Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:29])[CH2:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:29])[CH2:27][CH3:28])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)OC(=O)CC
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC)cc(OC(C)=O)c4[C@H]3CC[C@]12C

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (0.884 g, 26 mM), isopropenyl propionate (15.1 g, 123 mM) and p-toluenesulfonic acid monohydrate (0.134 g, 0.7 mM) is heated at 120° on a set-up employing a Vigreaux column as described in Example 9. After heating at 120° for 12 hrs, the temperature is raised to 150° for 1 hr. The pot residue is poured into ether. The ethereal solution is extracted with saturated sodium bicarbonate solution, cold H2O and dried over MgSO4. Evaporation of the solvent gives a residue which upon chromatography on neutral silica gel affords 1-acetoxy-3-methoxy-17-propionyloxyestra-1,3,5(10),16-tetraene.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([O:27][Si](C(C)(C)C)(C)C)[CH:17]=[C:18]([O:19][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40].[C:41]([O:45][C:46]([NH:48][C@H:49]([C:52](O)=[O:53])[CH2:50][OH:51])=[O:47])([CH3:44])([CH3:43])[CH3:42].Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[C:41]([O:45][C:46]([NH:48][C@@H:49]([CH2:52][OH:53])[C:50]([NH:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([OH:27])[CH:17]=[C:18]([OH:19])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40])=[O:51])=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](N)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 61 mg of methyl (4R, 7S)-7-amino-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate and 21 mg N-(tert-butoxycarbonyl)-L-serine in 2 ml of acetonitrile, cooled to 0° C., were added 20 mg of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 hours, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 2 ml of methanol, 20 mg of ammonium fluoride were added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with 40 ml of ethyl acetate and washed with 30 ml of water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was triturated with 2 ml of ether, then hexane was added, and the white solid was isolated by filtration to give 22 mg of methyl (4R, 7S)-7-[(S)-2-(1-tert-butoxyformamido)-3-hydroxypropionylamino]-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Br:17])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:17][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[C:14]=2[O:15][CH3:16]
Reactant: COc1c2ccc(Br)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2ccc(Br)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (50 mg, described in Example 129) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 96%). MS (ES): M/Z [M+H]=513. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.89 (d, 1H), 6.97 (dd, J=9.1, 1.5 Hz, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.94-7.99 (m, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [Cl:1][O-].[Na+].[CH3:4][N:5]1[C:9]([CH:10]([OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[CH:8][CH:7]=[N:6]1>C(O)(=O)C>[CH3:4][N:5]1[C:9]([C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[O:23])=[C:8]([Cl:1])[CH:7]=[N:6]1
Reactant: [O-]Cl
Reactant: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2c(Cl)cnn2C)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.3 g of an aqueous 10 % sodium hypochlorite solution are added to a solution of 3.9 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol in acetic acid and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated to remove acetic acid, and ethyl acetate is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 2.1 g of (1-methyl-4-chloropyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanon e.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15]I)=[O:9])=[CH:4][CH:3]=1.CO.[CH3:19][NH2:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][NH:20][CH3:19])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CI
Solvent: CO
Product: CNC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 59 %

Procedure:
The title compound (80 mg, 0.20 mmol) produced in step (ix) of Reference Example 8 was dissolved in 1 ml of a 40% methylamine methanol solution, and the mixture was stirred at room temperature for 44 hr. The reaction solution was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=5:1:0.1) to give 36 mg (yield 59%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([NH2:8])[CH3:7].[CH3:20][C:21]([C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[CH2:22]>CO>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([N:8]1[CH2:25][CH:24]([CH3:26])[C:23](=[O:27])[CH:21]([CH3:22])[CH2:20]1)[CH3:7]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)N
Reactant: C=C(C)C(=O)C(=C)C
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)N1CC(C)C(=O)C(C)C1
Temperature: 65 °C
Yield: 89 %

Procedure:
53.9 parts by weight of 6,10,14-trimethyl-2-amino-pentadecane are dissolved in 200 parts of methanol. A solution of 22 parts of 2,4-dimethyl-penta-1,4-dien-3-one in 100 parts of methanol is added at room temperature and this mixture is then heated at the reflux temperature (65° C.) for 3 hours. The reaction product is worked up by distillation, giving 67.5 parts ( 89% of theory) of N-(6,10,14-trimethyl-pentadec-2-yl)-3,5-dimethyl-piperidin-4-one, boiling point=171° C./0.01 mm Hg (active ingredient No. 20).
Reaction SMILES: C[Si]([C:5]#[C:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])#[CH:5]
Reactant: C[Si](C)(C)C#CC(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Place a mixture of α-[(trimethylsilyl)ethynyl]-benzene-methanol (4.09 g, 20 mmol) and tetrahydrofuran (25 mL) under argon atmosphere and cool to 0° C. Add, by dropwise addition, tetra-n-butylammonium fluoride (25 mL of a 1M solution in tetrahydrofuran, 25 mmol). Allow to warm to room temperature and stir for 1 hour. Partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride and concentrate in vacuo. Purify by silica gel chromatography (15% ethyl acetate/hexane) then purify further by distillation to yield 2.15 g of the title compound; bp 100°-110° C. @0.1 mm Hg.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][S:6]([C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=O>CO>[CH3:5][S:6][C:8]([NH:4][CH2:1][C:2]#[CH:3])=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: C#CCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: C#CCNC(=C[N+](=O)[O-])SC

Procedure:
A solution of propargylamine (1.10 g, 0.02 mole) in 22 ml of methanol was added dropwise to a stirred suspension of 1-methylsulfinyl-1-methylthio-2-nitroethylene [prepared according to the procedure described in Belgian Patent 841,353], at 25°. After 1 hour at ambient temperature the solution was evaporated under reduced pressure, triturated under 20 ml of cold isopropanol, and filtered to give the product. Recrystallization from isopropanol gave the title product, mp 131°-132°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:11]=[C:12]([CH2:14][CH2:15][NH:16][S:17]([CH2:20][C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:18])[CH:13]=2)[CH:2]=1.N.C(O)(=O)C>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:11]=[C:12]([CH2:14][CH2:15][NH:16][S:17]([CH2:20][C:21]([F:23])([F:24])[F:22])(=[O:18])=[O:19])[CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)CCc1cc(CCNS(=O)(=O)CC(F)(F)F)cc(Cc2cccnc2)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: O=C(O)CCc1cc(CCNS(=O)(=O)CC(F)(F)F)cc(Cc2cccnc2)c1
Yield: 70.6 %

Procedure:
A stirred solution of ethyl 3-{3-(3-pyridylmethyl)-5-[2-(2,2,2-trifluoroethylsulphonylamino)ethyl]phenyl}propanoate (Example 10; 400 mg) in 6N hydrochloric acid (4.0 ml) was heated at 100° C. for 4 hours. The cool solution was basified with aqueous ammonia solution (SG 0.880) and then re-acidified by the dropwise addition of glacial acetic acid. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (MgSO4). Evaporation under vacuum of the solvent gave the title compound as a gum (265 mg); Rf 0.35 (SS 7). Found: C,53.26; H,4.78; N,6.31. C19H21F3N2O4S requires C,53.01; H,4.92; N,6.51%.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]1[C:9](=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:23])[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=31)[O:8]2)(=O)C>S(=O)(=O)(O)O.C(O)C.O>[NH2:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]1[C:9](=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:23])[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=31)[O:8]2
Reactant: CCOC(=O)c1c2oc3cc(NC(C)=O)ccc3nc-2c2ccccc2c1=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c2oc3cc(N)ccc3nc-2c2ccccc2c1=O

Procedure:
The 9-acetamido-6-carbethoxybenzo[a]phenoxazin-5-one obtained in point 3.2 was dissolved in a mixture of sulfuric acid (3 ml) and ethanol (3 ml). The mixture was heated to 80° C. while at the same time gradually adding water (1 ml). The purple color characteristic of the amine rapidly appeared. The hydrolysis was continued until the sample, diluted with water, and then extracted in ethyl acetate, no longer showed any 9-acetamido-6-carbethoxybenzo[a]phenoxazin-5-one by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].[H-].[Na+]>COCCOC>[CH:16]([CH:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc(OC)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over 1.5 hours to a stirred suspension of sodium hydride in oil (50%. 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2°, allowed to stand overnight at room temperature and was poured on to ice. The mixture was extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2 N sulphuric acid. An oil was precipitated and crystallised on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, 70%) m.p. 91.5°-94°. A sample recrystallised from aqueous ethanol had m.p. 93°-94°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21](Cl)[Cl:22]>O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:21][Cl:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (1 g, 4.6 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.55 g, 18.4 mmol), TBAHSO4 (156 mg, 0.46 mmol) and a solution of chloromethyl sulfochloridate (559 μL, 5.5 mmol) in DCM (5 mL). The title compound was obtained as colorless oil (877 mg, 71.8%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][CH:29]2[NH2:34]>>[CH2:1]([C:3]1[C:4]([NH:34][CH:29]2[C:30]3[C:25](=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1cccc2c1CCCC2N
Product: CCc1cnc(CC)c(NC2CCCc3c(OC)cccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.66, 7.19, 7.00, 6.78, 5.47, 4.54, 3.87, 2.83, 2.68, 2.54, 2.06, 2.02, 1.97, 1.31; 13C NMR (100 MHz, CDCl3) δ 157.50, 153.66, 161.36, 140.81, 139.90, 129.80, 127.37, 126.82, 121.33, 108.49, 55.75, 48.72, 29.44, 28.55, 26.08, 23.59, 19.62, 13.93, 11.14; HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2066.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
3-Bromo-4-methoxybenzoic acid (22.8 g, 98.8 mmol) was dissolved in thionyl chloride (42 ml) and stirred at 60° C. for 30 min. The volatiles were evaporated in vacuo and the residue was stripped with dioxane. The obtained acid chloride was dissolved in DCM (50 ml). 2-Amino-indane-2-carboxylic acid methyl ester hydrochloride (15.0 g, 65.9 mmol) was suspended in DCM (100 ml), EDIA (10.2 g, 79.1 mmol) was added, the mixture was cooled in an ice bath, and the solution of the acid chloride was slowly added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/methanol gradient) and subsequent crystallization from EA to give 21.8 g of the title compound.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[I:10][C:11]1[CH:18]=[CH:17]C(CBr)=[CH:13][CH:12]=1.[OH-].[K+].O>C1(C)C=CC=CC=1>[I:10][C:11]1[CH:18]=[CH:17][C:9]([CH2:2][O:3][CH2:4][C@H:5]([OH:6])[CH2:7][OH:8])=[CH:13][CH:12]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC1(C)OC[C@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC[C@@H](O)COCc1ccc(I)cc1
Yield: 88.9 %

Procedure:
(S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (6, 1.17 g, 8.9 mmol) and 4-iodobenzylbromide (2.5 g, 8.4 mmol) were refluxed under Dean-Stark conditions in toluene (80 mL) in the presence of KOH (8.8 g, 154.0 mmol) for 12 h. The reaction mixture was allowed to cool down and H2O (30 mL) was added. After separation of the phases the water layer was washed with toluene (2×15 mL). Combined organic layers were washed with H2O (30 mL) and concentrated in vacuo. The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt. The solvent was removed in vacuo and the residue was co-evaporated twice with toluene/EtOH (30 mL, 5:1, v/v). The residue was dried under diminished pressure to afford (R)-3-(4-iodobenzyloxy)propane-1,2-diol (7, 100%, 2.3 g) as yellowish oil that was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([O:11][C:12]([C:14](=[CH:35][CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1)[N:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH3:10]>C(#N)C>[CH2:44]([C:41]1[CH:40]=[CH:39][C:38]([C:37]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:15][C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)[CH3:45]
Reactant: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccn2)n1

Procedure:
Following General Procedure K, 2-pyridinecarboxaldehyde (41 mg, 0.38 mmol) and 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-1λ5-phosphahexa-1,3,5-triene (Compound 46, 193 mg, 0.38 mmol) in dry acetonitrile (5 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(#N)C.C(Cl)Cl>[O:41]([CH2:40][CH2:39][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4CCOc3ccccc3)n2)ccn1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine and 70 mg (0.48 mmol) potassium carbonate in 5 mL acetonitrile was treated with 0.074 mL (0.48 mmol) β-bromophenetole at 0° C. The mixture was stirred at 50° C. for 8 h before it was cooled to ambient temperature for 16 h at which time MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromotography, the title compound was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][CH2:26][CH:27]=[O:28].[NH4+].[Cl-]>C1COCC1>[F:23][C:24]([F:30])([F:29])[CH2:25][CH2:26][CH:27]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:28]
Reactant: O=CCCC(F)(F)F
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Yield: 66.6 %

Procedure:
n-Butyllithium (150 uL of a 2.5M solution in hexanes, 0.38 mmol) was added dropwise to a −78° C. solution of 4-bromo-4′-(trifluoromethyl)biphenyl (113 mg, 0.375 mmol) in 3 mL THF. The resulting solution was stirred at −78° C. 15 min. 4,4,4-trifluorobutyraldehyde (98 mg, 0.78 mmol) was added neat. The resulting colorless solution was stirred at −78° C. 20 min. 1 mL sat. aqueous NH4Cl was added, and the mixture warmed to room temperature. The reaction mixture was partitioned between Et2O and water. The organic layer was dried over MgSO4 and concentrated to give a colorless oil. The crude material was purified by silica gel chromatography to provide 4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (87 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.64-7.71 (m, 4H), 7.57-7.62) m, 2H), 7.41-7.47 (m, 2H), 4.78-4.87 (m, 1H), 2.10-2.39 (m, 3H), 1.96-2.09 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#N.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzonitrile (20 g, 0.15 mol), 2,4-pentanedione (17 g, 0.17 mol), piperidine (130 mg, 1.5 mmol) and p-toluene sulfonic acid (260 mg, 1.5 mmol) in toluene (400 ml) is refluxed overnight with a Dean-Stark trap. The solution is concentrated in vacuo and purified over silica gel with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>>[C:1]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCC(=O)O
Reactant: C=CCCO
Product: C=CCCCCCCCC(=O)OCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from dec-9-enoic acid and but-3-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (30:1 hexanes: diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2927 (s), 2855 (s), 1737 (s), 1641 (m), 1458 (m), 1418 (m), 1353 (m), 1243 (s), 1170 (s), 1115 (m), 992 (s), 912 (s), 725 (m), 635 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.74 (2H, m), 5.14-4.91 (4H, m), 4.12 (2H, t, J=6.8 Hz), 2.38 (2H, ddt, J=13.6, 6.8, 1.4 Hz), 2.29 (2H, t, J=7.6 Hz), 2.06-2.01 (2H, m), 1.63-1.59 (2H, m), 1.39-1.26 (8H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.3, 134.2, 117.3, 114.3, 63.4, 34.5, 33.9, 33.3, 29.2, 29.2, 29.1, 29.0, 25.1; HRMS (ESI+) [M+H]+ calcd for C14H25O2: 225.1855. found: 225.1855.