Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:24]([CH3:33])[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:34]>O1CCOCC1>[Cl-:34].[CH2:1]([N:3]([CH:24]([CH3:33])[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][NH2+:14][CH2:15][CH2:16]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C(C)C(=O)c1ccccc1
Reactant: Cl
Solvent: C1COCCO1
Product: CCN(C(=O)c1csc(C2CC[NH2+]CC2)n1)C(C)C(=O)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-{4-[ethyl(1-methyl-2-oxo-2-phenylethyl)carbamoyl]thiazol-2-yl}-piperidine-1-carboxylate (5.5 mmol; 2.59 g) is dissolved in 13.75 ml of a 4M solution of hydrochloric acid in dioxane. The reaction medium is stirred at room temperature overnight and is then evaporated to dryness to give 2.24 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:26]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: C1CN2CCN1CC2
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Temperature: 130 °C
Yield: 132.3 %

Procedure:
7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (708 mg), DABCO (112 mg), and N,N-Dimethylformamide (4 mL) were added to dimethyl carbonate (10 mL) at room temperature under stirring. The reaction mixture was heated to 130° C. for 36 h. After cooling the reaction, the organic solvent was evaporated off. The residue was purified by column chromatography (25% EtOAc in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (486 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.46 (6H, d), 3.78 (3H, s), 4.71-4.76 (1H, m), 6.60 (1H, d), 7.08 (1H, dd), 7.21 (1H, t), 7.56 (1H, dd), 7.80 (1H, dd), 7.96 (1H, dd), 8.27 (1H, d). MS (ES): C20H15ClN3O2 requires 367; found 368.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].[CH:66]([C:68]1[CH:76]=[CH:75][C:71]([C:72]([OH:74])=[O:73])=[CH:70][CH:69]=1)=O>>[C:72]([C:71]1[CH:75]=[CH:76][C:68]([CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]2([C:49]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)=[O:50])[CH2:42][C@@H:41]2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])=[CH:69][CH:70]=1)([OH:74])=[O:73]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)Cc1ccc(C(=O)O)cc1)C(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of Intermediate 61, by reaction of 15 mg of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) with 4-formylbenzoic acid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][C:11]1[C:27]([Cl:28])=[CH:26][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[O:24][CH3:25])=[O:16])=[C:13]([O:29][CH3:30])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:10][C:11]1[C:27]([Cl:28])=[CH:26][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH2:20][C@H:19]2[O:24][CH3:25])=[O:16])=[C:13]([O:29][CH3:30])[CH:12]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cccnc2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 2.8 parts of 3-(chloromethyl)pyridine hydrochloride, 4.7 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 5.3 parts of sodium carbonate and 68 parts of N,N-dimethylformamide was stirred for 5 hours at about 60° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated. The solid residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 3.84 parts (64.2%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(3-pyridinylmethyl)-4-piperidinyl]benzamide; mp. 188.9° C. (compound 91).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]#[N:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[C:16]([CH2:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])#[N:17]
Reactant: CCOC(=O)c1cc2ccccc2n1CC#N
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#CCn1c(C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
To a solution of 1.0 eq. of 1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester, in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at RT, acidified to pH2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a light yellow solid (70%).
Reaction SMILES: C(OCC)(=O)CC(C)=O.Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].[CH:17]1([C:20]2N(C(C)C)N=[CH:22][C:21]=2[CH:28]=[O:29])CC1>>[C:11]([N:15]1[C:20]([CH3:17])=[C:21]([CH:28]=[O:29])[CH:22]=[N:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NN
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: Cl
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C(C)(C)C

Procedure:
1-tert-Butyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl acetoacetate and tert-butyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C=O.[C:22]([BH3-])#N.[Na+].C(O)(=O)C>CCO>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:22])=[CH:4][C:3]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: [BH3-]C#N
Reactant: Clc1ncc(OC[C@@H]2CCCN2)cc1-c1cccs1
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2cccs2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-chloro-3-(2-(S)-pyrrolidinylmethoxy)-5-(2-thienyl)pyridine from step 152b above (48 mg, 0.14 mmol) in EtOH (2 mL) was added formalin (37%, 2 mL), sodium cyanoborohydride (50 mg, 0.72 mmol) and acetic acid (0.05 mL), and the mixture was stirred at 25° C. for 24 h. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with EtOAc, which was dried (MgSO4) and concentrated. (44 mg, 100%). The residue was converted to the salt by treatment with hydrogen chloride in Et2O/THF to afford the title compound: mp 160-163° C.; 1H NMR (D2O) δ 1.86-1.96 (m, 2H), 2.06 (m, 1H), 2.24 (m, 1H), 2.88 (s, 3H), 3.09 (m, 1H), 3.61 (m, 1H), 3.72 (m, 1H), 4.12 (dd, 1H, J=3.5, 7.0 Hz), 4.27 (dd, 1H, J=1.5, 7.0 Hz), 7.05 (dd, 1H, J=2.0, 3.0 Hz), 7.34 (d, 1H, J=2.0 Hz), 7.41 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=3.0 Hz), 7.83 (d, 1H, J=1.5 Hz); MS (CI/NH3) m/z 309 (M+H)+. Anal. Calcd for C15H17ClN2OS.HCl.0.3 H2O: C, 51.37; H, 5.35; N, 7.99. Found: C, 51.38; H, 5.47; N, 7.85.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:7])C.[OH-].[Li+]>C(O)C.O>[F:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([F:17])[CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[CH:5]([CH3:18])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
To a solution of 4.0 g (14.75 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid ethyl ester in 300 ml of ethanol, 15 ml of water and 1.41 g (59 mmol) of lithium hydroxide were added and the mixture was refluxed for 5 hours. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (four times 30 ml).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])C.S(=O)(=O)(O)O>O>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])(=[O:11])[CH3:10]
Reactant: CCOC(CCCNC(C)=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NCCCC=O

Procedure:
Dissolve 5 gms. of 4-acetamidobutyraldehyde diethyl acetal in 75 ml. of distilled water and 5 ml. of 1 N sulfuric acid. Allow the solution to stand at room temperature until the hydrolysis is complete as determined by thin layer chromatography. Neutralize the solution with sodium bicarbonate, then saturate the solution with sodium chloride and extract with chloroform. Distill the combined chloroform extracts to a residue comprising 4-acetamidobutyraldehyde, which can be used without further purification in the procedure of Example 7A.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[CH2:11][CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[CH2:11][CH2:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCC1=COc2ccccc2O1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NCCC1=COc2ccccc2O1

Procedure:
0.837 g (2.37 mmol) of the phthalimide obtained in Step E and 0.358 g (7.16 mmol) of hydrazine monohydrate are dissolved in 20 ml of tetrahydrofuran; the mixture is then heated at reflux for 5 hours. After filtering off the solid, the filtrate is concentrated in vacuo; the residue is then taken up in dichloromethane and dried over magnesium sulphate. The filtered organic phase is concentrated in vacuo to yield the amine in the form of a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: NC(CC(=O)O)c1cccnc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 41.3 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-pyridin-3-yl-propionic acid (52 mg, 0.31 mmol) (commercially available from Combi-Blocks SS-4195) in DMA (2 mL) was added sodium methoxide (17 mg, 0.31 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 2 h. After cooled, reaction mixture was diluted with water (75 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 30 mg (0.066 mmol) in 42% yield. LC-MS ESI−: 453 (M−1)−.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]([S:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([CH3:8])[C:5]([OH:7])=[O:6].C(O)C>O>[CH3:8][C:4]([S:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([CH3:3])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: CC(C)(SCCc1ccc2c(c1)OCO2)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(SCCc1ccc2c(c1)OCO2)C(=O)[O-]
Yield: 92.4 %

Procedure:
A solution of 0.90 g of sodium hydroxide in 9.0 ml of water was added to 6 g of 2-methyl-2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionic acid to obtain a solution. 100 ml of ethanol was added to the solution and the solvent was distilled off. The residue was washed with ether. After filtration, the product was dried under reduced pressure to obtain 6 g of the intended compound in the form of a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:12]([C@H:7]1[C:8]2[C:4](=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C#N)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To (R)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-52 (0.700 g, 2.7 mmol) was added anhydrous DMF (10 mL) and the reaction mixture was stirred in a 0° C. ice bath under N2. Sodium hydride (0.541 g, 13.5 mmol) was added and the mixture was stirred at 0° C. for 2 h. After 2 h, (2-bromoethoxy)-tert-butyldimethylsilane (1.43 g, 5.9 mmol) was added and the reaction mixture was allowed to warm to room temperature for 1 h. The reaction was cooled to 0° C. and quenched with MeOH followed by saturated NaHCO3. The mixture was extracted with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to produce a brown oil. The crude product was purified by silica gel flash chromatography (20% EA/Hexanes) to afford 0.868 g (77%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate INT-59 as a yellow oil. LCMS-ESI (m/z) calculated for C23H36N2O3Si: 416.6; found 317.1 [M+H−Boc]+, tR=4.05 min. 1H NMR (400 MHz, (CD3)2SO) δ 7.50 (m, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 5.78 (m, 1H), 4.02 (m, 2H), 3.51 (m, 2H), 3.29 (m, 1H), 2.97 (m, 1H), 2.26 (m, 2H), 1.40 (s, 9H), 0.83 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: C(O)(=O)CC(O)=[O:4].[C:8]([OH:16])(=[O:15])[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[OH:10].C(O)(=O)/C=C\C(O)=O.[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28]>>[C:8]([OH:16])(=[O:15])[CH:9]([CH:11]([C:12]([OH:14])=[O:13])[OH:4])[OH:10].[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28]
Reactant: O=C(O)CC(=O)O
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Aged (and brittle) carboxylated cellulose, malonic acid, malic acid and maleic acid each was separately reacted with ZnO to produce adhesive material followed by formation of hard cement in a way similar to that with citric acid. One sample of tartaric acid, however, did not yield a "stringy" adhesive mass like with citric acid but it was found that this sample of tartaric acid was somewhat slow to wet in spite of being very soluble. In general it appears that polycarboxylic acids that are readily (quickly) soluble, considerably soluble and quickly wet show reaction with ZnO as does citric acid.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[CH:8]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23]([CH3:25])=[O:24]>CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:8]=1[C:23]([OH:24])([CH3:25])[C:22]([F:27])([F:26])[F:21]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a THF (100 ml) solution of 1,3-difluoro-5-methoxybenzene (7 g, 48.6 mmol) was added dropwise 1.6 M hexane solution of n-butyllithium (30 ml, 48.6 mmol) at −78° C. over 30 minutes and the mixture was stirred for 2 hours at −78° C. Then 1,1,1-Trifluoroacetone (6.5 g, 58.3 mmol) was added at −78° C. and the mixture was stirred for 2 hours at −78° C. After stirring at room temperature for an additional 1 hour, the reaction was quenched with water. The whole was extracted with EtOAc and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography eluting with hexane/EtOAc (10:1) gave the title compound (9.7 g, 78% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]C)=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O-].[Na+]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11](=[O:13])[NH:1]2)=[N:4][CH:5]=1
Reactant: COC(=O)/C=C/c1ncc(Cl)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccc2ncc(Cl)cc2[nH]1

Procedure:
A suspension of (E)-methyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (1.2 g, 5.64 mmol) and sodium methoxide (0.786 ml, 14.11 mmol) in 20 mL of ethanol was refluxed for 3 h until the starting material disappeared. The reaction mixture was evaporated to dryness to give crude product 7-chloro-1,5-naphthyridin-2(1H)-one. To the crude residue was added phosphorus oxychloride (5.17 ml, 56.4 mmol) and the resulting mixture was stirred at 70° C. for 4 h. The excess POCl3 was removed under reduced pressure and the residue was directly submitted to flash column (DCM) to give 2,7-dichloro-1,5-naphthyridine (540 mg, 2.71 mmol, 48.1% yield) as an off-white solid. 1H NMR (400 MHz, chloroFORM-d) δ ppm=8.90 (d, J=2.2 Hz, 1 H), 8.35 (d, J=8.8 Hz, 1 H), 8.31 (d, J=1.8 Hz, 1 H), 7.63 (d, J=8.8 Hz, 1 H). m/z=199 (M+1).
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([O-:12])(=O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>>[ClH:2].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([Cl:15])(=[O:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(Cl)nc1
Agent: [Na+]
Product: Cl
Product: O=S(=O)(Cl)c1ccc(Cl)nc1
Temperature: 70 °C

Procedure:
A mixture of the product of Step 1 (430 mg, 2 mmol) in thionyl chloride (3 ml) and N,N-dimethylformide (2 drops) was heated at 70° C. for 3 hours. After cooling to room temperature the solvent was evaporated and the residue co-evaporated with toluene (×2) to give the title compound (D32) which was used directly in Step 1 of Example 272. 1H-NMR (CDCl3) δ 7.61 (1H, m), 8.25 (1H, m), 9.03 (1H, m).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:7]([OH:22])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27]C.C[O-].[Na+]>CCOCC>[C:1]([C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:17])=[C:7]([OH:22])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Reactant: CCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCOC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O

Procedure:
5 Parts of methyl 5-(4-t-butyl-2,5-dihydroxyphenyl)-5-methylhexanoate is converted to the corresponding n-hexyl ester after reaction with 20 parts n-hexanol and 0.25 part of sodium methoxide in a sealed glass tube for 7 days. The reaction mixture is diluted with ether, washed with dilute hydrochloric acid, then water, and stripped of ether and excess hexanol under reduced pressure to give a residue. Short-path distillation of the residue at 0.4 mb yields n-hexyl 5-(4-t-butyl-2,5-dihydroxyphenyl)-5-methyl-hexanoate [formula (125)] as an amber oil with the following percentage composition by weight:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]CCCC>C1COCC1>[CH3:15][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CCCCC
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33 g, 6.5 mmol) in THF (80 ml) was added pentane washed sodium hydride(1.2 g, 60% in oil dispersion) followed by methyl iodide (2 ml, excess). The reaction mixture was stirred overnight and then poured into an iced solution of citric acid (0.5N). The aqueous THF solution was extracted into ethyl acetate. Then the required acid was back extracted between ethyl acetate, sodium hydrogen carbonate and potassium hydrogen sulphate solutions. The organic extracts were dried (MgSO4) and evaporated to afford the title compound. (1.00 g, 71%), Anal: C10H19NO4.0.3H2O, Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:20]1[C:21](=[O:38])[O:22]/[C:23](=[CH:27]\[C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)/[C:24]=1[O:25][CH3:26].O1CCOCC1.C1COCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[C:21](=[O:38])[O:22]/[C:23](=[CH:27]\[C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)/[C:24]=2[O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: COC1=C(Br)C(=O)O/C1=C\c1cccc2ccccc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(c2ccc(Cl)cc2)C(=O)O/C1=C\c1cccc2ccccc12
Temperature: 90 °C
Yield: 69 %

Procedure:
A stirred mixture of 4-chlorophenylboronic acid (259 mg, 166 mmol), K3PO4 (962 mg, 4.53 mmol) and Pd(PPh3)4 (52 mg, 45.3 μmol) under N2 is treated sequentially with of 3-bromo-4-methoxy-5[(Z)-1-naphthylmethylidene]furan-2(5H)-one (500 mg, 1.51 mmol) and 9.3 mL of a 2:1 v/v mixture of dioxane/THF, heated at 90° C. until the disappearance of starting material by thin layer chromatography, cooled to room temperature, diluted with water and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 380 mg (69% yield), identified by NMR and mass spectral analyses.