Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.C[Si]([CH2:10][C:11](=[C:24]=[CH2:25])[CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15](O)[O:14]1)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:10]=[C:11]1[C:24](=[CH2:25])[CH:15]2[O:14][CH:13]([CH2:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12]1
Reactant: C=C=C(CC1Cc2ccccc2C(O)O1)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CC2Cc3ccccc3C(O2)C1=C
Temperature: -78 °C
Yield: 78.5 %

Procedure:
1.20 mL of diethyl ether was added to 3-(2-trimethylsilanylmethyl-buta-2,3-dienyl)-isochroman-1-ol (78 mg, 0.27 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (49 μL, 0.27 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=⅙) to obtain 42 mg of the product (78%).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([CH:32]([CH3:34])[CH3:33])[CH:26]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=1[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(S)c(C(C)C)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p.75°-76 ° C.). 1H NMR (DMSO-d6) δ 1.15 (m, 6 H), 2.16 (s, 3 H), 2.19-2.36 (m, 3 H), 2.62 (m, 1 H), 3.21 (m, 1 H), 3.44 (q, 2 H), 5.82 (d, 1 H), 6.40 (dd, 1 H), 6.95 (d, 1 H), 7.10-7.18 (m, 3 H), 7.25 (m, 2 H), 7.44 (m, 5 H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([O:20][C:21]([C:23]1([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:13]2>C(#N)C>[CH:21]([O-:22])=[O:20].[O:1]([CH2:8][CH2:9][CH2:10][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([O:20][C:21]([C:23]1([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O[C@@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Product: O=C(O[C@@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)C1(c2ccccc2)CCCCCC1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-phenoxypropyl bromide (0.026 mL) was added to a solution of 1-phenyl -cycloheptanecarboxylic acid (S)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 33a) (50 mg) in acetonitrile (1 mL). The reaction mixture was allowed to stir at room temperature for 72 hrs then heated to 50° C. for 3 days. The volatiles were evaporated and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give 57 mg of a hygroscopic foam. Further purification was achieved by reverse phase HPLC using a C18 column eluting with 5-95% MeCN/H2O containing 0.1% formic acid ° over 30 mins gave the title compound (43 mg) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCCO3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCO3
Yield: 95 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (65 μL, 0.6 mmol) was added to a stirred solution of chloride 235 (47 mg, 0.2 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (50 mL) and dilute aqueous NH3 solution (20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 236 (55 mg, 95%) as a pale yellow solid: mp (MeOH/EtOAc) 119-120° C.; 1H NMR δ 7.35 (d, J=9.2 Hz, 1H, H-6), 7.23 (d, J=9.2 Hz, 1H, H-5), 5.66 (br s, 1H, NH), 4.19 (br dd, J=5.1, 5.0 Hz, 2H, H-8), 3.47-3.53 (m, 4H, H-10, CH2N), 2.54 (br t, J=6.0 Hz, 2H, CH2N), 2.27 [s, 6H, N(CH3)2], 1.97-2.04 (m, 2H, H-9); 13C NMR δ 158.0, 152.2, 146.7, 130.3, 128.4, 125.2, 114.0, 65.9, 57.7, 45.1 (2), 38.7, 24.9, 22.2. Anal. calcd for C14H19N5O2.¼H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.5; H, 6.6; N, 23.8%.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.S(C1C=CC(C)=CC=1)([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:17][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Temperature: 5 °C
Reaction time: 20.5 h
Yield: 16 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 20.5 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (50%→60% acetone in hexanes) affording the desired product (1.11 g) as a tan solid. ESMS: MH 202.2.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].C(O)(=[O:10])CC.CC(C)=O.[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:10]
Reactant: CC(C)(O)C#N
Reactant: CCC(=O)O
Agent: CC(C)(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(O)C(N)=O
Reaction time: 4 h

Procedure:
A suspension of 0.383 g (wet cell paste) Comamonas testosteroni 5-MGAM4D cells (ATCC 55744) in 5.56 mL of 50 mM potassium phosphate buffer (pH 6.0) was placed into a 15-mL polypropylene centrifuge tube, then 51.0 mg of acetone cyanohydrin (0.10 M final concentration of acetone cyanohydrin in the suspension) was added and the resulting suspension mixed on a rotating platform at 25° C. Samples for analysis (0.180 mL) were mixed with 0.020 mL of 1.0 M propionic acid (HPLC external standard), centrifuged, and the supernatant analyzed by HPLC for acetone cyanohydrin, acetone, and 2-hydroxyisobutyric acid. After 4 h, the yields of 2-hydroxyisobutyric acid, 2-hydroxyisobutyramide, and acetone were 73.5%, 0%, and 20.4%, respectively, with no acetone cyanohydrin remaining.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(CBr)c1
Reaction time: 2 h
Yield: 114.4 %

Procedure:
A mixture of 32 g of 3-methyl-benzophenone (process of Ador et al, Berichte, Vol. 12, p. 2299), 96 ml of carbon tetrachloride, 26 g of N-bromosuccinimide and 100mg of benzoyl peroxide was refluxed for one hour and after the addition of another 100mg of benzoyl peroxide, the mixture was refluxed for 1 hour. Another 100 mg of benzoyl peroxide were added and reflux was maintained for 11/2 hours. Another 100 mg of benzoyl peroxide were added and reflux was maintained with stirring for 11/2 hours. The mixture was cooled, filtered and the filtrate was distilled to dryness under reduced pressure to obtain 46 g of 3-bromomethyl-benzophenone which was used as is for the next step.
Reaction SMILES: [N:1]1([C:7](OCC)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.CC(=O)CC>O>[CH2:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCCCN1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
A mixture of 2.02 g of ethyl 1-piperazinecarboxylate, 1.92 g of anhydrous potassium carbonate, 3.08 g of decyl bromide and 20 ml of 2-butanone was stirred overnight at 80° C. After addition of water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with 3N hydrochloric acid. The extract was made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure Ethanol (20 ml) and ml of 10% aqueous sodium hydroxide were added to the residue, and the mixture was stirred overnight at 100° C. The reaction mixture was cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.38 g of 1-decylpiperazine as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.Cl.[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:35][CH:36]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid (12.0 g) in DMF (600 ml) was added [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (18.2 g) and 1-hydroxybenzotriazole. The mixture was cooled to 0–5° C. and EDC (15.8 g) and trietylamine (62 ml) were added. The mixture was stirred 1 h at 0–5° C. and over night at rt. The solvent was evaporated and the residue was dissolved in CH2Cl2 and washed with H2O (600 ml), and brine (300 ml). The aqueous layers were extracted with more CH2Cl2 (2×300 ml). The combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC(CH2Cl2/2 N NH3 in MeOH 97:3 to 19:1) afforded 10.2 g (40%) of (RS)-[(4-{[2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White foam. MS 498.2 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]2([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]2)[CH:35]=[C:34]([Cl:44])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:44][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]2([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]2)[CH:35]=1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C2(C#N)CCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (314.5 mg, 1.02 mmol), ethyl (S)-3-amino-3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)propanoate hydrochloride salt (from step 1 above) (345.15 mg, 1.006 mmol) and 1-hydroxybenzotriazole hydrate (31.2 mg, 0.204 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimde (225 μL, 1.453 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight (19 h). The solvent was evaporated in vacuo to give a yellow-orange gummy residue. LC-MS analysis of the gummy residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 597 (35ClM+H), m/z 599 (37ClM+H), m/z 619 (35ClM+Na) and m/z 621 (37ClM+Na); Calcd for C29H33ClN6O6: 597.06. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1.O>[CH2:16]([O:15][C:14]([N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:1])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccc(C(=O)OC)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Methyl 4-((methylamino)methyl)benzoate was dissolved in the mixed solution of THF (12 mL) and water (12 mL), then benzyl carbonochloridate (2.57 g, 15.0 mmol) was dropped into it. To the mixture sodium bicarbonate (1.7 g, 20.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ethyl acetate (50 mL×3) and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate and condensed to get methyl 4-(((benzyloxycarbonyl)(methyl)amino)methyl)benzoate (2.3 g, 53.5%), LC-MS (ESI) m/z 314 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]#[CH:6])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C=O.[CH:17](NC(C)C)(C)C.Cl>O.[Cu](Br)Br.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]=[CH2:17])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)NC(C)C
Reactant: C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Br[Cu]Br
Agent: C=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C=C=C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 80 °C

Procedure:
A mixture of 131 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate, 32 g of paraformaldehyde, 111 ml of diisopropylamine, 31 g of copper bromide and 1,300 ml of dioxane was heated at 80° C. for 161/2 hours and was cooled to 20° C. and diluted with water. The mixture was adjusted to a pH of 1 with aqueous N hydrochloric acid and was extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 hexane-methylene chloride mixture yielded 44 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1nn(C)cc1Cl
Yield: 81.4 %

Procedure:
In the same manner as in Example 259 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (235 mg, 82%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH3:32])[CH:34]=[CH:35]3)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(ccn2C)c1
Yield: 68.7 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.321 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.142 g (69%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].[CH2:11]([O:18][NH:19][C:20]([C:22]1[N:27]=[CH:26][C:25]2[C:28](=[O:31])[O:29][CH2:30][C:24]=2[C:23]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:23]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:24]([CH2:30][OH:29])[C:25]([C:28]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)=[O:31])=[CH:26][N:27]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OCc2c1cnc(C(=O)NOCc1ccccc1)c2OCc1ccccc1
Reactant: NCc1cc(F)cc(F)c1
Product: O=C(NCc1cc(F)cc(F)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 26.8 %

Procedure:
3,5-difluorobenzylamine (0.02 g, 0.154 mmol, 2.5 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.030 g, 0.077 mmol, 1 eq) were heated neat at 70° C. for 30 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.011 g of N2,3-bis(benzyloxy)-N5-(3,5-difluorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (15% yield) as a white solid; MS-ESI m/z 534 [MH]+.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccc(C=O)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: BrCCCCCCc1ccccc1
Product: CC(=O)NC(CCc1ccc(C(O)CCCCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 65.2 %

Procedure:
2-Acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-formylphenyl)ethyl)propane (3.0 g) and 1-bromo-6-phenylhexane (3.1 g) were reacted and treated in the same manner as in Working example 1(6) to give the title compound (2.6 g) as a pale yellow oily substance.