Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH2:5].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][N:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:31][C:32]1=[O:36]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(Cn1ccc(OCc2ccccc2)cc1=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (900 mg, 3.0 mmol), and 4-benzyloxy-1H-pyridin-2-one (630 mg, 1.03 equiv) in acetonitrile (2.5 mL) was added cesium carbonate (100 mg, 0.10 equiv). The resulting suspension was heated to 80° C. via microwave for 2 h. The reaction was concentrated, dissolved in water, and extracted with methylene chloride (3×). The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 1.47 g (97%) which was used without purification. Mass spec.: 503.56 (MH)+.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[N+:7]([O-:10])(O)=[O:8].[N+](C1C=CC=CC=1)([O-])=O.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:7]([C:23]1[CH:24]=[CH:25][C:20]([CH3:26])=[CH:21][CH:22]=1)([O-:10])=[O:8]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
An 86 gram portion of soluble anhydrite regenerated from Example II by first heating in a vacuum at 100°C for 7 hours for removal of organic material and then over night at 200°C. was added to a 100 milliliter portion of toluene. This mixture was heated to 45°C. and stirred while an 18.1 gram portion of anhydrous nitric acid was added drop by drop over a 30-minute period. Agitation was continued for 1 1/2 hours, then a 26 gram portion of nitrobenzene was added to the reaction mixture and stirring was continued for an additional hour. After this one hour period, the reaction mixture was filtered and the filtrate analyzed by gas chromotography using the nitrobenzene as the internal standard. A yield of 61% mononitrotoluene was obtained based on the nitric acid charged. The mononitrotoluene had the following composition: 44.1% ortho-nitrotoluene, 2.8% meta-nitrotoluene, and 53.1% paranitrotoluene. Thus the results show a substantial increase in the proportion of para-isomer was obtained by the addition of the soluble anhydrite to the reaction medium.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=S)=S.O=[C:22]([CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:23]>O>[CH3:9][C:17]1([CH3:16])[C:6]2[CH:5]=[C:17]3[C:9]([C:10]4[CH:11]=[C:12]5[C:22]([CH3:23])=[CH:24][C:25]([CH3:27])([CH3:26])[C:13]5=[CH:14][C:15]=4[CH2:16]3)=[CH:8][C:7]=2[C:6]([CH3:7])=[CH:5]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C=C2C
Reaction time: 0.25 h

Procedure:
To a 300-ml three-neck flask, 25.8 g of anhydrous aluminum chloride, 5.18 g of fluorene, and 200 ml of carbon disulfide were charged under nitrogen atmosphere. 6.18 g of mesityl oxide was added dropwise thereto over 15 minutes in a water bath, and the mixture was stirred for 10 hours under reflux. After standing to cool, 100 ml of water was added thereto, and the organic layer was separated. The aqueous layer was extracted with 300 ml of hexane, and the separated organic layer was combined, and washed with water and a saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography, and recrystallized with a mixed solvent of ethanol/hexane. The yield was 1.14 g. Identification was performed by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[OH:34]>CC1C=CC(C)=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]1[O:34][C:25]2[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:7]
Reactant: Nc1cccc(C(F)(F)F)c1O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)Cc1nc2cccc(C(F)(F)F)c2o1
Temperature: 25 °C

Procedure:
2-Nitro-6-trifluoromethyl-phenol (1.8 g) (J. Org. Chem. 1962, 27, 4660-4662) was dissolved in MeOH (20 ml) prior to the addition of 10% Pd/C (1.0 g). The reaction was placed on a Parr aparatus under hydrogen at 60 psi for 4 h. The palladium was filtered off and the solution was concentrated to give 2-amino-6-trifluoromethyl-phenol (1.1 g): 1H NMR (CD3OD, δ ppm, 300 mHz) 6.78 (m, 2H), 6.90 (d, 1H). (22b) A portion (200 mg) of the above derivative (22a) was dissolved in p-xylene prior to the addition of diethyl malonate (0.9 ml) and p-toluenesulfonic acid (22 mg). The reaction was heated to reflux with azeotropic removal of the water. After cooling to rt, the solution was concentrated. Flash chromatography of the resulting residue gave (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid ethyl ester (130 mg). 1H NMR (CDCl3, δ ppm, 300 mHz) 1.30 (t, 3H), 4.09 (s, 2H), 4.25 (q, 2H), 7.41 (t, 1H), 7.60 (d, 2H), 7.90 (d, 1H). (22c) The above derivative (22b) (130 mg) was dissolved in THF (1 ml) prior to the addition of a solution of LiOH in water (1 ml). A couple drops of MeOH were added until the solution became clear. After 2 h at rt, the reaction was partially concentrated and 1N HCl was added to neutralize the reaction. This was exacted with EtOAc. The organic layer was dried, filtered and concentrated to provide (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid (85 mg). 1H NMR (CD3OD, δ ppm, 300 mHz) 4.13 (s, 2H), 7.54 (t, 1H), 7.70 (d, 2H), 7.95 (d, 1H). (22d) (±)(1S*,2R*,4R*)—N4-Isopropyl-N4-methyl-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexane-1,4-diamine TFA salt, from example (19g), (65 mg) was dissolved in DMF (2 ml) prior to the addition of 4-methylmorpholine (74 μl) and example (22c) (39 mg). After cooling to 0° C., BOP reagent (77 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (28 mg). MS found: (M+H)+=598.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([NH:34][C@H:35]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH3:43])(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[C@H](NS(=O)(=O)c1ccccc1Br)C(=O)OC(C)(C)C
Product: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared using analogous conditions to those described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and (S)-tert-butyl 2-(2-bromophenylsulfonamido)propanoate. MS (ESI): mass calcd. for C23H25FN4O4S, 472.16; m/z found, 473.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=1.1, 2H), 8.08 (dd, J=8.0, 1.2, 1H), 7.66 (m, 1H), 7.61-7.49 (m, 2H), 7.37 (m, 3H), 3.66 (q, J=107.2, 1H), 1.34 (s, 9H), 1.26 (d, J=7.2, 3H).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1(Cl)[NH:12][C:11]([Cl:13])=[CH:10][S:9]1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:15][NH2:16]>>[CH:1]([N:4]([NH:16][CH3:15])[S:5]([C:8]1[S:9][CH:10]=[C:11]([Cl:13])[N:12]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)NS(=O)(=O)C1(Cl)NC(Cl)=CS1
Product: CNN(C(C)C)S(=O)(=O)c1nc(Cl)cs1
Yield: 78 %

Procedure:
In analogy to Example 5, the N-isopropyl-2-N-methylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-isopropyl-2,4-dichlorothiazole-sulphonamide from Example 3 with 30% strength aqueous methylamine solution. Following recrystallization from toluene, the product of m.p. 187-8° C. was obtained in a yield of 78% of the theoretical yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Br[CH2:18][CH2:19][O:20][CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccc(C#N)c(F)c2)cc1

Procedure:
A mixture of 3-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile (0.50 g, 2.35×10−3 mol), 1-bromo-2-methoxyethane (0.33 g, 2.35×10−3 mol), potassium iodide (0.04 g, 2.35×10−4 mol) and potassium carbonate (1.30 g, 9.40×10−3 mol) in butanone (20 cm3) was reacted, worked up and purified as described for compound 3 in Example 2. Yield 0.40 g (63%), GC purity (99.86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:41]1([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:48]3[CH2:49][CH2:50][CH2:51][CH:47]3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: c1ccc(C2CCCN2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC1c1ccccc1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 30 mg of 1-(4-chlorophenyl)cyclopropanecarboxylic acid and 81 mg BOP reagent in 0.5 mL methylene chloride wad added 27 mg of 2-phenylpyrrolidine, followed by the addition of 53 ul of Hunig base. The reaction mixture was stirred at r.t. for 2 hours and directly purified by flash column using ethyl/hexane as the eluting solvent to provide the desired 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2-phenylpyrrolidine. LCMS (ESI): 326.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 79.2 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mmol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[C:33](OC(=O)C)(=O)[CH3:34]>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:20])[C:3]=1[OH:21])[O:19][C:33]([CH3:34])=[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH:8]2[OH:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)c(C)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(C)Oc3c(cc(Cl)c(O)c3C)C2O)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(5-chloro-2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) in an. DMF (7 ml) was added K2CO3 (3 eq). Acetic anhydride (3 eq) was added dropwise to the solution, which was then refluxed under nitrogen whilst stirring for 5 h. The solution was taken up in water and extracted using ethyl acetate, dried over MgSO4 and concentrated in vacuo to give 6-chloro-3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol as a crystalline solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH2:15][Cl:16])[CH2:13][S:14][C@H:9]12)=[O:6].ClC1C=CC=C(C(OO)=[O:68])C=1>C1C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40][C:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH2:15][Cl:16])[CH2:13][S:14](=[O:68])[C@H:9]12)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (2.97 mmol) of benzhydryl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 25 ml of benzene, and 640 mg (3.27 mmol) of m-chloroperbenzoic acid was added under cooling with ice. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extracted solution was washed with a 5% sodium bisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby the above identified compound was obtained as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:25])[CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:27]\[OH:28])=[C:4]([F:25])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2F)C2CCCC2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2F)C2CCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=421.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[C:1]1([CH2:7][C@H:8]([N:60]=[N+:61]=[N-:62])[C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H](Cc1ccccc1)c1nccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H](Cc1ccccc1)c1nccs1
Temperature: 25 °C
Reaction time: 47 h
Yield: 82.7 %

Procedure:
Following the method of Itako et al. (Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 48(35), 1992, 7251-7264), a solution of (1R)-2-phenyl-1-(1,3-thiazol-2-yl)ethanol (1.3 g, 6.3 mmol, from Reference Example 3) in tetrahydrofuran (60 mL) is cooled to 0° C. (ice-water bath). To the solution is added successively triphenylphosphine (1.8 g, 6.9 mmol), diethylazodicarboxylate (1.1 mL, 6.9 mmol), and diphenylphosphoryl azide (DPPA, 1.6 mL, 6.9 mmol). Following the addition of reagents, the reaction mixture is allowed to warm to room temperature and stir for 47 hours. Following this period, the mixture is concentrated under reduced pressure and purified by flash chromatography (silica gel, hexanes/toluene/diethyl ether) to give 1.2 g of (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylazide as a pale blond oil contaminated with DPPA (detected by 1H NMR).
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4](=[O:6])=[O:5]>O>[C:4](=[O:1])([OH:6])[O-:5].[Ca+2:2].[C:4](=[O:1])([OH:6])[O-:5]
Reactant: [OH-]
Reactant: O=C=O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])O

Procedure:
In the next step, calcium hydroxide (Ca(OH)2) is added at the downstream end 48 of the second flow channel 36. The sequestered carbon dioxide (CO2), dissolved in the desalinated water, then reacts with the added calcium hydroxide (Ca(OH)2) to produce calcium bicarbonate (Ca(HCO3)2) in accordance with the following equation: Ca(OH)2+CO2→Ca(HCO3)2  Eq. 2
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[OH-].[Na+]>>[O:2]1[CH2:19][CH2:20][O:21][CH:1]1[CH:3]1[NH:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: OCCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])cc1N1CCNC1C1OCCO1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Into a round bottom flask equipped with a Dean Stark trap, 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile (10.48 g, 0.04327 mol), 1,2-ethanediol (15.0 mL, 0.269 mol), p-toluenesulfonic acid monohydrate (8.23 g, 0.0433 mol), and benzene (150 mL, 1.7 mol) were added. The reaction was heated to reflux for 6 hours. The reaction was cooled to room temperature. 1N NaOH was added to adjust the pH to 10. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded 2-(2-[1,3]dioxolan-2-yl-imidazolidin-1-yl)-4-nitro-benzonitrile as a yellow solid (8.20 g, 66%). 1H-NMR (DMSO-D6, 400 MHz): δ8.53 (d, 1H), 8.42 (s, 1H), 8.35 (d, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 5.82 (s, 1H), 3.65 (bs, 2H), 3.45 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(F)cc1)CS(=O)(=O)/C=C/c1ccc(F)cc1
Yield: 74 %

Procedure:
A solution of 4-fluorobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 74% yield. m.p. 183-185° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12].[I:19][C:20]1[CH:21]=[N:22][NH:23][CH:24]=1>C(Cl)Cl>[I:19][C:20]1[CH:21]=[N:22][N:23]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:24]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, diisopropylethylamine (DIEA, 1.75 ml, 10 mmol) and trimethylsilylethoxymethyl chloride (SEMCl, 1.83 ml, 10 mmol) are added to a solution of 4-iodopyrazole (1.94 g, 10 mmol) in CH2Cl2 (100 ml). The mixture is stirred overnight at room temperature. The solvent is evaporated under vacuum. The residue is taken up in a diethyl ether/water mixture. The organic phase after drying and evaporation gives a colourless oil which is purified by eluting on silica gel with an AcOEt/CH2Cl2 (5/95) mixture.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[O:11]COC.Cl.O.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COCOc1ccc(C=Cc2ccc(-c3ccccn3)nc2)cc1OCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(C=Cc2ccc(-c3ccccn3)nc2)cc1O
Yield: 85.3 %

Procedure:
A solution of 5-{2-[3,4-bis(methoxymethoxy)phenyl]vinyl}-[2,2′]bipyridinyl (0.85 g, 2.246 mmol), concentrated hydrochloric acid (5 mL) and water (2 mL) in methanol (100 mL) was stirred under argon atmosphere at room temperature for 15 hoursw. Water (50 mL) was added to the mixture and methanol was rotary evaporated. More water (100 mL) was added and the resulting mixture was neutralized to pH 7 with sodium hydroxide solution. The solid precipitate was collected by filtration and washed with water and a mixed solvent of hexane and EtOAc (3:1, v/v). The resulting orange solid was dried under high vacuum giving 0.5559 g of 5-{2-[3,4-dihydroxyphenyl]vinyl}-[2,2′]bipyridinyl (1.915 mmol, yield 85.3%) as a Z/E mixture. 1H NMR (MeOH, 300.16 MHz): 8.71 (d, J=1.7 Hz, 0.70H), 8.65-8.62 (m, 1.56H), 8.51 (d, J=1.4 Hz, 1.03H), 8.31-8.23 (m, 2.29H), 8.16 (d, J=8.3 Hz, 1.00H), 8.0 (dd, J=2.0 Hz, 0.78H), 7.94-7.89 (m, 1.63H), 7.80 (dd, J=8.2 & 2.0 Hz, 1.04H), 7.44-7.40 (m, 1.52H), 7.23 (d, J=16.4 Hz, 0.74H), 7.08 (d, J=1.8 Hz, 0.71H), 7.00 (d, J=16.4 Hz, 0.74H), 6.95 (dd, J=8.2 & 1.8 Hz, 0.70H), 6.77 (d, J=8.2 Hz, 0.74H), 6.72-6.67 (m, 2.80H), 6.61 (dd, J=8.1 & 1.5 Hz, 1.01H), 6.47 (d, J=12.1 Hz, 1.00H). UV-Vis (MeOH): Emax=252 nm, 288 nm and 352 nm. MS (ESI) m/z: 291 (M+1)+.