Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:38][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(OC(F)(F)F)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 21 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.27 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-trifluoro-methoxyphenyl) cyclopropane (Example 19) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 3 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxy-phenyl)prop-1-enyl)-1-(4-trifluoromethoxy phenyl) cyclopropane (29.4 mg, 21%).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][O:8][CH2:7]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:6]1[CH2:7][O:8][CH2:9][CH:10]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1COCC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1COCC(N=[N+]=[N-])C1
Temperature: 25 °C
Yield: 137.6 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-3-yl methanesulfonate (90 mg, 0.3 mmol) and sodium azide (30 mg, 0.5 mmol) in 10 mL of dry N,N-dimethylformamide was heated to 100° C. for 3 h. The reaction mixture was cooled to room temperature, 40 mL of water were added, product extracted with ethyl acetate (2×50 mL), organics combined dried with sodium sulfate, filtered and concentrated to give tert-butyl 5-azido-tetrahydro-2H-pyran-3-ylcarbamate (100 mg, crude) which was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:17])[NH2:16])[CH:7]=1)C.[OH-].[Na+]>CO.O>[C:15]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([OH:18])=[O:3])=[CH:7]1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)Cc1cn(C(N)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)n1cc(CC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (1-carbamoyl-1H-indol-3-yl)-acetic acid ethyl ester in methanol (61 mL) and water (6.1 mL) was added an 1N aqueous solution of NaOH (12.2 mL, 12.2 mmol) and the resulting yellow solution was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in HCl 1N. The aqueous mixture was extracted with EtOAC (3×), the combined organic extracts were dried (phase separator) and concentrated in vacuo. The crude product was used directly in the next step without any further purification. MS: 219 [M+H]+, 437 [2M+H]+; tR (HPLC conditions b) 2.16 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1)[CH3:36])([CH3:31])([CH3:30])[CH3:29].O1CCOCC1>CN1CCCC1=O>[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)=[CH:39][CH:38]=1)[CH3:36])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(CCN)cc1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(CCNc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1

Procedure:
The mixture of 1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.20 g, 053 mmol) and {1-[4-(2-amino -ethyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.304 g, 0.79 mmol) in 1:1 dioxane: 1-methyl -2-pyrrolidinone (6 mL) was heated to 100° C. for 17 h. The mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% MeOH/CH2Cl2to afford a white solid. M+1=568.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 97 %

Procedure:
A suspension of 6 g of 5-(2-chlorophenyl)-7-[2-(4-n-hexylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 149°-151° C. and 5.2 g of Lawesson reagent in 100 ml of toluene is stirred at 40°-42° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 6 g of 5-(2-chlorophenyl)-7-[2-(4-n-hexylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 140°-145° C. with decomposition.
Reaction SMILES: [O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]1([CH3:18])[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[O:1]=[C:2]([CH2:9][CH:10]([S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(S)cc1
Reactant: C#CC(=O)CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(SC(CC(=O)CCCC(=O)O)Sc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-oxohept-6-ynoic acid 3 (1.0 g), 4-dimethylaminopyridine (DMAP, 0.87 g) and p-toluenethiol (1.77 g) dissolved in dry dichloromethane (15 mL) was stirred at room temperature for 72 h. The reaction mixture was then diluted with ethyl acetate (40 mL) and the resulting organic phase washed with acidified water (2×15 mL, made from adding 2 ml of 1N HCl to 250 ml of deionised water) and finally saturated brine (1×10 mL). Volatiles were removed under reduced pressure (rotary evaporation) to yield a reddish brown ‘sticky’ residue which was further purified using silica based flash chromatography (Silica gel 100 C18-reversed phase, Fluka cat. No. 60754). A mobile phase consisting of hexane:ethyl acetate (60:40 v:v) was used to elute the product 7, (0.32 g, TLC Rf=0.50 using a mobile phase of hexane:ethyl acetate (25:10 v/v) acidified with acetic acid). 1H NMR (400 MHz, acetone-d6): δ 1.71 (p, 2H), 2.21 (t, 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.83 (d, 2H), 4.78 (t, 1H), 7.09 (d, 4H), 7.30 (d, 4H).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl:23][SiH:24]([Cl:26])[Cl:25]>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Si:24]([Cl:26])([Cl:25])[Cl:23])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: Clc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 92.3 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.21 g (7.5 mmol) of 4-chlorobenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.8 g of (4-Chlorobenzyl)trichlorosilane; H-NMR (CDCl3, ppm):2.93 (s, 2H, —CH2—), 7.29-7.38 (m, 4H, ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]1([P:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:20]CC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)C>C(N(CC)CC)C>[C:13]1([P:19]([C:4](=[O:5])[C:3]2[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=2[CH3:12])(=[O:20])[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CCOP(Oc1ccc(OC)cc1)c1ccccc1
Agent: CCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OP(=O)(C(=O)c2c(C)cc(C)cc2C)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
59.5 g (0.326 mol) of 2,4,6-trimethylbenzoyl chloride and 0.75 g of triethylamine were heated to 115° C. and 45 g (0.163 mol) of monoethyl mono-4-methoxyphenyl phenylphosphonite were added dropwise in one hour under a nitrogen atmosphere and with vigorous stirring. Ethyl chloride was given off as a gas and was condensed in a downstream cold trap. The mixture was then further stirred at 110° to 115° C. for 90 minutes. In total, at the end of the reaction, 9 g (88% of theory) of ethyl chloride were situated in the cold trap. The excess 2,4,6-trimethylbenzoyl chloride was then distilled off at 1 mbar and the residue was distilled with the aid of a thin-film evaporator (bath temperature: 260° C.; 0.4 mbar). 40 g were obtained. The yield was 65% of theory.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)=[O:13])=[CH:16][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylcarboxamide (E1) and 4-pyridylboronic acid following a similar procedure to Example 4.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][N:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccccc1CCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H2O (2×). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/0-10% methanol-CH2Cl2) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). 1HNMR (400 MHz, CD3OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H17NO3: 235. found: 236 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1N=C(Cl)C(C)=CN=1.OC1C=C(C=CC=1)N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([CH3:25])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Nc1cccc(O)c1
Product: Cc1cnc(Nc2cccc(O)c2)nc1Nc1cccc(O)c1

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 3-hydroxyaniline gave N2,N4-bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret. time: 16.76 min.; purity: 100%, MS (m/e): 309 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccncc2)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (31 mg, 0.10 mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in a pressure tube in that order. The tube was charged with methylene chloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5 h. The reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate. After concentration, the crude product was purified by prep HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water gave the title compound (8 mg, 21%) as a yellow solid. 1H NMR (CD3OD) δ 8.31 (d, 2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85 (dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS(ESI+) m/z 384.21 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:24]/[NH:23][C:20](=[NH:21])[NH2:22])/[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: N=C(N)NN
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: N=C(N)N/N=C(\CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a screw cap pressure vessel was added the intermediate from Step B (0.450 g, 1.2 mmol), aminoguanidine hydrochloride (0.456 g, 6.2 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.94 mL, 7.4 mmol). The reaction solution was heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed twice with aqueous 1N NaOH and brine (1×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the indicated compound as a mixture of E,Z hyrazone isomers. 1H NMR (500 MHz, CH3OH-d4): δ 7.60 (d, J=8.6 Hz, 1H); 7.26-7.23 (m, 1H); 7.18 (d, J=2.5 Hz, 1H); 2.74 (s, 2H); 2.56 (s, 2H). m/z=421.2 (M+H).
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([CH2:17][C:18]([O:10][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCC/C=C/CO
Solvent: CCOCC
Product: CCCCCC/C=C/COC(=O)Cc1ccccc1

Procedure:
To a flask equipped with a reflux condenser, mechanical stirrer and dropping funnel is added trans-2-nonenol (14.2 g, 0.1 mole), N1N-dimethylaniline (12 g, 0.1 mole) and 20 ml ether. To the stirred mixture is added dropwise phenylacetyl chloride (15.5 g, 0.1 mole) at a rate to maintain a vigorous reflux of ether. After the addition, the mixture is warmed on a water bath for 2 hours and then allowed to stand several hours. The ether layer is separated from the precipitate and extracted with 10% sulfuric acid. The ether layer is dried over anhydrous sodium sulfide and purified up to give trans-2-nonenyl phenylacetate.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.Cl[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>CN(C)C=O.[Mn]>[CH2:11]([S:8]([NH:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][C:4]=1[F:15])(=[O:10])=[O:9])[CH3:12]
Reactant: CCOC(=O)C(C)Cl
Reactant: CCS(=O)(=O)NCc1ccc(Br)cc1F
Agent: [Mn]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1.03 mmol) in dimethylformamide, Manganese (113 mg, 2.06 mmol), (2,2′-Bipyridine)nickel(II)-dibromide (27 mg, 0.07 mmol), ethyl 2-chloropropanoate (0.17 mL, 1.34 mmol) was added. It was followed by addition of trifluoroacetic acid (0.002 mL, 0.028 mmol). The mixture was stirred for 24 h at 65° C. The reaction mixture was quenched by concentrated HCl (7 drops). Then it was extracted with diethyl ether, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to obtain ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate in pure form (65 mg, 20%).
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][C:8]2=O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH:9]=[C:8]2[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)C(C)=CC(C)(C)O2
Temperature: 10 °C

Procedure:
A solution of methylmagnesium bromide (3.0 M in THF, 1.67 mL, 5.0 mmol) was added slowly into a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 710 mg, 2.5 mmol) in 10 mL of THF at −30° C. The mixture was stirred and warmed to 10° C. for 2 h. The reaction mixture was quenched with 10% HCl and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of NH4Cl, dried (MgSO4) and concentrated at reduced pressure to give a crude oil, which was then dissolved in 10 mL of dichloromethane and cooled to 0° C. with an ice bath. To this solution was added p-toluenesulfonic acid (100 mg). After stirring for 3 h at 0° C., the reaction mixture was quenched with water, extracted with dichloromethane, washed with brine, dried (MgSO4) and concentrated at reduced pressure to give a colorless oil. Purification by flash chromatography (silica gel, 95.5 hexane/ethyl acetate) gave the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:12]1[CH2:26][CH2:27][C:9]2([O:28][CH2:29][CH2:30][OH:31])[CH2:10][CH2:11]1)=[O:5])C.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:12]1[CH2:26][CH2:27][C:9]2([O:28][CH2:29][CH2:30][O:31][CH3:34])[CH2:10][CH2:11]1)=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC12CCC(CC1)Cn1c2nc(C(=O)OC)c(OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
To a solution of 5-benzyloxy-1-(2-hydroxy-ethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (105 mg, 0.245 mmol) in DMF (1 mL) was added 60% NaH (15 mg, 0.37 mmol) and the mixture stirred at room temp. for 15 min. under N2. After H2 gas evolution had ceased, MeI (0.031 mL, 0.490 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue was taken up in ethyl acetate (10 mL), washed with water followed by brine, then dried (Na2SO4) and concentrated to provide 85 mg of a crude oil which was purified by C-18 reverse phase column chromatography (YMC AQ, 18-22-26-30-34% CH3CN/H2O with 01% trifluoroacetic acid) to provide 8 mg (0.019 mmol, 8% yield) of the title compound as an amber film: HPLC: retention time=2.30 min (area percent=91%); LC/MS: m/z 429 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.66-1.70 (2H, m), 1.87-2.02 (2H, m), 2.12 (4H, t, J=7.5 Hz), 2.46 (1H, brs), 3.39 (3H, s), 3.62 (2H, t, J=4.7 Hz), 3.73 (2H, d, J=4.7 Hz), 3.84 (3H, s), 4.07 (2H, d, J=3.7 Hz), 5.26 (2H, s), 7.31 (1H, t, J=7.0 Hz), 7.36 (2H, t, J=7.3 Hz), 7.48 (2H, d, J=7.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[C:9](=[O:20])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OC)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].IC1C=C(C=CC=1)[C:29]#[N:30]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:22])[CH3:23])[C:9](=[O:20])/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:29]#[N:30])[CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cccc(I)c1
Reactant: COc1cccc(/C=C/C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)/C=C\c1cccc(C#N)c1
Yield: 90 %

Procedure:
Following the procedure described for [(R)-(E)-1-isopropyl-4-(3-methoxy-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester with 3-iodobenzonitrile (5.50 g, 24.0 mmol, 1 equiv) afforded the title compound as a yellow solid (7.4 g of ˜90% purity material). ESMS [M+H]+: 329.2.