Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1(=[O:18])[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[CH2:19]([OH:23])[CH:20]([OH:22])[CH3:21].[OH-].[K+].C1(C)C=CC(S(O)(=O)=[O:33])=CC=1.C=CC1C=CC=CC=1>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:12])=[O:5].[C:11]([OH:12])(=[O:22])/[CH:10]=[CH:9]\[C:8]([OH:13])=[O:18].[CH2:19]([OH:23])[CH:20]([OH:22])[CH3:21].[C:8]([O-:13])(=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([O-:33])=[O:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(O)CO
Solvent: C=Cc1ccccc1
Product: O=C(O)/C=C\C(=O)O
Product: O=C([O-])c1ccccc1C(=O)[O-]
Temperature: 70 °C
Yield: 89 %

Procedure:
A three-liter reactor equipped as described in Example 2 is charged with a mixture of maleic anhydride (750 g) and phthalic anhydride (250 g), which is melted by heating to 70° C. Propylene glycol (348 g) is added, and the exothermic reaction is maintained at 130° C. or less until the reaction subsides (about 2 h). The acid number of this bis-maleate/phthalate intermediate is 417 mg KOH/g. A 3000 mol. wt. polyoxypropylene triol (1152 g) and p-toluenesulfonic acid (2.5 g) are added, and the mixture is heated at 190° C. until the acid number drops to 123 mg KOH/g. Propylene glycol (237 g) is added, and heating continues until the acid number reaches 42 mg KOH/g. The product is cooled and isolated (2372 g, 89% yield). GPC analysis shows: Mn =1475, Mw=7590. A blend of the resin with 40 wt. % styrene has APHA color =150.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20].S(=O)(=O)(O)O.C>C(O)(=O)C.C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Br
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)CCCCCCCCCCCCCCCBr
Temperature: 0 °C

Procedure:
A mixture of 18 g. of 16-hydroxyhexadecanoic acid and 160 g. of 30-34% hydrogen bromide in acetic acid is treated with 32 ml. of concentrated sulfuric acid and stirred at ambient temperature for 18 hours. The solution is stirred under reflux for 7 hours and then poured into 500 ml. of ice-water and filtered.A methylene chloride solution of the product is Darco clarified, dried over magnesium sulfate, and evaporated. Crystallization of the residue from ether-petroleum ether and then acetonitrile affords 16-bromohexadecanoic acid as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38]([I:25])[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)COC1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCC(I)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (1.18 g, 4.49 mmol), imidazole (0.31 g, 4.49 mmol) and iodine (1.14 g, 4.49 mmol) are added to a solution of (4-hydroxy-cyclohexyloxy)-acetic acid tert-butyl ester (cis:trans=ca. 1:1) (0.86 g, 3.74 mmol) in a mixture of CH2Cl2 (10 ml)/CCl4 (20 ml) at 0° C. The cooling bath is removed and the reaction mixture is stirred at room temperature for 18 hours. Saturated aq. Na2S2O3 (10 ml) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is re-extracted with CH2Cl2 (×3). The combined organic extracts are washed with brine (×1), dried (Na2SO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 5% ethyl acetate in isohexane, gives the product.
Reaction SMILES: [C:1]1([O:7]C)C=CC=C[CH:2]=1.[CH:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2[NH:23][C:24]2[CH:25]=[C:26]([CH:39]=[C:40]([CH2:42][OH:43])[CH:41]=2)[NH:27]C(=O)CNC(=O)OC(C)(C)C)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(#[N:50])C.ClCCl>>[CH:19]1[C:20]2[C:15](=[N:14][C:13]3[C:22]([C:21]=2[NH:23][C:24]2[CH:25]=[C:26]([NH:27][NH:50][C:1](=[O:7])[CH3:2])[CH:39]=[C:40]([CH2:42][OH:43])[CH:41]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: CC#N
Reactant: COc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NNc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 62.7 %

Procedure:
Anisole (0.47 g, 4.28 mmol) and acetonitrile/dichloromethane (1/2, v/v, 25 ml) were added to t-butyl N-{2-[3-(9-acridinylamino)-5-(hydroxymethyl)anilino]-2-oxoethyl}carbamate (0.34 g, 0.71 mmol). To the resulting mixture, aluminium chloride (0.57 g, 4.28 mmol) was slowly added with stirring and stirred for 2 hours at the room temperature. The resulting product was concentrated under the reduced pressure and purified by column chromatography to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>>[Cl:1][C:2]1[N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: ClCc1ccccc1Cl
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Cl)n(C)c1=O

Procedure:
From 8-Chorotheophylline (10 g, 47 mmol)) and 2-chlorobenzyl chloride (19.4 ml, 153.9 mmol). The 2-chlorobenzyl chloride was added in three portions. First third at reaction start as described in general procedure (E), and the other thirds after 24 and 48 hours respectively as the reaction had not completed. Total reaction time 7 days at RT. Due to incomplete precipitation in water the product was extracted with DCM (700 and 300 ml), dried (MgSO4), and evaporated to dryness in vacuo. Excess 2-chlorobenzyl bromide was removed by washing the product in Et2O.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:21][CH:20]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCN1CCCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 14.5 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-prop-2-enyl-1,4-diazepan-1-yl)benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol, 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum, which solidified on trituration with DCM/Ether to afford the title compound (0.071 g, 14.50%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH:22][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Nc1cc(Br)ccc1Oc1ccccc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(Br)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 124b (351 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (470 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.35 Hz, 3H) 1.72-1.93 (m, 2H) 2.91-3.02 (m, 2H) 6.70 (d, J=6.99 Hz, 1H) 6.97 (d, J=7.72 Hz, 2H) 7.10 (t, J=8.27 Hz, 2H) 7.27-7.36 (m, 2H) 7.68 (dd, J=8.82, 2.57 Hz, 1H) 7.78 (d, J=8.46 Hz, 1H) 7.82 (d, J=2.57 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 8.89 (d, J=8.82 Hz, 1H) 10.90 (s, 1H) 14.49 (s, 1H); MS (ESI+) m/z 436 (M+H−TFA)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26](Cl)[C:27]([O:29]CC)=O)=[CH:21][CH:20]=1)([CH3:16])[CH2:9][C:8]2=[O:33])(=O)C.[NH2:34][C:35](N)=[S:36].S1(CCCC1)(=O)=[O:39].Cl>COCCO>[Cl:15][C:14]1[CH:13]=[C:12]2[C:7]([C:8](=[O:33])[CH2:9][C:10]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH:26]4[S:36][C:35](=[O:39])[NH:34][C:27]4=[O:29])=[CH:23][CH:24]=3)([CH3:16])[O:11]2)=[CH:6][C:5]=1[OH:4]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(Cl)cc3O2)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Agent: Cl
Solvent: COCCO
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CC(=O)c2cc(O)c(Cl)cc2O1

Procedure:
Following a procedure similar to that described in Example 1, but using 780 mg of ethyl 3-[4-(6-acetoxy-7-chloro-2-methyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 37), 360 mg of thiourea, 3 ml of sulfolane, 10 ml of ethylene glycol monomethyl ether and 5 ml of 3N aqueous hydrochloric acid, 286 mg of the title compound were obtained as a greyish white powder, softening at 195°-206° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH2:9]=O.[OH:11][PH:12]([OH:14])=[O:13].P(Cl)(Cl)Cl>>[P:12]([CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]([OH:8])=[O:7])([OH:14])([OH:11])=[O:13]
Reactant: O=[PH](O)O
Reactant: C=O
Reactant: CC(=O)NCC(=O)O
Solvent: ClP(Cl)Cl
Product: CC(=O)N(CC(=O)O)CP(=O)(O)O

Procedure:
In contrast to Reaction Scheme 6, however, N-acetylglycine XVIII is reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)-N-acetylglycine XIX which is hydrolyzed using water and an acid such as hydrochloric acid to produce Glyphosate I and acetic acid. Acetic acid which is produced in the hydrolysis step can be reacted with ammonia to generate acetamide for the carboxymethylation step.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C:9]=2[CH:18]=1)#[N:3].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22].[CH3:27]I>C(O)C>[C:2]([C:4]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C:9]=2[CH:18]=1)([CH3:27])[C:19]([O:20][CH2:21][CH3:22])=[O:23])#[N:3]
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccc2c(c1)Cc1cccnc1O2
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C#N)c1ccc2c(c1)Cc1cccnc1O2

Procedure:
A solution of 0.76 g of metallic sodium in 15 ml of ethanol is added to a mixture of 6.6 g of 7-cyanomethyl-5H-[1]benzopyrano[2,3-b]pyridine and 46 ml of diethyl carbonate, and the whole mixture is refluxed for 1 hour. After cooling, 5.2 g of methyl iodide is added to the reaction mixture. The temperature of the mixture is raised gradually, and the mixture is refluxed for 2 hours. The excess diethyl carbonate is distilled off, and toluene is added to the residue. The mixture is washed with water, and the toluene layer is dried. The toluene is distilled off, and the residue is recrystallized from isopropyl alcohol to give ethyl 2-cyano-2-(5H-[1]benzopyrano-[2,3-b]pyridin-7-yl)propionate melting at 119°-120°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:21][C:18]([C:13]1[CH:14]=[C:15]([NH:17][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[O:6])[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:22])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C=NCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)NCCCl)cc(C(C)(C)C)c1O
Temperature: 23 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
0.17 ml (2 mmol) of chloroethylisocyanate is added to a flask containing a solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml of DMF. The reaction mixture is agitated for 2 hours at 23° C. and finally diluted with 100 ml of ethyl acetate and 25 ml of water. After decantation, the organic solution is washed with 25 ml of water, twice with 25 ml of salt water and finally dried over magnesium sulphate. After filtration and evaporation, the residue is taken up in isopentane in order to finally produce the expected product, in the form of a pink solid, with a yield of 83%. Melting point: 169-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 79.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{1-[5-(4-chlorophenyl)-2-methyl-3-furyl]-3-methylbutoxy}benzoic acid (128 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (124 mg, 86%) as an amorphous compound.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O-:21])=[O:20])=[CH:16][CH:17]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O-:21])=[O:20])=[CH:16][CH:17]=1.[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])Cc1ccc(O)cc1
Yield: 99 %

Procedure:
A mixture of 24.9 g (0.10 moles) dibutyltin oxide, 30.4 g (0.20 mole) 4-hydroxyphenylacetic acid, and 300 ml toluene were charged to a 3-necked round bottom flask equipped with a stirrer, thermocouple or thermometer, and condenser with a DEAN-STARK water trap, and heated at reflux temperature until all the water of reaction was collected in the trap. The toluene was removed using a flash evaporator to yield 53 g (99%) of dibutyltin bis(4-hydroxyphenyl acetate) having a melting point of 121°-126° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[NH:11][C:12](=O)OC(C)(C)C)=O.CO/C=[CH:22]/[C:23]([O:25][CH3:26])=[O:24].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]2[C:4]=1[N:11]=[CH:12][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:1]2
Reactant: CO/C=C/C(=O)OC
Reactant: COc1cccc(C=O)c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2c(OC)cccc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of tert-butyl N-(2-formyl-6-methoxyphenyl)carbamate (2.85 g, 11.35 mmol) [described in Org. Lett. 2002, 4(1), 39-42] and methyl trans-3-methoxyacrylate (2.70 mL, 24.96 mmol) dissolved in 60 ml of methanol, was added slowly 40 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×70 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum giving 2.12 g of compound of molecular formula C12H11NO3. The crude product was used without further purification in the next stage. Aspect: orange powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:19](=[O:21])=[O:20]>C1COCC1>[CH3:13][S:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:19]([OH:21])=[O:20])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: CSc1ccc2ccc(Br)cc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2ccc(C(=O)O)cc2c1
Temperature: -78 °C
Yield: 79 %

Procedure:
A stirred solution of 199 (850 mg, 3.36 mmol) in THF (10 mL) was treated at −78° C. with n-BuLi (2.5 M in hexanes, 1.48 mL, 3.70 mmol) under N2. The mixture was stirred at −78° C. for 15 nm in, then treated with excess CO2(g) and allowed to warm to room temperature. The solvent was removed under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was acidified, and the resulting solid was crystallised from MeOH to give 7-(methylsulfanyl)-2-naphthoic acid (200) (577 mg, 79%): mp 217° C.; 1H NMR [(CD3)2SO] δ 13.0 (v br, 1H), 8.53 (d, J=0.7 Hz, 1H), 7.98-7.87 (m, 4H), 7.53 (dd, J=8.7, 1.9 Hz, 1H), 2.60 (s, 3H). Anal. (C12H10O2S) C, H.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(O)(=O)C.Br>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.6 %

Procedure:
To a stirred solution of 4-acetylpyridine (10 mL, 90 mmol) in glacial acetic acid (40 mL) and 48% hydrobromic acid (15 mL), bromine (4.65 mL, 90 mmol) in glacial acetic acid (10 mL) was added dropwise. After addition, the solution was stirred at room temperature overnight. The white precipitate was filtered off and washed with absolute ethanol, thus obtaining the title compound (22.2 g, 90%) as a white solid containing traces of dibromoderivative, that was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C([C:21](OO)=[O:22])C=1>ClCCl>[O:22]=[C:21]1[CH:10]2[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.5 %

Procedure:
To the solution of N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine (110 g, 0.60 mol) obtained in Step 1 in 300 ml of dichloromethane, was added 3-chloroperbenzoic acid (m-CPBA; 311 g, 1.80 mol). The reaction mixture was stirred overnight at room temperature and filtered to remove benzoic acid produced. The resulting filtrate was washed with a saturated potassium carbonate solution, brine and distilled water. The resulting organic layer was dried and concentrated on magnesium sulfate to give the titled compound (180.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C@H:6]([NH:15]CCN(C(OC(C)(C)C)=O)CCCC1C=CC2CCCNC=2N=1)[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1)[CH3:2].Cl.CO>CCOC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C@@H:6]([C:7]1[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:15])[CH3:2]
Reactant: CCOC(=O)C[C@H](NCCN(CCCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C)c1ccc(OC)nc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C[C@H](N)c1ccc(OC)nc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of the ester 7-6 (14.1 g, 26 mmol) in EtOAc (350 mL) cooled to -20° C. was treated with HCl (gas) for 10 minutes then stoppered and stirred at 0° C. for 1.5 hr. The volatiles were removed in vacuo, the residue taken up in 150 mL of water and treated with solid K2CO3 to pH~10. This solution was extracted with EtOAc (3×150 mL), washed with brine, dried (Na2SO4) and concentrated to give an oil. Column chromatography (silica gel; 5% MeOH in CHCl3) gave the β-alanine 7-5; further elution with 5% MeOH in CHCl3 saturated with NH3 gave 7-7 as a viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (3H, t), 1.8-1.95 (4H, m), 2.5-2.8 (12H, m), 3.39 (2H, m), 3.92 (3H, s), 4.09 (2H, q), 5.01 (1H, bs), 6.34 (1H, d), 6.72 (1H, d), 7.06 (1H, d), 7.59 (1H, dd), 8.07 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.[NH2:29][CH2:30][C@@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:32][C@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[CH2:30][NH:29][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([CH2:20][N:17]2[CH2:16][CH2:15][C:13]3([O:12][CH2:11][CH2:10][N:9]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH2:14]3)[CH2:19][CH2:18]2)[CH:22]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C=O)c4)CC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 0 °C

Procedure:
A solution of 3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzaldehyde (example 96, step a) (0.303 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.330 g) and acetic acid (0.043 mL) in methanol (5 mL) was stirred at room temperature for 30 minutes, then cooled in an ice-water bath under nitrogen and treated with sodium triacetoxyborohydride (0.243 g) in one portion. The mixture was stirred in ice-water for 2 hours, then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the phases were separated, and the aqueous phase was extracted twice more with ethyl acetate. Any insoluble gummy residues were dissolved in methanol. The combined ethyl acetate phases were washed with brine, dried over magnesium sulphate and combined with the methanol solution. The whole was purified by flash chromatography on silica eluted with 1:7:92 triethylamine:methanol:dichloromethane to afford the slightly impure subtitled product as a yellow foam. Yield 0.324 g.