Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2]C(C1C=CC=CC=1)C(O)=O.[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH:22]1([NH:21][C:20]([NH:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:2])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(C(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In 50 ml of ethyl acetate was dissolved with heating 1.0 g (2.73 mmole) of the compound obtained in step 1 of Example 1 above. To the resultant solution were added 0.68 g (4.10 mmole) of (-)-α-methoxyphenylacetic acid and then 0.67 g (3.28 mmole) of 1,3-dicyclohexyl carbodiimide at room temperature. Subsequently, 0.040 g (0.33 mmole) of 4-dimethylaminopyridine as a catalyst was added. The resultant mixture was stirred for 24 hours. Dicyclohexyl urea in the form of a white solid produced during the reaction as a side-product was removed by filtration, and the remaining filtrate was concentrated and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1) as an eluent to obtain 0.70 g (1.36 mmole, yield 50%) of (+) dimethoxymethyl-3-(O-α-methoxy-α-phenylacethoxy)-4-(2'-oxo-1'-pyrrolidinyl)-6-cyano-3,4-dihydro-2H-1-benzopyran having Rf value of 0.23 and 0.54 g (1.05 mmole, yield 38%) of (-) dimethoxymethyl-3-(O-α-methoxy-α-phenylacethoxy)-4-(2'-oxo-1'-pyrrolidinyl)-6-cyano-3,4-dihydro-2H-1-benzopyran having Rf value of 0.30.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13](=[S:15])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23](=[O:29])[CH:24](Br)[C:25](=O)[CH3:26])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[C:18]([O:22][C:23]([C:24]1[S:15][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=3)=[N:14][C:25]=1[CH3:26])=[O:29])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: NC(=S)c1cc2ccc(O)cc2oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide (221 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) stirred at 0° C., sodium hydride (60% in oil, 44 mg, 1.1 mmol) was added portionwise. During addition a clear solution was formed with moderate effervescence. After 10 min, a solution of 2-bromo-3-oxo butyric acid tert-butyl ester (474 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added dropwise and the mixture was stirred at room temperature for 16 h. The reaction was poured into water (20 mL) and extracted with chloroform (3×10 mL). The combined organic extracts were washed with water (3×5 mL), dried over MgSO4 and concentrated. The residue was triturated with diethyl ether, the solid product was collected and washed with diethyl ether. The title compound (224 mg, 0.623 mmol, 62.3%) was obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:2]=1
Reactant: N#CCc1cccc(-c2ccccc2)c1
Reactant: BrCCOCCBr
Product: N#CC1(c2cccc(-c3ccccc3)c2)CCOCC1

Procedure:
This compound was synthesized from 2-([1,1′-biphenyl]-3-yl)acetonitrile as described in example 1 step 2 using 2-bromoethyl ether (0.5 g, 73%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.71 (m, 1H), 7.62-7.57 (m, 3H), 7.51-7.45 (m, 4H), 7.42-7.37 (m, 1H), 4.15-4.10 (m, 2H), 3.99-3.91 (m, 2H), 2.28-2.20 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:12]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:11]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+]>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][NH:9][C:10]2[N:15]([CH3:16])[C:14](=[O:17])[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:12]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:11]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cn1c(NCc2ccccc2Br)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(NCc2ccccc2-c2cccc(C(F)(F)F)c2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O

Procedure:
2-((2-bromophenylmethyl)amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-3-methyl-4(3H)-pyrimidinone (175 mg, 0.38 mmol) was dipersed in 2M sodium carbonate solution (12 ml) and 3-trifluromethylbenzene-boronic acid (170 mg, 0.89 mmol), toluene (12 ml) were added to the above mixture and the reaction mixture was degassed and catalyst tetrakistriphenylphosphine Pd(0) (50 mg) was added. The reaction mixture was refluxed for 16 h. The formation of the product was monitored by TLC. Then it was cooled, diluted with toluene (12 ml) and washed with water. The organic layer was dried over sodium sulfate, concentrated and the product was purified by silica gel chromatgraphy to give the title compound. MS(m/z): 531.1 C30H22F4N4O requir. 530.53; 1H-NMR(CDCl3): d 8.43 (m, 2H, pyridyl), 7.69-7.12 (m, 8H, Ph), 7.11-6.88 (m, 6H, pyridyl and Ph—CF3), 4.85 (m, 3H, CH2—Ph and NH), 3.32(N—CH3)
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1.C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:19]=[O:20])(=[O:11])=[O:12])[C:4]=2[CH2:3][S:2]1
Reactant: NS(=O)(=O)c1cccc2c1CSC2
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5.5 g of 1,3-dihydrobenzo[c]thiophene-4-sulfonamide, 2.5 g of butyl isocyanate and 0.05 g of DABCO® in 50 ml of xylene was heated to 135° and 2.2 ml of liquid phosgene was added in small portions at approximately 135°. When the addition of phosgene was complete, heating was continued for 5 minutes before the dark brown suspension was cooled to ambient temperature under a slow stream of nitrogen. The reaction mixture was filtered under nitrogen and the filtrate was concentrated in vacuo to give 1,3-dihydrobenzo[c]thiophene-4-sulfonyl isocyanate as a dark red-brown oil. The crude sulfonyl isocyanate was dissolved in methylene chloride (total volume=26 ml) for reaction with aminoheterocycles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-bromobenzyl)methane-sulfonamide (675 mg) was obtained in 95% yield.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:19]2[CH:18]=[C:15]([C:16]#[N:17])[C:14]([O:13][CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:21][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCNC(=O)c1ccccc1

Procedure:
In the following Examples 28-31, the procedure described in Example 27 was repeated but substituting the appropriate acid chloride for benzoyl chloride in the reaction with 2-(2-aminoethoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-nicotinonitrile from Example 26 to afford the following compounds:
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:20])([F:19])[C:7](=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(O)C>[NH2:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[CH2:8][C:7]([C:6]([F:20])([F:19])[F:5])=[N:32]2)=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2ccc(F)cc2F)cc1
Yield: 65 %

Procedure:
In a flask with an inert atmosphere sodium ethoxide (0.53 g, 7.72 mmoles) is dissolved in 45 ml of ethanol. 1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (prepared according to method E-1) (0.913 g, 3.86 mmoles) and 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.87 g, 3.87 mmoles) are added and the mixture was refluxed for 16 hours. The mixture was cooled, evaporated to dryness, cold water added, and the mixture acidified by adding acetic acid and the precipitated solid filtered. This solid was redissolved in ether, treated with active C, filtered and the solvent eliminated with a rotavapor. The resulting residue was crystallised from ethyl ether-petrol ether (50:50) to give 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole (1.02 g, yield: 65%) in the form of a solid m.p.=160-2° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([O:30]CC)=[O:29])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:17]([NH:19]C(=O)C2C=CC=CC=2)=[S:18])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([OH:30])=[O:29])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(NC(=S)NC(=O)c2ccccc2)s1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(NC(N)=S)s1)C(=O)O
Temperature: 25 °C

Procedure:
To a stirred solution of Ethyl N-(tert-butoxycarbonyl)-3-(5-(3-benzoylthioureido)-2-thienyl)-DL-alaninate (4.90 g, 10.2 mmol) in tetrahydrofuran (100 ml) was added 2N aqueous sodium hydroxide (12 ml, 24.0 mmol). The mixture was heated to reflux for 2.5 hours and cooled to room temperature. The mixture was placed in an ice bath and carefully neutralized to approximately pH7 with concentrated hydrochloric acid. The solvent was removed at reduced pressure to a volume of approximately 20-25 ml of a dark aqueous solution, and was extracted four times with ethyl acetate. The aqueous layer was adjusted to approximately pH4 with concentrated hydrochloric acid and concentrated at reduced pressure to give a dark red gummy solid. This material was taken up into ethyl acetate. All of the combined organic layers were dried over magnesium sulphate and the solvent was removed at reduced pressure to give a dark red gummy oil. This material was purified by column chromatography on silica gel eluting with 7.5:92.5:0.5 methanol:dichloromethane: acetic acid. The fractions containing the desired product were combined and concentrated at reduced pressure. The residue was redissolved in a small amount of methanol, diluted with toluene and reconcentrated at reduced pressure to azeotropically remove any remaining acetic acid. This process was repeated three times. N-(Tert-butoxycarbonyl)-3-(5-thioureido-2-thienyl)-DL-alanine. (2.33 g, 66%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=O)[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:23])[C:15]=3[N:14]=2)=[O:35])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1COCCN1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCOCC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 450 mg (0.90 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 87 μl (2.70 mmol) morpholine. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: BrC1C=C(C=CC=O)C=C(OC)C=1OC.COC1C=C(C=C(OC)C=1OC)C=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=[O:45])[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]([OH:54])[CH:51]=[CH:52][CH:53]=1.N1CCOCC1>CO>[CH3:41][O:40][C:36]1[CH:35]=[C:34]([CH:42]=[CH:43][CH:44]=[O:45])[CH:33]=[C:32]([O:31][CH3:30])[C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:51]([CH:42]([C:34]3[CH:33]=[C:32]([O:31][CH3:30])[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:43][CH:44]([OH:45])[O:54]2)=[CH:52][CH:53]=1
Reactant: COc1cccc(O)c1
Agent: COc1cc(C=CC=O)cc(Br)c1OC
Agent: COc1cc(C=CC=O)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Solvent: C1COCCN1
Product: COc1ccc2c(c1)OC(O)CC2c1cc(OC)c(OC)c(OC)c1

Procedure:
3-(3,4,5-Trimethoxyphenyl)-propenal was prepared following the procedure for 3-(3-bromo-4,5-dimethoxyphenyl)-propenal as described in Example 15a using 3,4,5-trimethoxy benzaldehyde. 7-Methoxy-2-hydroxy-4-(3,4,5-trimethoxy-phenyl)-chroman was synthesized by the same procedure as Example 18 from 3-(3,4,5-trimethoxyphenyl)-propenal (71 mg; 0.32 mmol) and 3-methoxy phenol (43 mg; 0.35 mmol) using morpholine (30 μl) as a base in methanol (2.5 ml) (14 mg; 13%). 1H NMR (acetone-d6): 6.64 (dd, J=1.1, 8.5 Hz) and 6.59 (dd, J=1.0, 8.4 Hz) (1H), 6.54 (one doublet and one singlet overlapped, J=2.7 Hz; 2H), 6.38 (dd, J=2.6, 8.5 Hz; 1H), 6.34 (d overlapping with other small signals, J=2.3 Hz; 1H), 6.13 (d, J=6.8 Hz) and 6.08 (dd, J=1.0, 4.5 Hz) (1H), 5.62-5.65 and 5.47-5.51 (m each, 1H), 4.13-4.21 (overlapping dd, J=6.6, 10.2 Hz; 1H), 3.78, 3.77, 3.73, 3.72 (s each, 12H), 2.31 (ddd, J=2.1, 5.7, 13.1 Hz) and 2.08-2.13 (m) (2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chloro -hydrocinnamic acid and 1.09 g (0.007 mol) of 1,1'carbonyldiimidazole are stirred at room temperature for 1.5 hours in 20 ml of tetrahydrofuran and 1.04 g (0.007 mol) of ethyl L-alaninate hydrochloride and 0.94 ml (0.007 mol) of triethylamine are then added thereto. After stirring at room temperature for 2 hours, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetatemethanol (9:1) and then on aluminum oxide with ethyl acetate and subsequent crystallization from ethyl acetate/ hexane gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-alaninate as white crystals with melting point 106°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][C:8]#[N:9].[ClH:15].C[CH2:17][OH:18]>>[ClH:15].[CH3:17][O:18][C:8](=[NH:9])[CH:7]=[CH:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCO
Reactant: COc1ccc(C=CC#N)cc1OC
Agent: Cl
Product: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reaction time: 18 h
Yield: 60 %

Procedure:
A suspension of 3,4-dimethoxycinnamonitrile (10 g; 52 mmol) in EtOH (150 mL) was cooled in an ice bath. The cold mixture was then saturated with hydrogen chloride. The reaction solution was refrigerated for 18 hours. The precipitate formed was collected by filtration. The colorless solid gave 8.0 g (60% yield) of methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride which was used in the next reaction, 1H-NMR (DMSO-d6; 200 MHz) δ11.8 (broad s, 1H), 10.9 (broad s, 1H), 7.82-7.9 (d, 1H), 7.3 (d, 2H), 7.02-7.12 (d, 1H), 6.81-6.9 (d, 1H), 4.2 (s, 3H), and 3.76 (s, 3H), 3.82 ppm (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:18]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[C:15]([CH3:24])[N:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[C:18]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[C:15]([CH3:24])[N+:14]=1[O-:6]
Reactant: Cc1ccc(C2(F)CCC2)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C2(F)CCC2)c(Cl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
3-Chlorobenzoperoxoic acid (173 mg, 1.00 mmol) was added in 2 portions to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine (Example 130 b, 100 mg, 501 μmol) in dichloromethane (2 mL). The reaction mixture was stirred at ambient temperature for 72 h, poured onto a 10% aqueous Na2S2O3 solution (30 mL) and extracted with dichloromethane (2×40 mL). The combined organic layers were washed with ice water/brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with sat. NaHCO3 solution (30 mL) and ice water (30 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (81 mg, 74%) as yellow oil, MS (ESI): m/e=216.3 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18]CC)=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.Cl>>[OH:1][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cnn2c1c(O)nc1c(C)nn(C)c12
Agent: Cl
Product: Cc1nn(C)c2c1nc(O)c1c(C(=O)O)cnn12

Procedure:
2.75 gms. of 5-hydroxy-1,3-dimethyl-1H-dipyrazolo-[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester are suspended in 20 ml. of concentrated hydrochloric acid. On warming, a clear solution results from which the product, 5-hydroxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, precipitates after 40 minutes as a crystal-like mass. The product is purified by dissolving the precipitate in concentrated ammonia solution, treating with charcoal, reprecipitating with hydrochloric acid and recrystallizing from dimethylformamide, m.p. > 300°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])[CH2:25][CH2:24][O:23][CH2:22]C1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]([C:2]1[CH:1]=[CH:25][C:24]([O:23][CH3:22])=[CH:4][CH:3]=1)[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(OCc2ccccc2)c1CO
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: COc1ccc(C(O)c2c(OC)cccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 145 %

Procedure:
In a nitrogen stream, a solution of (2-benzyloxy-6-methoxyphenyl)-methanol (3.52 g, 14.41 mmol) and N-methylmorpholine N-oxide (NMO, 2.53 g, 21.61 mmol) in dichloromethane (14.5 mL) was cooled in a water bath, and tetra-n-propylammonium perruthenate (TPAP, 152 mg, 0.43 mmol) was added thereto. The reaction mixture was stirred for 20 minutes at the same temperature and at room temperature for 1.75 hours, and then subjected to Celite filtration and the solvent was distilled under reduced pressure. The obtained residue was treated by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:3 to 1:2.5)]. The obtained compound was dissolved in THF and cooled in a water bath, and a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 30.3 mL) was added dropwise thereto in a nitrogen stream. The reaction mixture was stirred at room temperature for 1.25 hours, and then a saturated ammonium chloride aqueous solution was added thereto at room temperature and the mixture was extracted with ether. The organic layer was washed with a saturated ammonium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4 to 1:3.5)] to obtain the title compound (3.66 g, 72%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[N:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[N:9]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1nc(Cn2ncc(N)n2)co1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3coc(C(C)(F)F)n3)n2)c1

Procedure:
Following general procedure A, starting from 2-((2-(1,1-difluoroethyl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.53 g (10 mmol) of 3-methyl-4-nitrophenol, 1.95 g (10 mmol) of t-butyl bromoacetate and 2.76 g (20 mmol) of potassium carbonate in 10 mL of DMF are stirred at RT for 2 h. Water is added and the mixture is extracted with EtOAc and the organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residual oil is filtered through a pad of silica gel using CH2Cl2 as the eluant to give (3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester as an oil: 1H-NMR (CDCl3) δ 8.08 (d, J=9.56, 1H), 6.82-6.75 (m, 2H), 4.58 (s, 2H), 2.63 (s, 3H), 1.49 (s, 9H); Anal. Calcd for C13H17NO5 C, 58.42; H, 6.41; N, 5.24; Found C, 58.04; H, 6.51; N, 5.09.