Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:22])[CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)C(C)(C)OCc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Yield: 91.5 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 419 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-benzyloxy-2-methylpropionyloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 169, above] and 8.1 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 263 mg of the title compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:3]=1>C(OCC)(=O)C.O=[Pt]=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([Br:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
4-Bromo-2-(4-nitro-phenyl)-2H-phthalazin-1-one (see Method B) (1.0 g, 2.9 mmol) and PtO2 (0.13 g, 0.58 mmol) were dissolved in ethyl acetate (40 ml) at room temperature. The mixture was hydrogenated at ambient pressure for 2 h, before the catalyst was filtered off to yield title compound (0.61 g, 67% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.34 (1H, d), 8.07 (1H, t), 7.99 (2H, t), 7.18 (2H, d), 6.63 (2H, d), 5.35 (2H, s); MS (ESI+)=318.42 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12.C([Li])CCC.CN(C)[CH:25]=[O:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH:25]=[O:26])[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: CN(C)C=O
Reactant: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.1 %

Procedure:
To a solution of 7-chloro-2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (13, scheme 4) (1.50 g, 5.69 mmol) in tetrahydrofuran at −78° C. (1.3 mL) was added n-Butyllithium (3.4 mL, 8.53 mmol) and the reaction mixture was stirred for about 15 minutes. Dimethylformamide (0.66 mL, 8.53 mmol) was added slowly and the reaction mixture was stirred at −78° C. until completion of the reaction. The mixture was warmed to room temperature and quenched with water. The precipitate was removed by filteration, washed with water and dried well. The crude product was purified by trituration with dichloromethane, filtered, washed with additional dichloromethane and dried to afford the title compound 111 as a yellow solid (682 mg, 41% yield). MS (m/z): 291.9 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[F:15][C:16]([F:34])([F:33])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[CH:23][CH:22]=1)=O>>[Cl:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[N:28]=[CH:29][S:30][CH:31]=4)=[CH:25][CH:26]=3)=[CH:18][C:17]([C:16]([F:34])([F:33])[F:15])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)cc1
Reactant: CS(=O)(=O)c1ccc(NN)cc1Cl
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 60 using [3-chloro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride from step 1 of Example 155 instead of [3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride, 4,4,4-trifluoro-1-[4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione from step 3 of Example 82 instead of 4,4,4-trifluorro-1-[4-(2-furyl)phenyl]-1,3-butanedione.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 77.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 187 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (323 mg) was obtained.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:4]([N:9]2[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][C:11](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1>BrCBr>[Br:1][C:11]1[CH2:12][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]([C:4]2[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][N:5]=2)[N:10]=1
Reactant: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)=NN1c1ncccc1Cl
Reactant: Br
Solvent: BrCBr
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Yield: 100 %

Procedure:
Hydrogen bromide was passed through a solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate (i.e. product of Step A) (5 g, 11.8 mmol) in dibromomethane (50 mL). After about 60 minutes the gas flow was terminated, and the reaction mixture was washed with aqueous sodium bicarbonate solution (50 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (3.92 g, 100% yield), which crystallized on standing. The 1H NMR spectrum of the product was the same as reported for the product of Example 1, Step C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[CH3:15]C1C=CC=CC=1C=O>>[CH3:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: Cc1ccccc1C=O
Product: Cc1cccc(-c2ccccc2C)n1

Procedure:
6-(2-methylphenyl)-2-methylpyridine was prepared substantially according to the procedures of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2-methylbenzaldehyde was used to afford 6-(2-methylphenyl)-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17](OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[OH:92][CH2:93][C:94]1[S:98][C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]4/[S:112][C:113]5[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=5[N:115]/4[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:123])([CH3:122])[CH3:121])[CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[N:96][C:95]=1[C:129]([O:131][CH3:132])=[O:130].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:66][CH:67]=2)[O:92][CH2:93][C:94]2[S:98][C:97]([N:99]3[CH2:108][CH2:107][C:106]4[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]5/[S:112][C:113]6[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=6[N:115]/5[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:123])([CH3:122])[CH3:121])[CH:103]=[CH:104][CH:105]=4)[CH2:100]3)=[N:96][C:95]=2[C:129]([O:131][CH3:132])=[O:130])[C:3]=1[C:68]#[N:69]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1COc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
The title compound (46A) was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 45D and compound 36A, respectively, in step 1 of Example 35: LCMS (ESI(+)): m/z 892 (M+NH4—H2O).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CCO>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:16])[NH:18][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Yield: 102.8 %

Procedure:
A solution of 3-benzoylthiophene-2-carboxylic acid (0.497 g, 2.14 mmol) (Alfa Aesar) and hydrazine hydrate (0.50 mL, 8.8 mmol) in EtOH (6 mL) was stirred at 85° C. for 4 hours, concentrated, and azeotroped with toluene to give the title compound (0.50 g, 2.2 mmol) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.69-7.75 (m, 2H), 7.51-7.59 (m, 4H).
Reaction SMILES: [C:1]([CH:4]1[N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:8][CH2:7][N:6]([C:23]([C@@H:25]2[CH2:29][C@H:28]([S:30][C:31]3[C@H:32]([CH3:55])[C@@H:33]4[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]4[C:35]=3[C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[CH2:27][N:26]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:24])[CH2:5]1)(=[O:3])[NH2:2].[ClH:69]>O1CCCC1.O>[ClH:69].[C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:23]([C@@H:25]2[CH2:29][C@H:28]([S:30][C:31]3[C@H:32]([CH3:55])[C@@H:33]4[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]4[C:35]=3[C:36]([OH:38])=[O:37])[CH2:27][NH:26]2)=[O:24])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C(N)=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C(N)=O)C4)C3)[C@H](C)[C@H]12

Procedure:
2.33 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-carbamoyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 25 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 2.7 ml of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 2.33 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 160 mg of the title compound, as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4](=[O:30])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Yield: 53.3 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl }-acetic acid ethyl ester (prepared as in Example 23, 160 mg, 0.37 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 68 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (82.3 mg, 53.3%) as a pale yellow oil: FAB-HRMS m/e calcd for C20H23N3O5S (M+H)+ 418.1436, found 418.1424.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.[OH-].[Na+]>[CH2:21]([O:28][C:29]([NH:4][C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)=[NH:3])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCCOc1ccc(C(=N)N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCOc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 5-(4-amidinophenoxy)valerate hydrochloride (14.6 g) in a mixture of tetrahydrofuran (150 ml) and 1N sodium hydroxide solution was added benzyloxycarbonyl chloride (10.4 ml) under cooling with ice-water for 1 hour. The mixture was stirred for 2 hours at 10° C. maintaining pH≈10 with 1N sodium hydroxide solution. The reaction mixture was poured into ethyl acetate (300 ml), and separated organic layer was washed with aqueous solution of sodium chloride, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give ethyl 5-[4-(N-benzyloxycarbonylamidino)phenoxy]valerate (171.48 g).
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][O:6][C:5]([C:15]([O:17]CC)=O)=[CH:4]1>C(O)C>[O:2]=[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][O:6][C:5]([C:15]([NH2:1])=[O:17])=[CH:4]1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c(-c2ccccc2)co1
Solvent: CCO
Product: NC(=O)c1cc(=O)c(-c2ccccc2)co1
Reaction time: 0.5 h

Procedure:
Concentrated ammonia solution (40 ml) was added to a stirred suspension of ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate (4.8 g) in ethanol (40 ml) at 10°-15° C. The mixture was then stirred for 30 minutes at 10°-15° C. Then the solid product was recrystallised from dimethylformamide-ethanol to give 4-oxo-5-phenyl-4H-pyran-2-carboxamide (mp 245°-248° with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:17](Cl)(=O)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[C:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:17](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:1][C:2]=2[CH:14]=1)#[N:16]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: N#Cc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: N#Cc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
(E)-5-Cyano-1-(2-pyridyl)-2-styryl-1H-benzimidazole was prepared from 2-amino-4-cyano-N-(2-pyridyl)aniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:13]([CH:14]=[CH:15][CH:16]=1)=[C:12]1[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]1)=[N:6][C:5]=2[CH3:17].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][C:51]=1[CH3:60]>O1CCCC1.ClCCl>[CH:16]1[CH:15]=[CH:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=1.[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH:5]([CH3:17])[N:6]([S:56]([C:53]1[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[C:51]([CH3:60])[CH:52]=1)(=[O:58])=[O:57])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: COc1cccc2c1c(C)nc1ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cccc(OC)c3C2C)cc1C

Procedure:
The intermediate dihydrophenanthridine was prepared from 7-methoxy-6-methylphenanthridine, (Example 36, Step b, 0.61 g, 2.7 mmol), by treatment with sodium borohydride (0.62 g, 16 mmol) and trifluoroacetic acid (0.84 mL, 10.8 mmol) in tetrahydrofuran (12 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (0.85 mL, 6.1 mmol) and 4-methoxy-3-methylbenzenesulfonyl chloride (0.67 g, 3.0 mmol, 2 equivalents) in dichloromethane (3 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), to yield 7-methoxy-5-[(4-methoxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine as a homogeneous, white solid (0.21 g, 34% from the dihydrophenanthridine);
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CCc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (837 mg, 2.0 mmol, prepared in Synthetic Example 10) in DMF (20 ml) was added hydrazine monohydrate (80%, 350 μl, 8.74 mmol, 4.4 eq.), and the mixture was then stirred at 100 to 110° C. overnight. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (790 mg, 95%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][C:48]=1[N+:54]([O-:56])=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:51][C:50]1[CH:52]=[CH:53][C:47]([CH3:46])=[C:48]([N+:54]([O-:56])=[O:55])[CH:49]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 63.3 %

Procedure:
3-(2-cyanopropan-2-yl)benzoic acid 3 (25 g, 132 mmol), TBTU (63 g, 98 mmol), DIPEA (396 mmol, 65.4 mL) and 4-methyl-3-nitroaniline (20.1 g, 132 mmol) were dissolved in DMF (500 mL) and stirred for 72 h. The reaction mixture was poured into citric acid solution (3%) and extracted twice with EtOAc. The combined organic layers were washed with water (5×), brine (2×), dried, and evaporated. Purification by chromatography (CH2Cl2) gave 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-nitrophenyl)benzamide 4 (27 g, 63%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.60 (s, 3H), (d, J=8.5 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.73 (m, 1H), 7.80 (m, 1H), 7.90 (m, 1H), 7.99 (m, 1H), 8.06 (br s, 1H), 8.28 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:3][C:4]=1[CH3:10]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: COc1ccc(Br)cc1C
Product: COc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-methoxy-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 311.3 [M+H]+) was prepared from 4-bromo-2-methyl-anisole instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([CH:17]([F:19])[F:18])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1>[F:19][CH:17]([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[C:15]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(-c2noc(C(F)F)c2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)F
Reaction time: 20 h
Yield: 99.8 %

Procedure:
A solution of 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid ethyl ester (Preparative Example 25, 1.0 g, 3.48 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (292 mg, 6.96 mmol) and allowed to stir for 20 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution to a pH of −2 and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (900 mg, 99%). 1H NMR (DMSO-d6) 2.29 (s, 3 H), 7.44 (t, J=51.9, 1 H), 7.66 (d, J=2.6, 1 H), 7.78 (d, J=2.6, 1 H). 13C NMR 7.7, 108.1 (t, J=236), 115.0, 130.3, 134.3, 134.5, 137.4, 157.8, 159.6 (t, J=26), 163.1. 19F NMR −118.8 (J=51.5). LC/MS 5.41 min, [M+1]+ 260.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([OH:18])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:28](OS(C(F)(F)F)(=O)=O)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)Cl.CCOC(C)=O>[CH2:11]([O:10][CH2:9][CH:8]([O:18][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(O)COCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CC(COCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl-4-(benzyloxy)-3-hydroxybutanoate XXXV [Tetrahedron (1993), 49(10), 1997-2010] (2.3 g, 8.84 mmol) in DCM (100 mL) at 0° C. was added 2,6-lutidine (3.07 mL, 26.52 mmol) and TBSOTf (4 mL, 4. 17.68 mmol). After stirring for 16 h at 0° C., the reaction was diluted with EtOAc (400 mL). The mixture was washed with 1N HCl, saturated aq NaHCO3, water and dried. The extract was dried (MgSO4) and concentrated under reduced pressure. Purification of the crude product by column chromatography (100% hexane→25% EtOAc/hexane) afforded tert-butyl 4-(benzyloxy)-3-(tert-butyldimethylsilyloxy)butanoate XXXVI (3.1 g, 8.15 mmol, 92.1% yield) as a colorless oil.