Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].CCN(CC)CC.[F:18][C:19]1([F:34])[O:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]3([C:31](Cl)=[O:32])[CH2:30][CH2:29]3)=[CH:27][C:21]=2[O:20]1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:31]([C:28]2([C:26]3[CH:25]=[CH:24][C:22]4[O:23][C:19]([F:34])([F:18])[O:20][C:21]=4[CH:27]=3)[CH2:30][CH2:29]2)=[O:32])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COc1ccc(N)nc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 6-bromo-5-methoxypyridin-2-amine (510 mg, 2.5 mmol) and Et3N (690 L, 4.9 mmol) in dichloromethane (10 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (650 mg, 2.5 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N HCl (1×20 mL) and saturated aqueous NaHCO3 (1×20 mL). The organics were dried over sodium sulfate and evaporated to yield the product (850 mg, 81%). ESI-MS m/z calc. 426.0. found 427.3 (M+1)+. Retention time 2.05 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17]([C:29]#[C:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17]([CH2:29][CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: C#Cc1ccccc1
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-5-methyl-8-phenylethynyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.33 g) was prepared from 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and phenylacetylene by a procedure analogous to that described in Example 42a. Hydrogenation as described in Example 42b afforded 0.18 g of the title compound as white needles, m.p. 128°-129.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:23]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-:25].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>>[ClH:25].[CH3:28][NH:29][CH2:23][C:3]1[C:2]([CH3:1])=[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH:4]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)cc1
Reactant: [Cl-]
Agent: C[NH3+]
Agent: [Na+]
Product: CNCc1cn(S(=O)(=O)c2ccc(C)cc2)c(-c2ccccc2)c1C
Product: Cl
Yield: 50.1 %

Procedure:
Using 4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (310 mg), methylammonium chloride (617 mg) and sodium cyanoborohydride (172 mg), a procedure as in Example 4 was performed to give the title compound as colorless crystals (yield 179 mg, 50%).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])([OH:3])=O.Cl.[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])=[O:3]
Reactant: CNC
Reactant: CN(CC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN(CC(=O)N(C)C)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[(N-carboxymethyl-N-methyl-amino)-methyl]-nitrobenzene and dimethylamine hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH:14]=[C:15]2[O:19][CH2:18][O:17][C:16]=12)C=O.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([OH:28])[CH:14]=[C:15]2[O:19][CH2:18][O:17][C:16]=12
Reactant: COc1ccccc1-c1cc(C=O)cc2c1OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccccc1-c1cc(O)cc2c1OCO2
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A solution of 3-(2-methoxyphenyl)-4,5-methylenedioxybenzaldehyde (0.850 g, 3.32 mmol), m-chloroperbenzoic acid (1.431 g, 8.29 mmol) in CH2Cl2 (25 mL) was heated to reflux overnight. The resulting orange mixture was evaporated, dissolved into MeOH (15 mL) and 2.5 M NaOH (6 mL) and stirred for 45 minutes. The dark mixture was diluted with ethyl acetate and acidified with 1.0 N HCl. The layers were separated and the organics washed successively with water, 0.5 M NaHCO3, water, brine and dried (MgSO4). The mixture was filtered, evaporated and the residue was purified on silica gel (hexane:ethyl acetate 4:1) to give 0.55 g of 3-(2-methoxyphenyl)-4,5-methylenedioxyphenol (68%) as a tan solid, 1H NMR (500 MHz; CDCl3): δ 3.82 (s, 3H); 5.91 (s, 2H); 6.40–6.45 (m, 2H); 6.99 (d, J=9.0 Hz, 1H); 7.02 (d, J=7.0 Hz, 1H); 7.40–7.30 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([Mg]Br)[CH3:17]>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: Cc1c(Br)cccc1C1=NC(C)(C)CO1
Reactant: CC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCc1cccc(C2=NC(C)(C)CO2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-bromo-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (3.4 g, 12.7 mmol) was dissolved in 30 mL of ethyl ether under nitrogen atmosphere in a 100 mL round bottom flask equipped with magnetic stirring, thermometer, and reflux condenser. Ni(dppp)Cl2 (100 mg) was added and the mixture was cooled to 0° C. in an ice bath. Ethyl magnesium bromide (5.5 mL, 3M in ether) was added, the reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 2½ hours, and finally at reflux for 2 hours. The mixture was then cooled to 0° C., quenched with saturated aqueous NH4Cl. The organic layer was removed and the aqueous layer was extracted with ether. The organic phases were combined and dried over MgSO4. The solvent was removed in vacuo to give 2.84 g 2-(3-ethyl-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole, 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.5 (d, 2H), 7.2 (m, 2H), 4.1 (s, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 1.4 (s, 6H), 1.2 (t, 3H), Rf=0.25 (4:1 hexane:ether), containing ca. 5% original aryl bromide. The oxazoline was suspended in 100 mL of 6N HCl and refluxed for 5 hours with vigorous stirring. The mixture was allowed to cool to room temperature, whereupon 3-ethyl-2-methyl-benzoic acid crystallized: 1.74 g, m.p. 96-98° C., 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.85 (d, 1H), 7.4 (d, 1H), 7.22 (t, 1H), 2.7 (q, 2H), 2.6 (s, 3H), 1.21 (t, 3H). An additional 110 mg was recovered by ether extraction of the aqueous phase.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([C:25]2[C:26]([N:36]3[CH2:37][CH2:38][CH2:39][O:33][CH2:34][CH2:35]3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:32])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: C1CNCCOC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5F)ccc(F)c43)ccc21
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5N5CCCOCC5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and [1,4]oxazepane following a procedure analogous to that described for Example 128. LC (method 9): tR=0.87 min; Mass spectrum (ESI+): m/z=505 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:28]/[C:29](/[CH3:54])=[CH:30]/[CH2:31][CH2:32][C:33]1([CH3:53])[CH2:38][CH2:37][C:36]2[CH:39]=[C:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]=2[O:34]1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:52][C:49]([Si:46]([CH3:47])([CH3:48])[O:45][C:40]1[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]2[O:34][C:33]([CH2:32][CH2:31][CH:30]=[C:29]([CH3:28])[CH2:54][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)([CH3:53])[CH2:38][CH2:37][C:36]=2[CH:39]=1)([CH3:50])[CH3:51]
Reactant: C/C(=C\CCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CCl
Reactant: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(=CCCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CC(c1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h

Procedure:
4-Methyl-1-[[[3-(trifluoromethyl)phenyl]methyl]sulfonyl]benzene (30 mmole) was dissolved in 100 mL of dry THF. The mixture was cooled to about -78° under nitrogen, and n-butyllithium (30 mmole) was added dropwise giving rise to a colored anion [yellowish-orange]. The solution was stirred for about 1 hour at about -78° before the addition of HMPA (5 mL) and [2-(5-chloro-4-methyl-3(E)-pentenyl)]-3,4-dihydro-6-[(1,1- dimethylethyl)dimethyl silyloxy]-2,7,8-trimethyl-2H-1-benzopyran (25 mmole). The mixture was stirred for about 1 hour at about -78°, then warmed to about -5° for about 12 hours, and poured into 1N HCl. The mixture was extracted with fresh ether. The combined organic fractions were washed With water and dried (brine, MgSO4). Concentration in vacuo gave a crude material that was purified by flash chromatography (gradient 10:1 to 2:1 hexanes:ether) to give the coupled product as colorless oil: IR (film) 2930, 1472, 1450, 1424, 1330, 1166, 1146, 1130, 1088 cm-1 ; 1H NMR (CDCl3) δ 0.16 (s, 6H), 1.00 (s, 9H), 1.09, 1.10 (s, 3H), 1.28 (m, 2H), 1.41, 1.39 (s, 3H), 1.60 (m, 2H), 1.91 (m, 2H), 2.02 (s, 3H), 2.07 (s, 3H), 2.39 (s, 3H), 2.56 (m, 2H), 2.74 (t, J=13.9 Hz, 1H), 3.09 (d, J=11.9 Hz, 1H), 4.22 (d of t, J=12.1, 4.0 Hz, 1H), 5.06 (m, 1H), 6.30 (s, 1H), 7.10 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.36 (m, 4H), 7.48 (d, J=6.5 Hz, 1H); MS m/e 701 (MH+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[C:6]([C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCCCCCCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(C(=O)OCCCCCCC)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Heptyl 4-[(trimethylsilyl)ethynyl]benzoate (3a) (10.4 g, 32.8 mmol) was dissolved in tetrahydrofuran/methanol (3/1, v/v) (400 mL), potassium carbonate (1.00 g, 7.24 mmol) was added, and the mixture was stirred at −10° C. for 1 hr. The reaction solvent was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:25) to give heptyl 4-ethynylbenzoate (4a) (6.58 g, yield 82%) as an oily liquid.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:19])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1.[N-:20]=[N+]=[N-].[Na+]>CO>[CH3:6][O:7][C:8]1[C:9](=[O:19])[NH:20][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: COC1=CC(=O)C2=C(CCCC2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c([nH]c1=O)CCCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (10 mL, Baker), there was added 2-methoxy-5,6,7,8-tetrahydronaphthalene-1,4-dione (600 mg, 3.12 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (406 mg, 6.24 mmol, Aldrich) was added in portions. The reaction was allowed to slowly attain rt with stirring under N2. Gas evolution was noted. After 16 h, the reaction was judged complete by TLC analysis (10% MeOH/90% CHCl3). The reaction was added to crushed ice (100 mL) to give a yellow/brown solution. This was extracted with 30% MeOH/70% CHCl3 (4×30 mL) and CHCl3 (2×30 mL). The extract was washed with water (1×20 mL), saturated NaHCO3 (1×20 mL) and brine (1×20 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (280 mg). An additional portion was obtained in exactly the same manner (350 mg). The combined solids were subjected to vacuum chromatography (silica gel, 2.5×25 cm, initial CHCl3 elution to remove mobile impurities, 2% EtOH/98% CHCl3 elution to remove product) to yield a pink solid. Crystallization from 95% EtOH (dissolved in 20 mL, hot filtered, concd to 8 mL, allowed to cool to rt) yielded a pink solid (242 mg, 19%, >95% pure by 1H NMR, mp 227.5°-228.5° C.). A sample was further purified by recrystallization from 95% EtOH (25 mg dissolved in 2 mL, allowed to cool to rt, yielded a pale pink solid, 14 mg, 56% recovery); mp 228.5°-229.5° C.;
Reaction SMILES: Cl.Cl.[CH:3]12[CH2:14][CH:10]([CH2:11][NH:12][CH2:13]1)[C:9]1[CH:8]=[CH:7][C:6]([NH:15][C:16]3[N:21]=[C:20]([NH:22][CH:23]4[CH2:25][CH2:24]4)[C:19]([C:26]([F:29])([F:28])[F:27])=[CH:18][N:17]=3)=[CH:5][C:4]2=1.CC[N:32]([CH:36]([CH3:38])C)[CH:33]([CH3:35])C.O.[CH3:40]S(C)=O>>[CH:23]1([NH:22][C:20]2[C:19]([C:26]([F:28])([F:29])[F:27])=[CH:18][N:17]=[C:16]([NH:15][C:6]3[CH:7]=[CH:8][C:9]4[CH:10]5[CH2:14][CH:3]([CH2:13][N:12]([C:36]6[CH:38]=[CH:40][CH:35]=[CH:33][N:32]=6)[CH2:11]5)[C:4]=4[CH:5]=3)[N:21]=2)[CH2:25][CH2:24]1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cnc(Nc2ccc3c(c2)C2CNCC3C2)nc1NC1CC1
Reactant: CS(C)=O
Agent: Cl
Solvent: O
Product: FC(F)(F)c1cnc(Nc2ccc3c(c2)C2CC3CN(c3ccccn3)C2)nc1NC1CC1
Temperature: 130 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
Compound 13 (290 mg, 645 μmol) was dissolved in DMSO (2 mL) in a 15 mL screw cap pressure tube, and the resultant solution was treated with DIEA (431 μL, 2.48 mmol) and 2-fluoropyride (125 mg, 1.29 mmol). The reaction vessel was sealed and stirred at 130° C. for 14 hours. The reactor contents were cooled to 25° C., poured into H2O (30 mL), and stirred for 1 hour to produce an orange, gummy residue. The H2O was decanted off and the residue purified on silica gel (40% EtOAc/Hexanes) to provide 14 as an off-white powder (143 mg, 49% yield). HPLC Rt 6.57 minutes; LC/MS (Method F) m/z 453.3 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[CH2:42]([O:49][NH:50][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:6][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of 2-cyclopropylamino-5-fluoro-6-pyrrolidinyl-3-pyridinecarboxylic acid (Example G-2, 215 mg, 0.80 mmol) and 1-hydroxybenzotriazole (HOBT) (119 mg, 0.88 mmol) in chloroform (10 mL) was added 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide (EDCI) (169 mg, 0.88 mmol). After being stirred at room temperature for 30 minutes, O-benzylhydroxylamine hydrochloride (141 mg, 0.88 mmol) and triethylamine (0.122 mL, 0.88 mmol) were added. The reaction mixture was heated to reflux for 4 hours, diluted with dichloromethane, washed with water, and dried on sodium sulfate. The residue was purified by flash chromatography on a silica gel column with dichloromethane as eluent giving 155 mg of the title compound as an oil.
Reaction SMILES: [Cl-].CN([NH+]=CCl)C.Cl.[NH2:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:19]/[O:20][CH3:21])/[C:16](Cl)=[O:17])[N:14]=1.[CH2:22]([N:24]([CH2:27]C)[CH2:25]C)C.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1>O1CCCC1.O>[C:32]1([CH2:35][CH2:36][NH:37][C:16](=[O:17])[C:15]([C:13]2[N:14]=[C:10]([N:9]=[CH:27][N:24]([CH3:22])[CH3:25])[S:11][CH:12]=2)=[N:19][O:20][CH3:21])[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: CCN(CC)CC
Reactant: NCCc1ccccc1
Reactant: CO/N=C(\C(=O)Cl)c1csc(N)n1
Agent: CN(C)[NH+]=CCl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Dimethylaminochloromethyleneammonium chloride (430 mg, 3.36 mmol) was dissolved in 15 ml of tetrahydrofuran. Added to the solution were 860 mg (3.36 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride, followed by stirring at room temperature for 1 hour. To the solution so obtained, a solution of 1.02 g (10.1 mmol) of triethylamine and 0.35 g (2.9 mmol) of β-phenethylamine in 4 ml of tetrahydrofuran was added. The mixture so obtained was stirred for 2 hours under ice-cooling and further for 15 hours at room temperature. The reaction mixture was added with 100 ml of water and then extracted three times with 50 ml portions of chloroform. The organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue so obtained was purified by chromatography on a silica gel column, whereby 0.98 g of the title compound was obtained (yield: 95%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:6]=1.NNC(N)=S.ClC1C=CC=CC=1C(Cl)=O.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>CN(C)C=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]2=[N:1][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][N:6]2[N:5]=1
Reactant: Nc1nnc(-c2ccccc2Cl)s1
Reactant: O=C(CBr)c1ccccc1
Agent: NNC(N)=S
Agent: O=C(Cl)c1ccccc1Cl
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nn2cc(-c3ccccc3)nc2s1

Procedure:
10.5 g (0.05 mol) of 2-amino-5-(2-chlorophenyl)-1,3,4-thiadiazole, melting point 189,5° C. (prepared by reacting thiosemicarbazide with 2-chlorobenzoyl chloride) together with 10 g (0.05 mol) of bromoacetophenone are warmed to 120° C. in 100 ml of dimethylformamide for 3 hours and the mixture is then cooled and concentrated in a rotary evaporator. After digesting the residue with water, the digestion mixture is filtered and the residue is recrystallised from alcohol. A second fraction is obtained by concentrating the alcoholic mother liquor. A total yield of 12.5 g, corresponding to 80% of theory, of colourless crystals of melting point 126° C. is obtained.
Reaction SMILES: C(O[C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][NH:22][C:23](=[O:28])[NH:24][N:25]([CH3:27])N)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[O:42]1CCCC[CH:43]1ON>>[CH2:33]([O:40][NH:41][C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:19]([NH:21][N:22]1[C:43](=[O:42])[N:25]([CH3:27])[NH:24][C:23]1=[O:28])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)NN(C)N)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: NOC1CCCCO1
Reactant: NOCc1ccccc1
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]n(C)c1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In an analogous manner to that described in Example 1, parts (vi)-(viii), but using (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-[(1-methylhydrazinyl)carbamoyl]valerohydrazide and O-benzylhydroxylamine in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2 ′-glycinyl-4-methylvalerohydrazide and O-(tetrahydro-2H-pyran-2(RS)-yl)hydroxylamine respectively there was obtained 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)valeramide in the form of a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:11][C:3]([NH2:12])([CH3:2])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C

Procedure:
α,α-Dimethylphenethylamine hydrochloride (20 g, 108 mmol) was dissolved in concentrated sulfuric acid (40 mL). The solution was cooled to −10° C. Nitric acid (31 mL, 90%) was added dropwise over a 30 min period while maintaining a reaction tempurature below −5° C. The solution was stirred an addition 45 min then poured over ice and allowed to warm to room temperature over night. The product was collected via filtration (13.7 g). Aqueous sodium hydroxide(1 N) was added to the filtrate and the title compound was isolated as a clear oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[N:25][CH:26]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 6-(4-fluorophenyl)nicotinic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#N)[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N([O-])=[O:14].[Na+].[OH2:17]>S(=O)(=O)(O)O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:14])=[O:17])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C#N)n1
Reactant: O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 10.9 g (66.8 mmol) of 6-Methyl-4-nitro-pyridine-2-carbonitrile in 60 ml of 90% sulfuric acid was heated at 120° C. for 2 h and then allowed to cool to room temperature. A solution of 12.2 g (69.0 mmol, 2.65 equiv.) of sodium nitrite in 22 ml of water was added dropwise over a period of 30 min maintaining the temperature between 12-15° C. The reaction was stirred for 30 min at room temperature and then for 1 h at 80° C. The solution was allowed to cool to room temperature and poured onto 150 g of crushed ice. After stirring the yellow solution for 10 min, 200 ml of water were added whereby precipitation occurs. The product is filtered, washed with a small amount of water and dried in vaccuo to yield the title compound as a light yellow crystalline solid (11.2 g, 92%), MS (ISP): m/e=183.1 (M+H)+.