Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[OH-:2].[K+:3].[C:4](=[O:6])=[O:5]>>[Na:1].[C:4](=[O:2])([O-:6])[O-:5].[K+:3].[K+:3].[C:4](=[O:2])([OH:6])[O-:5]
Reactant: [OH-]
Reactant: O=C=O
Agent: [K+]
Agent: [Na]
Product: O=C([O-])O
Product: O=C([O-])[O-]

Procedure:
For example the method might involve nebulizing an aqueous solution of sodium or potassium hydroxide to generate an aerosol of droplets of size less than about 10 μm, contacting the aerosol with carbon dioxide gas, and drying the droplets in the aerosol, so as to form an aerosol of dry particles of sodium or potassium carbonate and/or bicarbonate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1>>[CH:11]1([CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]2=[NH:8])[CH2:13][CH2:12]1
Reactant: Cc1nc(N)sc1C
Reactant: BrCC1CC1
Product: Cc1sc(=N)n(CC2CC2)c1C
Temperature: 85 °C

Procedure:
A mixture of 4,5-dimethylthiazol-2-amine (0.30 g, 2.3 mmol, Aldrich) and (bromomethyl)cyclopropane (0.63 g, 4.7 mmol, Aldrich) was heated at 85° C. for 16 h. The reaction mixture was cooled to room temperature and triturated with ether to obtain the crude intermediate, hydrobromide salt of (cyclopropylmethyl)-4,5-dimethylthiazol-2(3H)-imine. To a solution of the above intermediate in tetrahydrofuran (10 mL) were added Example 24B (0.71, 2.3 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.54, 2.8 mmol, Aldrich), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol, Aldrich) and triethylamine (1.0 mL, 7.0 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 2 h, cooled and then quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 5-100% of triethylamine/MeOH/EtOAc (0.1/1/10) in hexanes) to afford 160 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.32-0.69 (m, 4H), 1.14-1.40 (m, 1H), 1.48-1.75 (m, 3H), 1.78-2.00 (m, 1H), 2.07-2.22 (m, 1H), 2.23 (s, 3H), 2.29 (s, 3H), 2.32 (s, 3H), 2.53-2.64 (m, 1H), 2.86-2.97 (m, 1H), 3.92-4.07 (m, 2H), 4.11 (d, J=7.1 Hz, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.72 (dd, J=8.7, 2.4 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])O.[Na+]>O>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: Nc1ccccc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of 30 g (0.277 mol) of o-phenylenediamine and 150 g of polyphosphoric acid ester (ppE) is heated to 120°. When the diamine has dissolved, 33 g (0.205 mol) of p-cyanophenylacetic acid are added thereto in one portion and the mixture is heated to 120° for a further 20 minuIes. After cooling to room temperature the viscous mass is treated with about 1 l of water and made weakly basic with solid sodium hydrogen carbonate. The mixture is extracted with methylene chloride and the extract is washed with water, dried over sodium sulphate and evaporated to dryness. Recrystallization of the residue from methylene chloride/ethyl acetate gives 29 g (60%) of 2-(p-cyanobenzyl)benzimidazole, m.p. 201°-203°, as a colourless crystalline powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[F:27])[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[C:28]([C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][C:25]=2[F:27])#[N:29]
Reactant: N#Cc1cc2cccc(F)c2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(F)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.18 g, 12 mmol) in THF (50 mL) was added NaH (0.464 g, 12 mmol) at 0° C. The mixture was stirred at RT for 30 minutes. Next, 1-chloro-8-fluoroisoquinoline-3-carbonitrile (1.6 g, 8 mmol) was added and the reaction mixture was warmed to RT and stirred for 4 hours. The reaction was subsequently quenched with H2O (20 mL) and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (1 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 2H), 7.61-7.59 (d, J=8 Hz, 1H), 7.38-7.32 (t, J=12 Hz, 1H), 5.8 (s, 1H), 3.75-3.59 (m, 4H), 2.29-2.28 (d, J=4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Cl.[OH:19][NH2:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:20][OH:19])=[O:10])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CCOC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(NO)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Ethyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (10 g, 0.0373 mol) and hydroxyl amine hydrochloride (13 g, 0.1868 mol) were refluxed in acetic acid for 12 hours and the organic layer was evaporated under vacuum to get oil. This oil was mixed with water (100 ml) and the obtained precipitate was stirred at room temperature for 1-2 hours. The obtained solid was filtered and washed thoroughly with water. The wet cake was vacuum dried at 50° C. to afford 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (6.8 g) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([Br:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 2-amino-isonicotinonitrile (10.0 g, 83.9 mmol) in DMF (20 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (16.5 g, 92.3 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (200 mL). The aqueous phase was separated and extracted with AcOEt (2×500 ml). The combined organic fractions were dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 98:2→6:4) to yield the title compound (13.0 g, 65.6 mmol, 78%) as a pale yellow solid. MS: 199 [M+1]+; HPLC: AtRet=1.13; TLC: RF 0.39 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].ClCC1ON=C([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)C=1.[OH2:36]>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:12][C:11]2[O:36][N:7]=[C:6]([O:5][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH:10]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1cc(Cc2ccc3ccccc3n2)no1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3ccc4ccccc4n3)no2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (371 mg) and 2-(5-chloromethyl-3-isoxazolylmethyl)quinoline (481 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain-ethyl 3-[3-ethoxy-1-[3-(2-quinolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (722 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([N:14]([CH2:17][CH3:18])CC)C>C(O)C>[CH3:10][C:9]1[NH:14][C:17]([CH2:18][CH2:4][CH2:3][CH2:9][CH3:10])=[N:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CCCCCc1nc(C(=O)OCC)c(C)[nH]1
Reaction time: 72 h

Procedure:
Ethyl 2-amino-3-ketobutanoate hydrochloride (3.0 g) was added portionwise to a solution of Intermediate 157 (30 g) and triethylamine (26 ml) in ethanol (500 ml) under nitrogen. The resulting solution was left to stand at 22° for 72 h. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate (200 ml) and washed with water (200 ml). The aqueous layer was further extracted with ethyl acetate (200 ml). The combined organic extracts were dried, concentrated in vacuo and the residue purified by chromatography eluting with System A (8:2) to obtain the title Compound (3.05 g) as a pale yellow solid, m.p. 89°-90° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[N:23]([CH2:24][C:25]([O:27]CC)=[O:26])[N:22]=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: CCOC(=O)Cn1nccc1-c1ncccc1COc1cnc(OC)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.46 mmol, 1 eq.) in a mixture of MeOH/THF (1/5, 12.0 mL) was added NaOH (2N, 2.3 mL, 4.6 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (135.1 mg, 80%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.71 (d, J=4.7 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.97 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.52 (dd, J=7.9, 4.9 Hz, 1H), 7.13 (s, 1H), 6.56 (d, J=1.7 Hz, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 3.91 (s, 3H). LRMS (M+H+) m/z 369.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].Cl.Cl[C:13]([NH2:15])=[NH:14]>COCCOCCOC>[NH2:15][C:13]1[N:14]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:10])[N:1]=1
Reactant: Cc1cccc(N)c1C#N
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1cccc2nc(N)nc(N)c12
Yield: 86.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 10.0 grams (0.076 mole) of 2-amino-6-methylbenzonitrile (prepared as in Example 1, Step B), and 10.0 grams (0.087 mole) of chloroformamidine hydrochloride in 40 mL of 2-methoxyethyl ether, yielding 11.5 grams of 2,4-diamino-5-methylquinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][Si:19]([CH3:30])([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH:12]1[OH:31])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC=CC=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:29][Si:26]([CH3:27])([CH3:28])[O:25][Si:19]([CH2:18][CH2:17][CH:14]1[CH2:13][CH:12]([O:31][C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH:11]([O:10][C:8](=[O:9])[CH2:7][NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:16][CH2:15]1)([CH3:30])[O:20][Si:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)O1
Reactant: C=C(C)C(=O)NCC(=O)OC1CCC(CC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCC(=O)OC1CCC(CC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1OC(=O)CCC(=O)O
Temperature: 62.5 °C

Procedure:
15 g of 4-(2-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)ethyl)-2-hydroxycyclohexyl 2-methacrylamidoacetate and 4.6 g of toluene and succinic anhydride are further charged into a round bottom flask equipped with a stirring bar, a reflux condenser, and nitrogen inlet. To this, triethylamine and hydroquinone are added as a catalyst and radical scavenger, respectively, and the reaction mixture is heated to 60-65° C. After completion, the product was vacuum striped, re-dissolved in chloroform, and washed with brine solution. The organic phase was passed over Tulsion T66-MP resin to remove traces of triethylamine and decolorized using activated charcoal. The organic layer was concentrated after removal of the charcoal to yield a pale yellow, viscous product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.S1(=O)(=O)[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[CH2:11]O1>>[I:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: O=S1(=O)OC[C@@H]2CCCCN21
Reactant: Ic1cccc(I)c1
Product: Ic1cccc(C[C@@H]2CCCCN2)c1

Procedure:
(S)-2-(3-Iodo-benzyl)-piperidine was prepared from 1,3-diiodobenzene and (S)-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1,1-dioxide in analogy to the procedure described for Example 4 in U.S. Pat. No. 5,130,432. LC-MS B: tR=0.54 min; [M+H]+=302.07.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42]CC2C=CC=CC=2)[C:35]=1[C:36]#[N:37]>>[C:36]([C:35]1[C:38]([OH:42])=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=1)#[N:37]
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: N#Cc1c(OCCCCN)cccc1OCc1ccccc1
Product: N#Cc1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 2-(4-aminobutoxy)-6-benzyloxybenzonitrile analogous to Example 100 steps C and D: (M−1)−=487. HPLC retention time: 0.82 min. (Method A).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:20]=1[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1.COC(C)(C)C>[CH3:16][C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=[C:2]([O:1][CH2:21][C:20]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:19]=3[F:18])[N:7]2[N:8]=1
Reactant: OCc1c(F)ccc(F)c1F
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
1.2 g (5.25 mmol) of ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 8A were dissolved in 48 ml of THF. 1.7 g (10.50 mmol) of 2,3,6-trifluorobenzyl alcohol and 2.9 g (11.03 mmol) of triphenylphosphine were added. Subsequently, 2.2 ml (11.03 mmol) of diisopropyl (E)-diazene-1,2-dicarboxylate were added to the solution, which was stirred at RT for 1 h. 120 ml of tert-butyl methyl ether were added, then the mixture was stirred briefly, and the solids formed were filtered off and dried under high vacuum. 1.2 g of the target compound were obtained (62% of theory).
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=O.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([NH:39]N)[CH2:35][CH2:34]1)=O)C1C=CC=CC=1>>[Br:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:16]=[C:7]([C:5]4[N:39]([CH:36]5[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]5)[N:2]=[CH:3][N:4]=4)[S:8][C:9]=3[CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN(C)/C=N\C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3C3CCNCC3)nc1-2

Procedure:
8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide was reacted with 4-Hydrazino-piperidine-1-carboxylic acid benzyl ester to give 8-bromo-2-(2-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS(ESI+) 432.0/434.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: O=C(CCC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Aluminum chloride (4.979 g, 37.34 mmol) was added in small portions to a solution of 3-cyclopentylpropionyl chloride (3 g, 18.67 mmol) in 1,2-dichloroethane (100 mL) cooled to 0° C. After 15 min., chlorobenzene (6.304 g, 56.01 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 48 h. It was then poured into a mixture of ice and water. The product was extracted with ethyl acetate. The organic layers were washed with saturated solution of sodium bicarbonate (1×30 mL), brine (1×20 mL) and dried over anhydrous magnesium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with hexanes yielded 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one (1.12 g, 25%) as yellow oil.
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1>O.O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:2])[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1

Procedure:
A solution of selenium dioxide (4.82 g, 43.4 mmol) in H2O (20 mL) was added to a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)-2-ethanone (9.33 g, 43.4 mmol) in dioxane (100 mL) and the resulting mixture was heated at reflux for 2 h. This mixture was concentrated in vacuo, triturated with ethyl acetate and filtered. The residue was purified by column chromatography using ethyl acetate/hexane (1:1) as an eluent to give 1-(4-fluorophenyl)-2-(4-pyridyl)-1,2-ethandione. A mixture of ammonium acetate (25.25 g, 0.328 mol) and hexamethylenetetraamine (9.18 g, 65.5 mmol) was added to a solution of the isolated dione dissolved in acetic acid (150 mL). This mixture was stirred at 80° C. for 2 h, poured into concentrated ammonium hydroxide (200 mL) and the resulting precipitate was filtered, washed with H2O and dried to give the title compound as a solid: mp 242-44.3° C.; MS 240 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:4]([CH:5]=C(C)C)[C@H:3]1[C:9]([O:11][CH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=1[F:23])=[O:10].CO.O=O.[O:29]=[O+][O-]>CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH:5]([C@@H:4]1[C@@H:3]([C:9]([O:11][CH2:12][C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=2[F:23])=[O:10])[C:2]1([CH3:24])[CH3:1])=[O:29]
Reactant: O=[O+][O-]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Reaction time: 24 h
Yield: 82 %

Procedure:
Into a mixture solution of 1.27 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate, 20 ml of methanol and 20 ml of ethyl acetate, oxygen containing ozone was blown at −78° C. until the color of the solution was changed to blue. Then nitrogen gas was blown into the solution for removing excess ozone, 5 ml of dimethylsulfide was added to the solution and the solution was brought to room temperature. After one day, the reaction solution was concentrated under reduced pressure. To the residue, 20 ml of acetone, 2 ml of water and 0.2 g of p-toluenesulfonic acid monohydrate were added and allowed to stand at room temperature for 2 hours. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to give 0.98 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-3-formyl-2,2-dimethylcyclopropanecarboxylate (yield 82%). m.p. 43.2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:48]3[N:49]=[CH:50][N:51]([CH3:53])[CH:52]=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:48]3[N:49]=[CH:50][N:51]([CH3:53])[CH:52]=3)[S:17][C:10]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1

Procedure:
Following the procedure described for compound 5a (example 1, step 5) but substituting amine 9 for compound 12, title compound 5c was obtained as a white solid (78% yield). MS (m/z): 502.0 (M+H).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][SH:7].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([CH2:25][S:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH3:4])=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Reactant: CC(C)(C)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)CSCc1ccc(CNC(=O)OC(C)(C)C)cn1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, add sodium methoxide (630 mg, 3.51 mmol, 30% w/w in methanol) to a stirring mixture of 2,2-dimethyl-propane-1-thiol (365 mg, 3.51 mmol) and methanol (10 mL) at room temperature and stir for 30 min. Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (450 mg, 1.76 mmol) in methanol (5 mL) and stir the mixture for 2 h. Dilute the mixture with water and ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo to obtain the desired intermediate suitable for use without additional purification. MS (APCI+) m/z: 325 (M+H)+.