Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[N:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[N:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1cnc(Br)cn1Cc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cn(Cc3ccc(Cl)cc3)c(=O)cn2)cc1
Yield: 70.1 %

Procedure:
According to Scheme 27 Step 2: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyrazin-2(1H)-one (1 eq, 0.67 mmol, 0.20 g) and 4-methoxyphenylboronic acid (1.5 eq, 1.00 mmol, 0.15 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 1 hour at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/MeOH (98/2) as the eluent to afford 1-(4-chlorobenzyl)-5-(4-methoxyphenyl)pyrazin-2(1H)-one (0.47 mmol, 0.15 g, 71%) as a beige solid.
Reaction SMILES: C1N2CCN(CC2)C1.[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]=[O:13].CN(C=O)C.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]([OH:13])[C:25](=[CH2:26])[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C(=O)OC(C)(C)C)C(O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 114.4 %

Procedure:
Alternate Preparation. This procedure uses DABCO as a more economical substitute for (4s)-quinuclidin-3-ol. A 1 L flask was charged with 2-bromo-5-fluorobenzaldehyde (13.4 g, 66.0 mmol), DABCO (14.81 g, 132 mmol), DMF (53.6 mL) and water (13.4 mL). To this reaction mixture was added tert-butyl acrylate (12.68 g, 99.0 mmol). The mixture was then stirred at rt for 12 h. At this time TLC indicated consumption of starting material. The reaction mixture was diluted with 25 mL of water and then extracted with two 100 mL portions of MTBE. The combined organic phases were washed with 0.1N HCl, water and brine. It was then dried over MgSO4, filtered and concentrated to yield 25 g (>100%) of the product as a colorless oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[C:17](=[S:19])=S.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[OH:16][C:13]1[C:3]2[C:2](=[C:7]([CH3:8])[C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=2)[O:1][C:17](=[S:19])[C:14]=1[CH3:15]
Reactant: S=C=S
Reactant: CCC(=O)c1ccc(OCOC)c(C)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc2c(O)c(C)c(=S)oc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
According to the method described in Eur. J. Med. Chem. 36 (2001) 697, a solution of 1-[2-hydroxy-4-(methoxymethoxy)-3-methylphenyl]propan-1-one (3.99 g, 17.8 mmol) obtained in Example 2-1 and carbon disulfide (1.07 mL, 17.8 mmol) in tetrahydrofuran (30 mL) was added to a solution of potassium t-butoxide (5.99 g, 53.4 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred overnight at room temperature. Water (50 mL) was added to the reaction solution, and then the pH of the mixture was adjusted to 5 with 2 M hydrochloric acid, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 5 again with 2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 3.80 g of the title compound (yield: 80%).
Reaction SMILES: [CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([F:27])[CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:27])[CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)c(F)c1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reaction time: 40 h

Procedure:
A solution of methyl 4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]-2-fluorobenzoate (Intermediate 25, 85 mg; 0.20 mmol) in THF (5 ml) and MeOH (5 ml) was treated with an aqueous solution (5 M) of sodium hydroxide (198 μl; 0.99 mmol). After stirring for 40 hours, HCl 1 N was added until pH 3, then the solution was concentrated under vacuum, AcOEt was added and the organic layer was washed with brine, dried (MgSO4) and removed under vacuum to afford an oily residue which was purified by preparative HPLC to give the title compound as an amorphous white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=O.[NH2:21][C@H:22]1[CH2:27][C:26]2[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23]1>CN(C)C=O>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:28]2[C:26]3[CH2:27][C@H:22]([NH:21][C:18]([C:14]4[NH:13][CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:23][O:24][C:25]=3[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc[nH]2)CO3)CC1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1,1′-carbonyldiimidazole (360 mg, 1.85 mmol) and pyrrole-2-carboxylic acid (225 mg, 2.03 mmol) in anhydrous N,N-dimethylformamide (8 mL) was stirred at 75° C. for 45 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (457 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred for 7 days at room temperature under nitrogen. The solvent was removed in vacuo, and the residue was extracted with diethyl ether (50 mL) and water (20 mL). The aqueous layer was extracted with another portion of diethyl ether (50 mL). The combined ethereal layers were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 90:10+0.5% conc. NH3) yielding the title compound as an oil. Evaporation with diethyl ether afforded 300 mg (48% yield) of the title compound as a white powder: mp sinters>96° C.; [α]21D−82.8° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 340 (10, M+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH2:25][CH2:24][OH:23])[CH:28]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1OCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OC)c(OCCO)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brown solid. MS 498 (MH+).
Reaction SMILES: [Br-].[C:2]1(=[O:34])[N:6]([CH2:7][CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5](=[O:29])[C:4]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:3]12.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[Cl:35][C:36]1[CH:37]=[C:38](/[CH:39]=[CH:9]\[CH2:8][CH2:7][N:6]2[C:2](=[O:34])[C:3]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:4]3[C:5]2=[O:29])[CH:41]=[CH:42][CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
A mixture of 3-phthalimidopropyltriphenylphosphonium bromide (15.1 g) and 3-chlorobenzaldehyde (4.0 g, Aldrich, U.S.A.) in tetrahydrofuran (150 mL) was cooled to −78° C. in a dry ice/acetone bath. Potassium tert-butoxide (3.2 g) was added and the mixture was stirred for 20 min, then allowed to warm to 0° C. After four hours, the solution was poured into 200 mL water and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, and reduced in vacuo. The residue was dissolved in 200 mL of a 1:1 mixture of ethyl acetate/hexanes, and filtered through a short silica gel plug to remove the triphenylphosphine oxide byproduct. Evaporation of the filtrate yielded 5.7 g of cis-N-[4-(3-chlorophenyl)-but-3-enyl]-phthalimide in a 10:1 ratio of cis:trans isomers.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[CH:38]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) was dissolved in CH2Cl2 (2.5 mL) and 2 M HCl in ether (2.5 mL) was added. This mixture was stirred for 2 h at room temperature and a yellow precipitate formed. The solvents were removed under reduced pressure and the resulting solid was suspended in ether and collected by filtration then dried overnight in vacuo at 50° C. to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (30 mg, 52%). MS (APCI); M++1: Calc'd, 480.3. Found 480.4. Anal. Calc'd for C25H33N7O3 2HCl 3.44 H2O: C, 48.87; H, 6.87; N, 15.96. Found; C, 48.48; H, 6.66; N, 15.66.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:30]=[CH:31][C:32]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=4)[CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:45]>CO.O1CCOCC1>[ClH:45].[CH2:38]([N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:8]3[CH:9]=[C:10]([C:11]4[N:12]=[C:13]([CH:16]5[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[S:14][CH:15]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:30]=[CH:31]2)=[N:35]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-{4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (586 mg, 0.97 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at rt for 16 h. The mixture was concentrated to afford 577 mg (100%) of, the desired product, which was used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH:26]([Mg]Br)([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH:26]([CH3:28])[CH3:27])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Reactant: CC(C)[Mg]Br
Product: CC(C)C(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and isopropylmagnesium bromide.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].S(=O)(=O)(O)[OH:12].[K].S(=O)(O)[O-].[Na+]>CCOCC.O>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:12])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCC(C)CO
Agent: O=S([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To 21.2 g (147 mmol) of (-)-2-methyloctanol were added an aqueous solution of 330 ml of water and 46.4 g of concentrated sulfuric acid, which was stirred to form an emulsion. To this emulsion was added dropwise 63.4 g (401 mmol) of potassium permaganate over 7 hours. Then, the reaction mixture was added with 51.5 g of sodium bisulfite and poured into 270 ml of ice water together with 70 ml of ice water and 200 ml of ether. After the separation into two layers, the reaction product was extracted from the aqueous layer with ether, which was further extracted with a 10% aqueous solution of sodium hydroxide, added with ice and further with a concentrated hydrochloric acid to adjust the pH to not more than 1. Thereafter, the extraction with chloroform on the aqueous layer was performed, which was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and distilled under a reduced pressure to obtain 16.5 g (yield: 71%) of a colorless and transparent liquid of (+)-2-methyl octanoic acid.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: CCC#CCCOc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 73.7 %

Procedure:
Piperidine (0.21 mL, 2.2 mmol) was added to a suspension of 4-methoxy-3-(hex-3-ynyloxy)benzaldehyde (0.50 g, 2.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.44 g, 2.0 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(3-(hex-3-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 75%) as a yellow crystalline solid; mp 163-165° C.; δH (400 MHz, DMSO-d6) 1.05 (t, J=7.6 Hz, 3H, CH3), 2.15 (q, J=7.6 Hz, 2H, CH3CH2), 2.62 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.80 (s, 3H, OCH3), 4.09 (t, J=7.6 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.8, 14.0, 19.3, 55.6, 67.0, 76.2, 83.0, 111.9, 112.0, 116.6, 120.0, 120.3, 122.6, 123.0, 127.3, 131.1, 134.0, 141.0, 141.6, 147.9, 150.8, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1648; vmax 755, 1253, 1510, 1604, 1657, 3238, 3524 cm−1.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[OH:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:25]([C:19]1[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[C:3]([OH:36])=[O:2])=[O:16])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=1)=[O:35]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[5-(3-Hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]propionic acid methyl ester (40 mg, 0.076 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (3 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 29.4 mg (75%). MS m/e 516.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (271 mg, 70%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1([C:25]([OH:27])=O)[CH2:24][CH2:23]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:28][NH2:29].O>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][C:22]1([C:25]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
CDI (12.5 g, 0.077 mol) was added to a 0° C. solution of 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (15.0 g, 0.07 mol) in THF (250 mL). The mixture was allowed to warm to rt, and stirred at rt. for 2 hrs, and then NH2NH2.H2O (10.5 g, 0.21 mol) was added rapidly. The mixture was stirred for another 1 hr. The reaction mixture was concentrated, and then CH2Cl2 (500 mL) was added. The combined organic layer was washed with H2O (100 mL), dried over Na2SO4, and concentrated to afford tert-butyl(1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (13.5 g, 84%). ESI-MS (EI+, m/z): 230.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[CH3:1][N:2]([CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CCO
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 10 h

Procedure:
To 3 l of ethanol was added 750 ml of a 40% aqueous solution of dimethylamine and 500 g. of p-nitrobenzyl chloride was added gradually thereto with stirring. After complete dissolution, the reaction was carried out at 40° C. for 10 hours. After the reaction mixture was concentrated by distilling off the ethanol, the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated by distilling off the ethyl acetate. The residue thus obtained was distilled under reduced pressure to give a yellow liquid which was the desired product boiling at 102° to 104° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(C(C)C#N)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile. LCMS (M+H)+=443.0/445.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (s, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 7.42 (s, 1H), 7.00 (s, 1H), 5.91 (q, J=7.1 Hz, 1H), 3.96 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][C:2]=1[CH2:8][OH:9].[O:10]=O>>[CH:8]([C:2]1[O:3][C:4]([C:6]([OH:10])=[O:7])=[CH:5][CH:1]=1)=[O:9]
Reactant: O=O
Reactant: O=Cc1ccc(CO)o1
Product: O=Cc1ccc(C(=O)O)o1

Procedure:
5-HMF feed is oxidized with elemental O2 in a multi-step reaction to form FDCA with 5-formyl furan-2-carboxylic acid (FFCA) as a key intermediate eq 1. Oxidation of 5-(acetoxymethyl)furfural (5-AMF), which contains an oxidizable ester and aldehydes moieties, produces FDCA, FFCA, and acetic acid, eq 2. Similarly oxidation of 5-(ethoxymethyl)furfural (5-EMF) produces FDCA, FFCA, 5-(ethoxycarbonyl)furan-2-carboxylic acid (EFCA) and acetic acid, eq 3.
Reaction SMILES: CC[O-].[Na+].S(O)(O)(=O)=O.[CH3:10][N:11]([CH3:15])[C:12]([NH2:14])=[NH:13].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[C:25](=[C:28](OC)[C:29]([F:32])([F:31])[F:30])[C:26]#[N:27]>CCO>[NH2:27][C:26]1[C:25]([C:18]2[CH:19]=[C:20]([Cl:24])[CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[C:28]([C:29]([F:32])([F:31])[F:30])[N:14]=[C:12]([N:11]([CH3:15])[CH3:10])[N:13]=1
Reactant: COC(=C(C#N)c1cc(Cl)cc(Cl)c1Cl)C(F)(F)F
Reactant: CN(C)C(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of NaOEt (from 0.144 g of Na) in EtOH (12.5 ml) was added 1,1-dimethylguanidine sulphate (1.4 g), (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2-(2,3,5-trichlorophenyl)-4,4,4-trifluoro-3-methoxybut-2-enonitrile (see Example 1.6) (0.85 g) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered, and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHCl3, gave the desired product, 0.61 g, mp. 124°-126° C.