added slowly and reflux for 3h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound 4-nitro-N-(3,4,5-trimethoxyphenyl)benzamide (18d). To a stirred solution of amide (18d, 6g, 18.0 mmol) taken in toluene lawessons reagent (5.1g, 12.6 mmol) is added and refluxed at 110° C. for 6h. after completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound 4-nitro-N-(3,4,5-trimethoxyphenyl) benzothioamide (19d). Treating the thioamide product (19d, 4g, 11.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,6,7-trimethoxy-2-(4-nitrophenyl) benzo[d]thiazole (20d) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20d. Reduction of the nitro compound (20d, 1 g, 2.8 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21d). The compound 4-(5,6,7-trimethoxybenzo[d]thiazol-2-yl)benzenamine (21d, 250 mg, 0.79 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 131 mg, 0.79 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 7d as a brown solid (62%).