Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH:9]=[CH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([NH:17][CH2:18][C:19]2[O:23][C:22]([C:24]([O:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=4)[CH:28]=3)=[O:25])=[CH:21][CH:20]=2)=[O:16])=[CH:13][CH:12]=1)=[O:8])(C)(C)C>C(O)(=O)C>[ClH:1].[C:7]([CH:9]=[CH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([NH:17][CH2:18][C:19]2[O:23][C:22]([C:24]([O:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=4)[CH:28]=3)=[O:25])=[CH:21][CH:20]=2)=[O:16])=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)NCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)c4ccc(C=CC(=O)O)cc4)o3)ccc2c1
Yield: 77.6 %

Procedure:
In 80 ml of acetic acid was dissolved 4 g of 6-amidino-2-naphthyl 5-[4-(2-t-butoxycarbonylvinyl)benzoylaminomethyl]furan-2-carboxylate hydrochloride. Then, hydrogen chloride gas was bubbled into the resulting solution for 1 hour while stirring and cooling with water. The precipitate was collected by filtration and washed with 120 ml of acetone to obtain 2.8 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O>ClCCl>[NH2:22][C:18]1([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:30][CH3:31])[CH:4]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(Oc2ccc(NC(=O)C3(NC(=O)OC(C)(C)C)CCC3)cn2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)C3(N)CCC3)cn2)ccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 1,1-dimethylethyl (1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}cyclobutyl)carbamate (Intermediate 101, 80 mg) in dry dichloromethane (2 mL) cooled to 0° C. TFA (0.865 mL, 11.23 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours, it was then allowed to reach room temperature. Dichloromethane and the excess of TFA were evaporated. The residue was diluted with dichloromethane (5 mL) and neutralized with a saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered and evaporated to afford the tilte as a white solid (60 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[S:25]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:24](=[S:25])[C:23]4[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: FC(F)(F)c1cccc(C(=S)Cl)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NC(=S)c4cccc(C(F)(F)F)c4)c3)c2[nH]1
Yield: 17 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-trifluoromethylthio-benzoyl chloride to afford the title compound (16 mg, 17.0%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93 (ddd, 1H, Harom, J=0.6 Hz, J=2.4 Hz, J=8.2 Hz), 7.44 (t, 1H, Harom, J=8.2 Hz), 7.62 (t, 1H, Harom, J=2.1 Hz), 7.66 (dd, 1H, Harom, J=1.1 Hz, J=8.2 Hz), 7.71 (t, 1H, Harom, J=7.8 Hz), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.94 (d, 1H, Harom, J=7.8 Hz), 8.16 (m, 1H, Harom), 8.26 (s, 1H, Harom), 10.50 (s, 1H, NHamide), 11.19 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.87 minutes, m/z: 447.07 (M+H)+, calculated for C20H14N4O3SF3. HRMS (EI): m/z [M+H] calculated for C20H14N4O3SF3: 447.0739; found: 447.0743.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>O>[C:17]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]c1=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c[nH]c(=O)c(C)n2)cc1

Procedure:
5-(4-Aminophenyl)-3-methyl-2(1H)-pyrazinone hydrobromide (1.0 g) in water (25 ml) was treated with acetic anhydride and sodium acetate in a similar manner to that described in Example 3. On recrystallisation from aqueous acetic acid the title compound (0.68 g) had m.p. >300° C.; δ(DMSO-d6) inter alia 2.08 (3H, s, CO--CH3), 2.39 (3H, d, 3---CH3), 10.0 (1H, s, NHCO); ν(Nujol mull) 1655 (C=O) cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([NH:20][S:39]([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (30 g, 82.8 mmol) in DCM (250 mL) was added pyridine (19.6 g, 248 mmol). The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (17.6 g, 82.8 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (300 mL), and extracted with DCM (2×400 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc:DCM 20:1:5) to afford the title compound (20.4 g, 45.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=5.3 Hz, 1H), 7.60-7.66 (m, 1H), 7.51-7.60 (m, 1H), 7.30-7.36 (m, 1H), 7.17-7.30 (m, 3H), 7.07-7.17 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 1.45 (s, 9H). MS (ES+): 539 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[CH:3][C:4]=1[O:11][CH3:12]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(O)CC2)ccc1N
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (3.0 g, 17.5 mmol), 4-hydroxypiperidine (1.77 g, 17.5 mmol) and potassium carbonate (2.9 g, 21 mmol) in DMSO was stirred for 24 h. The reaction was diluted with water and extracted three times with Ethyl acetate. The combined organic solutions were dried over MgSO4 and concentrated. The resulting residue was stirred in ethanol and acetic acid with 10% Pd/C under 30 psi of hydrogen for 16 hr. The reaction was filtered through a pad of celite, rinsed with Ethyl acetate. The filtrate was concentrated and dissolved in methylene chloride. The organic solution was washed with saturated sodium bicarbonate, dried over MgSO4, and concentrated to give 1-[4-amino-3-(methyloxy)phenyl]-4-piperidinol (2.44 g, 63% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 6.49-6.45 (m, 2H), 6.27 (dd, J=8.4 and 2.4 Hz, 1H), 4.60 (d, J=4.0 Hz, 1 H), 4.18 (s, 2H), 3.71 (s, 3H), 3.54-3.48 (m, 1H), 3.25-3.22 (m, 2H), 2.63-2.56 (M, 2H), 1.80-1.76 (m, 2H), 1.51-1.42 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ncc(Br)cn2)CC1

Procedure:
Following the procedure described for Intermediate 234 using 5-bromo-2-chloropyrimidine and N-methylpiperazine provided the title compound. ESMS [M+H]+: 257.0/259.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:3]=12.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]([CH3:12])[N:9]=1
Reactant: Cc1nn(C)c2ncnc(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(CBr)c2c(Cl)ncnc21

Procedure:
To a solution of 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (752 mg, 4.12 mmol, Example 4) in carbon tetrachloride (45 mL) were added N-bromosuccinimide (964.4 mg, 5.36 mmol, Aldrich) and AlBN (209.6 mg, 1.25 mmol, Aldrich). The mixture was heated at reflux for 7 hours. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 95/5 to 70/30) to give 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 941.3 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: Cc1ccc(C(F)(F)F)cc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(C(F)(F)F)cc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 45.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methyl-5-trifluoromethylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.19 mmol) obtained in step 2 and cyclopropanesulfonamide (115 mg, 0.95 mmol), the title compound (54 mg, 45%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2cc(/C=C/C(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A mixture of ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoate (300 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (3 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoic acid (270 mg, yield 95%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 194-195° C.
Reaction SMILES: Cl[CH2:2][C@@:3]([OH:18])([CH3:17])[CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(N(CC)CC)C.[CH3:26][OH:27]>>[CH3:26][O:27][C:7](=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([N:6]1[CH2:2][C@@:3]([OH:18])([CH3:17])[CH2:4][O:5]1)=[O:15]
Reactant: CO
Reactant: C[C@](O)(CCl)CON1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C(=O)N1C[C@](C)(O)CO1

Procedure:
A solution of 2-[[(2R)-3-Chloro-2-hydroxy-2-methylpropyl]oxy]-1H-isoindole-1,3 (2H)-dione (3.3 g, 12.2 mmol) in methanol (25 ml) was treated with triethylamine (3.4 ml) and heated under nitrogen at reflux for 1 h. The mixture was concentrated to dryness and purified by chromatography eluting with a gradient from dichloromethane to 5% methanol in dichloromethane. The chiral purity of the product was enhanced by recrystallising twice from acetonitrile to give the sub-title compound as a colourless solid (1.92 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O:9]=[C:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][C:25]2[C:29]3=[N:30][CH:31]=[CH:32][CH:33]=[C:28]3[O:27][C:26]=2[C:34](OC)=[O:35])=[O:23])[CH2:18][CH2:17]1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34]([C:26]2[O:27][C:28]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[C:25]=2[NH:24][C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][C:10]3=[O:9])[CH2:17][CH2:18]2)=[O:23])=[O:35])=[N:3][CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)c2oc3cccnc3c2NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)nc1
Reaction time: 0.5 h

Procedure:
2-Amino-5-methylpyridine (81 mg) is dissolved in chloroform (5 ml). After adding 0.98 M trimethyl alminum-hexane solution (763 μl) under ice-cooling, the reaction solution is stirred under ice-cooling for 10 minutes, and then at room temperature for 0.5 hours. To the resulting reaction solution is added methyl 3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxylate (150 mg) obtained in Reference Example 79, and the mixture is stirred at room temperature for 2 hours and at 50° C. under heating for 5 hours. To the reaction solution is added 10% hydrochloric acid (3 ml) under ice-cooling, and the mixture is stirred at room temperature for 0.5 hours. The reaction solution is then neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in diethyl ether, and collected by filtration to give the title compound (110 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)C.C(OCC)(=O)C>[CH3:16][C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:23][CH:24]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cccnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 160 °C

Procedure:
A solution of ethyl 2-chloro-3-pyridinecarboxylate (0.610 g, 3.29 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.580 mL, 3.29 mmol). The mixture was heated to 160° C. for 1 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-60% ethyl acetate in hexanes) afforded the title compound clear yellow oil (0.461 g, 45%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.34 (dd, J=4.8, 1.8 Hz, 1H), 8.18 (dd, J=7.8, 2.0 Hz, 1H), 7.30-7.42 (m, 4H), 6.58 (dd, J=7.6, 4.8 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.34 (s, 9H). MS(ES+) m/e 313 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:12]([OH:14])=O)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:31]=[N:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[CH:1]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:12]([NH:33][CH2:32][C:29]1[N:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=1)=[O:14])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncsc3C(C)C)c2)nc1
Reactant: Cc1ccc(CN)nn1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nn3)cc(-c3ncsc3C(C)C)c2)nc1

Procedure:
3-(5-Isopropyl-thiazol-4-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(6-methyl-pyridazin-3-yl)-methylamine using the procedure of Example 2 to give 3-(5-isopropyl-thiazol-4-yl)-N-(6-methyl-pyridazin-3-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=444.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[S:26]2)[S:21][CH2+:20]1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC#N>[CH2:12]([N:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[S:26]2)[S:21][C:20]1=[N:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CN1C(=C2SC(=Nc3ccccc3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Yield: 28.8 %

Procedure:
To an 8 mL vial was added 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate (100 mg, 0.18 mmol), aniline (16 μL, 0.18 mmol) and anhydrous MeCN (1 mL). After warming the mixture to 50° C., TEA (0.10 mL, 0.56 mmol) was added and continued heating the mixture at 50° C. for 12 h. After cooling to room temperature, the resulting precipitates were filtered under reduced pressure, washed with MeCN (2 mL) and dried under vacuum to yield the title product (22.3 mg, 29%) as a yellow solid. 1H-NMR (CDCl3): δ 7.59 (2H, m), 7.48 (1H, dd), 7.26–7.39 (6H, m), 7.10–7.18 (2H, m) 7.01 (3H, m), 5.16 (2H, s), 3.71 (3H, s); MS(ESI): 430 (MH+).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13]O>>[CH3:13][O:1][CH:2]1[O:10][CH:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[CH:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Product: COC1OC(CO)[C@@H](O)C(O)[C@H]1O
Temperature: 160 °C
Reaction time: 0.03 h

Procedure:
A mixture of methanol and glucose was initially charged in a stirred vessel A. The fraction of glucose was 30% of the methanol fraction. The mixture was conveyed by a suitable pump B at a pressure of 120 bar continuously through the reactor C. The tubular reactor C was heated to a temperature of 160° C. by the heater D. A carrier stream comprising pure methanol from the reservoir F was heated to approx. 300° using the preheater G. At the mixing point H, the carrier stream was mixed with the reactant stream and fed to the reactor. The preheating temperature was sufficiently high that reaction temperature was already present at the mixing point, so that the temperature gradient in the reactor was sufficiently low to prevent carbonization at the wall. The residence time in the tubular reactor was approx. 2 min. With the aid of the control valve E, the pressure was kept at the target value mentioned. At the outlet of the system, the reacted product mixture was collected. According to HPLC, the product mixture contained 3% product.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]>O1CCCC1>[CH:2]1([CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15])[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: CO[Si](CCl)(OC)OC
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO[Si](CC1C=CC=C1)(OC)OC
Yield: 93 %

Procedure:
27.5 g (417 mmol) of freshly distilled cyclopentadiene are added dropwise to a solution of 167 ml of n-butyllithium (2.5 molar) (417 mmol) in 250 ml of absolute tetrahydrofuran at RT over a period of one hour. 71.11 g of (chloromethyl)trimethoxysilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled under reduced pressure to give 72.2 g of (cyclopentadienylmethyl)trimethoxysilane (yield: 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:3])=[O:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 48.4 g of S-(o-nitrophenyl)-L-cysteine in 100 ml of 2N aqueous sodium hydroxide at 0° C. is added 28.8 ml of benzyl chloroformate and 50 ml of 4N aqueous sodium hydroxide simultaneously from two addition funnels. The mixture is mechanically stirred overnight at room temperature and then extracted with 150 ml of ether. The aqueous layer is separated and acidified to pH 1 with 12N aqueous hydrochloric acid. The resulting gummy yellow solid is stirred for 3 hr in 500 ml of water, collected by filtration, and dried overnight at 70° C. in vacuo to afford S-(o-nitrophenyl)-N-carbobenzyloxy-L-cysteine; m.p. 84°-88° C.; [α]D =+46.6° (c=1.25, methanol).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][CH2:23]I>CN(C)C=O.ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][O:1][C:2]2[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCI)cc1OC
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CCOc2cc(C(C)C)ccc(CO)c2=O)cc1OC
Temperature: 80 °C
Yield: 10.8 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (844 mg, 4.35 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (191 mg, 4.78 mg) in small portions were added thereto. Subsequently, 3,4-dimethoxyphenethyl iodide (2.54 mg, 8.70 mmol) was added, then the solution was heated at 80° C. for 7 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (3:2)] to give 169 mg of 2-[2-(3,4-dimethoxyphenyl)ethoxy]-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield: 11%).