Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:14][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)CCCC1
Yield: 100.5 %

Procedure:
Under nitrogen atmosphere 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.84 g (10 mmol) of cyclopentanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.73 g of the desired product (yield 94%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29]CC2C=CC=CC=2)=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OCc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(O)cc1OC

Procedure:
A solution of 2.46 g (4.64 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-benzyloxy-2-methoxyphenyl)octanamide (prepared as described in Example 123) in 100 ml of ethanol was vigorously stirred at 40° C. under a stream of hydrogen in the presence of 10% palladium-on-charcoal for 1.5 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was concentrated to dryness by evaporation under reduced pressure. The residue was purified by column chromatography through 100 g of silica gel using a 49:1 by volume mixture of ethyl acetate and methanol as the eluent, to give a crude product containing the title compound. This product was further purified by column chromatography through silica gel under the same conditions as above to give 1.62 g (yield 79%) of the title compound as a foam-like substance.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]([C:39]2[N:40]=[CH:41][N:42]3[CH:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[S:44][C:43]=23)=[O:38])[CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:45]3[S:44][C:43]4=[C:39]([C:37]([C:29]5[CH:28]=[N:27][C:36]6[C:31]([CH:30]=5)=[CH:32][CH:33]=[CH:34][CH:35]=6)=[O:38])[N:40]=[CH:41][N:42]4[CH:46]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cnc4ccccc4c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cnc6ccccc6c5)c4s3)[C@H](C)[C@H]12
Yield: 42.4 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinolin-3-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (86 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 180 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 185 mg of 7-(quinolin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C(N1C=C2C(C=CC=C2[N+]([O-])=O)=N1)C1C=CC=CC=1>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Agent: O=[N+]([O-])c1cccc2nn(Cc3ccccc3)cc12
Product: O=[N+]([O-])c1cccc2[nH]ncc12

Procedure:
The isomeric mixture of 1-benzyl-4-nitroindazole and 2-benzyl-4-nitroindazole obtained by the benzylation of 4-nitroindazole is reduced with hydrazine and Raney nickel in methanol and subsequently heated with excess sodium hydrogen sulphite in water. The 1-benzyl-4-aminoindazole (m.p. 73°-75° C.) thereby remains undissolved. Upon acidifying the solution, 2-benzyl-4-hydroxyindazole precipitates out and is obtained in the form of colorless crystals; m.p. 172°-174° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]2=[O:32])=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:17]1=[O:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2cccc(-c3ccccc3)c2C(=O)C1c1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(Br)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
N-bromosuccinimide (0.3 g ) was added portionwise over 15 minutes to a stirred solution of 2-(p-chlorophenyl)-4-phenylindane-1,3-dione (0.5 g) containing benzoyl peroxide (0.01 g) at ambient temperature and the reaction was allowed to stir for a further 15 minutes. The solvent was removed under reduced pressure and the crude product was chromatographed on silica. The fraction eluted with toluene was recrystallised from diethyl etherhexane to give 2-bromo-2-(p-chlorophenyl)-4-phenylindane-1,3-dione, m.p. 121-123.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Br:14])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 200 °C
Yield: 11.4 %

Procedure:
A mixture of 1-benzyl-piperazine (1.49 g, 8.44 mmol), 3,5-dibromo-pyridine (2.00 g, 8.44 mmol), and potassium carbonate (1.17 g, 8.44 mmol) in 15 ml DMF was heated at 200° C. for 1 h under a nitrogen atmosphere. Then the mixture was diluted with 100 ml of water and was extracted twice with ethyl acetate. The combined organic layers were extracted with aqueous HCl solution. The pH of the aqueous solution was adjusted to pH 10 with aqueous NaOH. After extraction with diethylether the combined organic phases were dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The so obtained oil was purified via silica gel chromatography with cyclohexane/ethyl acetate (2:1) as eluent to give 0.32 g of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.6 %

Procedure:
3-Aminopyridine (0.141 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.024 g, 0.0480 mmol, 10%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:29]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:30])=[O:7])#[N:3]
Reactant: O=C(O)C1CCCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1CCCCC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 438.1 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
A mixture of 2.2 mmol 2-bromo-5-trifluoromethyl-[1,3,4]thiadiazole (CA 37461-6-3; prepared according to DE2533605), 2.3 mmol piperazine-1-carboxylic acid tert-butyl ester and 4.3 mmol potassium carbonate in 10 ml acetonitrile was refluxed for 4 hours. The reaction mixture was cooled, poured into water and extracted 3 times with ethyl acetate. Concentration and recrystallisation of the crude material from diethyl ether yielded the title compound as a colorless solid. MS (m/e): 397.2 ([M+CH3COO]31 , 100%).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1.C([OH:24])C.CN(C)C=O>[OH-].[Na+]>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[O:13][CH2:12][C:4]1[NH:3][C:2](=[O:24])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CCO
Reactant: Nc1nc(COc2ccc(Cl)c(Cl)c2)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(COc2ccc(Cl)c(Cl)c2)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 15.0 g (0.0466 mole) of 4-amino-2-[(3,4-dichlorophenoxy)methyl]pteridine in 1500 ml of 5% aqueous sodium hydroxide. Heating time: 6 hours under reflux. Yld: 10.0 g (66%), m.p. 285°-287° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[N+:35]([C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)([O-:37])=[O:36]>CCOCC>[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([O:33][C:32](=[O:34])[CH:31]=[CH:30][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:16]4[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:19]=3)=[CH:29][CH:28]=2)=[CH:40][CH:39]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(C=CC(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CCOCC
Product: CC(C)(c1cc(-c2cccc(-c3ccc(C=CC(=O)Oc4ccc([N+](=O)[O-])cc4)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the procedure described in EXAMPLE 11, Step 3 but using 3-(3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl)-acrylic acid and 4-nitro-phenol as starting materials. Stirring in Et2O afforded the title compound after filtration.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[C:31]([S:32](Cl)(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1>>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:32]([C:31]5[C:27]([CH3:26])=[N:28][O:29][C:30]=5[CH3:36])(=[O:34])=[O:33])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and 3,5-dimethylisoxazole-4-sulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.94 (1H, s), 7.86 (1H, dd), 5.34 (2H, s), 4.65 (1H, m), 3.68 (2H, m), 2.86 (2H, m), 2.61 (3H, s), 2.33 (3H, s), 2.24 (2H, m), 2.00 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][Sn](C)(C)C>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:25])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 74.1 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (204 mg, 0.52 mmol), tetramethyltin (0.22 mL, 1.57 mmol), and PdCl2(PPh3)2 (74 mg, 0.10 mmol) in 5 mL of DMF was heated at 120° C. for 1 h under N2 atmosphere. Additional tetramethyltin (0.22 mL, 1.57 mmol) was added and the mixture was heated for 1 h at the same temperature. The mixture was cooled to r.t. and diluted with brine (10 mL) and EtOAc (40 mL). The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude residue was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 125 mg of the title compound as a pale yellow solid. MS: (+) m/z 325.05 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=O)=[CH:21][N:20]=[C:19]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)[CH3:15]>CN(C)C=O>[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=[CH:5][C:3]#[N:4])=[CH:21][N:20]=[C:19]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)[CH3:15]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2ccccc2)ncc1C=CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
To a room temperature suspension of sodium hydride (38 mg of a 60% suspension of NaH in oil) in 5 mL of dimethylformamide was added diethyl cyanomethylphosphonate (150 μL, 0.93 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldeyde (200 mg, 0.83 mmol) in 2 mL of dimethylformamide was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was partitioned between brine and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product were concentrated, and hexane was added to the residue. The resultant solid was collected by filtration to give 91 mg (43%) of 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylonitrile, mp 244-246° C. Concentration of the filtrate provided an additional 68 mg (32%) of product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:13]([NH:20][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: CCCCCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCCCNCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 1-methylindole-2-carbaldehyde (1.59 g, 10.0 mmol) and heptylamine (1.49 mL, 10.0 mmol) in ethanol (50 mL) were added acetic acid (2.3 mL, 40 mmol) and sodium cyanoborohydride (0.75 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (75 mL) and aqueous 1 M KOH (75 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2×75 mL) and the combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a column of silica gel (130 g) with ethyl acetate (17-33% gradient) in heptane as the eluent yielded 1.57 g (61%) of a yellow oil, which solidified upon standing.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[OH-].[K+]>C(O)CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:5]([C@H:4]([CH3:22])[C:3]([OH:2])=[O:23])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 4.7 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (42.5 g, 0.127 mole) in ethylene glycol (250 ml) was refluxed under nitrogen atmosphere for one hour and then cooled. Water (40 ml) and solid potassium hydroxide pellets (10.13 g, 0.181 mole) were added and the solution was refluxed for an additional two hours, filtered into ice water (1 liter) and acidified with 3N hydrochloric acid solution to give a solid which was collected by filtration and rinsed with water to give 29 g of crude title compound (76% yield). A 3.5-g portion of the solid was recrystallized twice from isopropyl alcohol/water and dried under high vacuum at 50° C. overnight to give 1.81 g of title compound, mp 225°-227° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:20]([O-])=O)[CH2:3][CH2:2]1.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])[C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCOCC1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1N1CCOCC1

Procedure:
By substituting 4-morpholino-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 297° C (decomp.) after recrystallization from aqueous methanol.
Reaction SMILES: C(NCC)C.C(O)=O.CC1(C)[O:17][C:15](=[O:16])[CH2:14][C:12](=O)O1.C(=O)[C:20]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[CH:21]=1>>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([CH2:12][CH2:14][C:15]([OH:17])=[O:16])[CH:29]=[CH:28][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCNCC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropwise adding 17.55 g (25 ml, 0.24 mol) of diethylamine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:27]([OH:29])=O)[NH2:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:31]>CN(C=O)C>[C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:27]([NH2:31])=[O:29])[NH2:26])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@@H](CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](N)CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of compound 2 (1.49 g, 3.71 mmol) in 10 ml DMF was cooled to −78° C. in a pressure tube. Ammonia gas was bubbled though the solution until approximately 1 ml has added. Ammonium hydroxide solution (12 ml, 185.6 mmol, 50+ equivalents) was then added, and the tube allowed to warm to room temperature. The mixture was then sonicated for 20 minutes and heated to 55° C. while stirring. After 24 hours, the solution was golden in color, after which it was removed from the oil bath and cooled to −78° C. for 5 minutes before removing pressure cap. The solution was then allowed to warm to room temperature, and the solvent removed by reduced pressure distillation. The product was purified by flash column chromatography (Silica Gel, 8% methanol/92% CH2Cl2). and isolated as a clear golden oil (0.987 g. Yield: 68%). 1H NMR (CDCl3, 300 MHz) δ1.3-1.6 (m, 4H), 1.76 (m, 2H), 2.13 (t,2H), 3.33 (t, 1H) 7.14-7.52 (m, 15H) 13C NMR (CDCl3) 75 MHz) δ23.8, 30.9, 35.2, 43.6, 55.3, 71.0, 126.3, 127.9, 128.8, 146.4, 178.3; ESI-MS calculated for C25H29N3O 387.52; found 388.4 [M++1].