Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12>>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:7]4[C:2]([CH3:1])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH2:23][C:22]=12
Reactant: CC1(C)CCCC=C1c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: CC1(C)CCCC=C1c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 85.5 %

Procedure:
4-(6,6-Dimethyl-cyclohex-1-en-1-yl)-benzoic acid of Step B (0.235 g, 1.02 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.205 g, 1.11 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.346 g) as white crystals, m.p. 118° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[CH2:33](I)[CH3:34]>CN(C)C=O>[CH2:33]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:17][CH:18]=1)[CH3:34]
Reactant: CCI
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1

Procedure:
6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (250 mg, 0.54 mmol) and K2CO3 (170 mg, 1.23 mmol) and EtI (155 mg, 0.99 mmol) in N,N-dimethylformamide (5 mL) were stirred at room temperature for 2 hours. After TLC suggested no starting material left, the N,N-dimethylformamide is removed through an aqueous work up, and the desired product is isolated through chromatography (125 mg, 48%). MS (ESI): 488.0 (M+1)+1.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])N=N1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:26][C:24]1([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][B:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][S:1][C:5]3[O:12][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[CH:4]=3)=[CH:20][CH:19]=2)[O:25]1
Reactant: Oc1ccccc1-c1csnn1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(CSc3cc4ccccc4o3)cc2)OC1(C)C
Temperature: 90 °C
Yield: 40 %

Procedure:
Starting material 2-[1,2,3]Thiadiazol-4-yl-phenol was prepared according to literature procedure (M. A. Abramov, W. Dehaen, B. D'hooge, M. L. Petrov, S. Smeets, S. Toppet and M. Voets Tetrahedron, 2000, 56, 3933-3940). 2-[1,2,3]Thiadiazol-4-yl-phenol (241 mg, 1.35 mmol), 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (406 mg, 1.37 mmol, 1 eq), and K2CO3 (396 mg, 2.87 mmol, 1.9 eq) was mixed in 8 mL of CH3CN and heat to 90° C. under nitrogen atmosphere. After reaction was complete as monitored by TLC, the mixture was cool to room temperature and solvent evaporated. The resulting crude material was subject to column chromatography (20% EtOAc in hexane) to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylsulfanyl]-benzofuran (198 mg) in 40% yield. NMR: G8475-125. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 4.1 (s, 2 H) 6.6 (d, J=1.0 Hz, 1 H) 7.2 (m, 4 H) 7.4 (d, J=7.8 Hz, 2 H) 7.7 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:21])[C:14]#[C:15][C:16](OCC)=[O:17])[CH3:11]>CO>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([OH:17])[C:7]2[C:5](=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[CH:8]=2)[N:6]=1)=[O:21])[CH3:11]
Reactant: Cc1cc(N)ccc1Cl
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cc(O)c2cc(Cl)c(C)cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of 4-chloro-3-methylaniline in 30 ml of methanol, 4.2 g of but-2-ynedioic acid diethyl ester were added dropwise over 30 min at 0° C. and stirred for 3 h at RT. Then, the solvents were removed under reduced pressure and the residue was dissolved in 70 ml of Dowtherm® and heated to 250° C. for 2 h. Then, the reaction mixture was allowed to cool to RT and 300 ml of n-heptane were added to precipitate the crude product, which was collected by filtration. The title compound was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:23]([O:26]CC)(=[O:25])[CH3:24]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:23]([OH:26])=[O:25])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(C)c1cc(Cc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) (assume 0.180 mmol) in concentrated hydrochloric acid (4 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium chloride solution (20 mL) and water (10 mL). The water layers were combined and extracted with ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was purified by HPLC (acetonitrile/water with 0.1% trifluoroacetic acid). The desired fractions were collected, concentrated and freeze dried. The resulting solid was purified by flash chromatography using silica gel eluted with 10% methanol in methylene chloride. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetic acid (56) (8.6 mg, 13% for 2 steps) as a white solid; EI(+)-HRMS m/z calcd for C16H16Cl2N2O3 (M+H)+ 355.0611, found 355.0611. MW=355.2235, Exact Mass=354.0538
Reaction SMILES: C(S[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)C.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:26])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:26][C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:5]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: CCSc1nc(O)cc(-c2ccccc2)n1
Reactant: COc1ccc(N)cc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Nc2nc(O)cc(-c3ccccc3)n2)cc1Cl

Procedure:
2-Ethylsulfanyl-6-phenyl-pyrimidin-4-ol (3.0 g, 12.8 mmol) was treated with 3-chloro-4-methoxy-phenylamine (2.0 g, 12.8 mmol) in diphenyl ether at 180° C. for 16 hours to give 2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-ol.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[C:31]2[CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[N:25]([CH3:33])[N:24]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[C:31]2[CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[N:25]([CH3:33])[N:24]=1)=[O:19]
Reactant: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c2c1C1CCC2C1
Agent: [Pd]
Solvent: CO
Product: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)c2c1C1CCC2C1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 150 (0.34 g, 0.75 mmol) and Pd/C (0.12 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 151 (0.27 g, quantitative yield) as a white foam.
Reaction SMILES: [Li][CH3:2].[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C:5](=[O:11])[CH2:4]2.O>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH:6]2[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]2)[CH2:4]1
Reactant: O=C1CN2CCC1CC2
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a well-stirred solution of MeLi [3.0M/diethyl ether](67.0 mL, 201 mmol) in anhydrous diethyl ether (150 mL) at −78° C. was added, dropwise, a solution of quinuclidin-3-one (12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting solution was maintained at −78° C. for 1 hour, then at room temperature for 18 hours. Water (60 mL) was added dropwise at 0° C. and the mixture was concentrated in vacuo to give a residue, which was purified by neutral aluminum oxide column chromatography (0-20% MeOH in CHCl3) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To stirred acetonitrile (250 mL) at 0° C. was slowly added concentrated sulfuric acid (100 mL). The resulting solution was added dropwise to a mixture of 3-methylquinuclidin-3-ol (9.10 g, 64.5 mmol) in acetonitrile (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 60 hours, then cooled with an ice bath and basified with aqueous sodium hydroxide solution to pH 10. The mixture was extracted with 5:1 (v/v) CHC3/i-PrOH. The organic layer was concentrated to afford a residue which was diluted with 2N aq. HCl and washed with 5:1 (v/v) CHC3/i-PrOH. The remaining aqueous layer was then basified with 2N NaOH and extracted with 5:1 (v/v) CHCl3/i-PrOH. The combined organic layers were washed with water, dried (Na2SO4) and concentrated to give 9.5 g (82%) of the desired compound as a light yellow oil. The 2 enantiomers of the above intermediate are separated from each other by using chiral column on supercritical fluid chromatography (SFC) system.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]([CH3:26])([CH3:25])[CH2:16][C@@:17]([C:21]([F:24])([F:23])[F:22])([OH:20])[CH2:18]O)[CH:14]=1.CS(Cl)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]([CH3:26])([CH3:25])[CH2:16][C@:17]2([C:21]([F:24])([F:23])[F:22])[CH2:18][O:20]2)[CH:14]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CO)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (8.2 mL, 58.8 mmol) was added to a solution of (2R)-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-(trifluoromethyl)-1,2-pentanediol (3.4 g, 10.9 mmol) in DCM (34 mL). This solution was then cooled to 0° C. and neat methanesulphonyl chloride (1.1 mL, 15.3 mmol) was added over 5 min keeping the temperature at 0-5° C. The resulting suspension was stirred at 0-5° C. for 15 min before warming to 20° C. The reaction mixture was then left to stir overnight. Further neat methanesulphonyl chloride (0.84 μL, 0.1 eq) was added at room temperature and the mixture stirred for 15 min. The reaction mixture was then washed successively with 1M HCl (3×12 mL), 9% aqueous sodium bicarbonate (12 mL) and water (12 mL) before evaporating to dryness to afford the title compound, 3.08 g.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8](Br)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](B(O)O)=[CH:15]1>COCCOC>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:14][CH:15]=2)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3]
Reactant: NC(=O)Nc1cc(Br)sc1C(N)=O
Reactant: OB(O)c1csc2ccccc12
Solvent: COCCOC
Product: NC(=O)Nc1cc(-c2csc3ccccc23)sc1C(N)=O
Reaction time: 4.5 h

Procedure:
3-[(Aminocarbonyl)amino-5-bromothiophene-2-carboxamide (0.222 g) and 1-benzothien-3-ylboronic acid (0.449 g) were sonicated in 1,2-dimethoxyethane (15 ml) and saturated aqueous sodium hydrogen carbonate solution (3.5 ml) and purged with argon. Tetrakis(triphenylphosphine)-palladium (95 mg) was added and the mixture was heated at reflux with stirring for 4.5 h, then allowed to cool and stirred at room temperature overnight. The solution was filtered and washed through with 1,2-dimethoxyethane and water. The filtrate was concentrated in vacuo and taken up in dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml). The solid product was collected by filtration, washed with dichloromethane, water, diethyl ether and dried (226 mg).
Reaction SMILES: C1(=O)[N:5]([C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][CH2:7]1
Reactant: O=C1Nc2ccccc2SC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@H]1CSc2ccccc2NC1=O
Yield: 62.6 %

Procedure:
A mixture of 3(R)-phthalimido-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (10 g), ethanol (500 ml) and hydrazine hydrate (6.2 g) is refluxed for 1 hour. After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added, and the mixture is extracted with ethyl acetate (400 ml). The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (3.75 g) as colorless leaflets.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 48.4 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 15, Step 1; 0.252 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.211 g), triethylamine (0.104 g), and ethylene glycol (2 mL) give 0.206 g of the title compound after crystallization from methanol/dichloromethane/hexane; mp 238-239° C.; MS m/z 413,415; IR (mineral oil) 1612, 1656, 3379, 1331, 1240 cm-1. 1H NMR (DMSO-d6) δ2.60, 3.25, 3.66, 6.92, 7.04, 7.32, 7.49, 7.71, 7.73, 7.83, 8.87.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:30]>>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]3[O:25][N:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=3)[CH2:9]2)=[O:7])[CH2:3]1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 42.3 mg (0.295 mmol) of N′-hydroxybenzenecarboximidamide (95% pure) were reacted according to the General Method 1. Yield: 48 mg (36% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: OC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(N)nc(OC2CCCCC2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, cyclohexanol and DBU in DME. EI-MS m/e (%): 308 (M+, 12), 226 ([M—C6H10]−, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCNC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCNCC3)cc21
Temperature: 140 °C
Yield: 40.2 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med. Chem., 23, 1358 (1980)] (2.7 g, 10 mmol) and homopiperzine, (5.0 g, 50 mmol) was heated at 140° C. for 51/2 hours. The excess homopiperazine was removed by distillation at 85°-95° C./10 mm Hg. The residue was triturated with water and filtered. The solid collected was dissolved in glacial acetic acid (1.5 mL), water (10 mL) was added, and the pH was adjusted to 8.0 with solid sodium bicarbonate. The resulting precipitate was collected by filtration, washed with water (3×5 mL) and air dried to give the product as a white crystalline solid (1.34 g, 40% yield): mp 196°-198° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:26][C:27]([C@H:29]([C@@:47]([OH:59])([CH2:55][C:56]([O-:58])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:28])[C:14]([O:16][CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Br[CH2:61][C:62]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:63].CCN(CC)CC>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:26][C:27]([C@H:29]([C@@:47]([OH:59])([CH2:55][C:56]([O:58][CH2:61][C:62](=[O:63])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:57])[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:28])[C:14]([O:16][CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)[O-])C(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)OCC(=O)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
1-tert-Butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-(2-oxo-2-phenyl-ethoxycarbonyl)-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (88.3 mg) was dissolved in ethyl acetate (5 mL), and a commercially available reagent of 2-bromoacetophenone (32 mg) and Et3N (24 μL) were added. The mixture was stirred at room temperature for 18 hours. To the reaction solution was added ethyl acetate and the mixture was washed with water and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The product was purified by silica gel chromatography (Megabondelute was used, elution solvent 20%-40% ethyl acetate/n-hexane) to obtain 56.6 mg (56%) of the title compound (LCMS m/z 937 (M+1) Rt 3.80 min.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.[ClH:19]>[Zn].Cl[Ti](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:8](/[C:9](/[CH2:11][CH2:12][Cl:19])=[C:9](\[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Reactant: Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 82 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Nitrogen atmosphere was applied during the reaction. Zinc dust (1.29 g; 19.76 mmol; 2.66 equiv.) and 2-methyl-THF (14 mL) were charged to a flask and cooled to below −5° C. TiCl4 (1.1 mL; 10.03 mmol; 1.35 equiv.) was slowly added (over 20 minutes; as the addition is exothermic) to the zinc-slurry, maintaining the temperature below 0° C. The reaction mixture was heated to reflux (82° C.) and refluxed for 2 hrs. A prepared solution of both ketones (1.80 g of 4-(2-hydroxyethoxy)benzophenone (see (A) above); 7.43 mmol; 1 equiv.; 1.25 g of 3-chloropropiophenone; 7.43 mmol; 1 equiv) in 2-methyl-THF (5 mL) was slowly added to the black reaction mixture at reflux. The temperature rose to 85° C. The reaction mixture was refluxed for 2 hours. The reaction mixture was then cooled to room temperature. 4.6 mL of 1M HCl and 4.2 mL of 6 M HCl were added and the mixture stirred for 10 minutes. Then 13 mL toluene was added and the reaction mixture was stirred for 15 min. The layers were separated. The toluene layer was washed with 4 mL water and dried over MgSO4. Quantitative HPLC from toluene solution shows 38% yield and the ratio of Z/E isomers of Ospemifene 4.3/1. The toluene solution was washed with 8.5 mL conc. NaHCO3, 6 mL water and dried over MgSO4. 3.05 g of crude product was obtained after concentration on a rotavapor (bath 34° C.). Crystallization in methanol (13 mL) and water (2.5 mL) gave an oil. This solution was heated until it was a clear solution and then let to cool slowly to room temperature (crystals appeared) and then left to stand overnight at +8° C. The crystals were filtered, rinsed with 60% MeOH/water and dried. 0.787 g of light yellow solid was obtained, at 92.8% purity by HPLC (area %), and a yield of 26% (calculated as pure product).
Reaction SMILES: CN(C=O)C.[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25]Br)[CH2:7][CH3:8].[NH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>C(OCC)(=O)C>[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])[CH2:7][CH3:8]
Reactant: O=C1NCCN1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCN2CCNC2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (5 mL) of 7-propyl-3-(trifluoromethyl)-6-(3-bromopropyloxy)-1,2-benzisoxazole as prepared in Example 7 (322 mg, 0.88 mmol), was added 2-imidazolidinone (320 mg, 3.52 mmol) and CsCO3 (320 mg, 0.97 mmol) then stirred at room temperature overnight. After aqueous work-up and silica gel chromatography (hexanes: 70% ethyl acetate), the title compound was obtained.