Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[H-].[Na+].[C:14](OCC)(=O)[CH2:15][CH2:16][CH3:17].Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:14]([CH2:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCCC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(=O)c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2'-hydroxy-5'-fluoroacetophenone (2 gm) in tetrahydrofuran (10 mL) was added dropwise to sodium hydride (600 mg), then ethyl butyrate (10 mL) was added. After 30 minutes, aqueous 1N HCl (50 mL) was added, and the mixture extracted with ethyl acetate, and the extracts washed with H2O, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (7 mL) added, and after stirring overnight at room temperature, dichloromethane and saturated aqueous NaHCO3 were added, and the layers separated. The organic layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 6-fluoro-2-propyl-4H-1-benzopyran-4-one (2.4 gm, Rf=0.4 1:1 diethyl ether/hexanes). This compound (9 gm) was dissolved in ethanol (250 mL) and sodium borohydride (1.6 gm) added, and the mixture heated under reflux. After 3.5 hours additional sodium borohydride (1.6 gm) added, and after 7 hours a further addition of sodium borohydride (1.6 gm) was made. After 10 hours more sodium borohydride (0.8 gm) was added and after 23 hours total reaction time the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 4-hydroxy-2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one (Rf=0.4 1:1 diethyl ether/hexanes). This material (10.8 gm) was dissolved in acetic acid (45 mL) and a solution of chromium trioxide (7.8 gm) in acetic acid (45 mL)/H2O (10 mL) was added dropwise. After one hour, the mixture was poured into ice/H2O (1L) and extracted with ethyl acetate. The extracts were washed with H2O, saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield the title compound (7.4 g, Rf=0.7, 1:1 diethyl ether/hexanes).
Reaction SMILES: [CH:1]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:2]=1[C:3]1[C:11]([CH:12]=[CH:13]2)=[C:10]([CH:18]=O)[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH3:26][C:21]([NH:20][CH2:18][C:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=[C:3]2[C:11]=1[CH:12]=[CH:13][C:14]1[C:2]2=[CH:1][CH:17]=[CH:16][CH:15]=1)([CH2:24][OH:25])[CH2:22][OH:23]
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccc3ccccc3c2cc2ccsc12
Solvent: CCO
Solvent: CCOCC
Product: CC(CO)(CO)NCc1c2ccc3ccccc3c2cc2ccsc12
Yield: 71.2 %

Procedure:
Using the procedure outlined in Example 1, phenanthro[2,3-b]thiophene-7-carbaldehyde (24A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 71.2% yield of 2-methyl-2-[[(phenanthro[2,3-b]thiophen-7-yl)methyl]amino]-1,3-propanediol methanesulsonate, mp 212°-215° (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:14][CH2:15]Br.[H-].[Na+]>CS(C)=O.CCOCC.CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 2-(3-nitrophenyl)acetonitrile (2.5 g, 15.42 mmol) and 1,2-dibromoethane (1.329 ml, 15.42 mmol) in DMSO/Et2O (1:1, 10 ml) was added dropwise to a suspension of NaH (1.233 g, 30.8 mmol) in DMSO (Volume: 10 ml, Ratio: 1.000), keeping the temperature at 0° C. Resulting mixture was stirred at ambient temperature for 24 h under N2 atm. The reaction mixture was quenched by addition of IPA (2 ml) and water; partitioned between water (300 ml) and EtOAc (300 ml). The aq. phase was re-extracted with EtOAc (300 ml). Combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.799 g, 9.56 mmol).
Reaction SMILES: [F:1][CH:2]([F:6])[CH2:3][NH:4][CH3:5].Cl.CCN(C(C)C)C(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2F)=[CH:20][C:19]=1[Cl:39]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2[N:4]([CH3:5])[CH2:3][CH:2]([F:6])[F:1])=[CH:20][C:19]=1[Cl:39]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: CNCC(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(N(C)CC(F)F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(2,2-difluoroethyl)-N-methyl-amine×HCl (64 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for two weeks at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, dried with Na2SO4 and concentrated and directly used in the next step.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:27]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C)c(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1c2cc(C)c(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:40])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH2:22][C:21]2[CH:20]=[C:19]([CH:39]=[CH:38][CH:37]=2)[O:18][CH2:17][C:16]([O:15][CH3:14])=[O:40])[C:24]([CH3:36])=[C:25]3[CH3:35])=[O:33])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][NH2:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1.C(N(CC)CC)C.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[O:16][C:32](=[O:33])[NH:18][N:17]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazide (150 mg, 0.44 mmol) was suspended in tetrahydrofuran (5.0 mL) and triethylamine (0.12 mL, 0.88 mmol) was added. N,N-Carbonyldiimidazole (108 mg, 0.66 mmol) was added and the whole stirred at room temperature for 1 h. No reaction was observed. The whole was sealed and heat at 80° C. for 2 h. More N,N-carbonyldiimidazole (150 mg, 0.92 mmol) was added and the whole heated at 85° C. for 10 min. LCMS indicated clean conversion to the desired product. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate. Concentration gave 125 mg colorless solid. A small amount was purified by reverse phase HPLC to give 266 as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br s, 1H), 7.70-7.00 (overlapping m, 4H), 4.23 (t, 2H), 3.21 (t, 2H). MS: (ESI+) 367.0
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N([N+:16]([O-:18])=[O:17])CN([N+]([O-])=O)CN1[N+]([O-])=O.C(O[N+]([O-])=O)C(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O>>[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: O=[N+]([O-])N1CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Agent: O=[N+]([O-])OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Product: CN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Considering the electrophilic nature of the NOx species generated by the photofragmentation of RDX and PETN and their resemblance to the active electrophiles in aromatic nitration reactions, reactions between electron-rich tertiary aromatic amines and the photofragments of RDX and PETN were selected. It was found that photolysis (λ=313 nm) of a mixture of N,N-dimethylaniline (DMA) and 2 equivalents of either RDX or PETN for 10 minutes in acetonitrile under anaerobic conditions afforded the formation of N,N-dimethyl-4-nitroaniline (DMNA) in 14% yield (GC yield). Higher yields of DMNA were obtained with longer photolysis times and DMNA was formed in ca. 80% yield after 1 hour. The photoreaction between DMA and either RDX or PETN under anaerobic conditions was observed to produce only a single, yellow-colored product (DMNA) and other side products were not evident by TLC or GC-MS analyses. The 1H-NMR, IR and high-resolution mass spectra of the isolated yellow product matched those obtained for an authentic commercial sample of DMNA. Conducting the photolysis under aerobic conditions resulted in partial demethylation of DMA and yielded a mixture of DMNA and its demethylated analog, N-methyl-4-nitroaniline (13) (see Scheme 1). Photolysis of DMA with ammonium nitrate was also found to produce DMNA, although relatively longer photolysis times (>30 minutes) were required and greater amounts of demethylated side products were observed (possibly due to the presence of water or other nucleophiles in the solutions).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17](O)[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O=P(Cl)(Cl)[Cl:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([Cl:28])[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nnc(O)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Product: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-ol (4.18 mmol, 1.7 g) in POCl3 (20 mL) was kept stirring at 70° C. for 2 h. The reaction mixture was concentrated, to the residue water was added, extracted with ethyl acetate washed with sat NaHCO3 solution, water, brine, dried and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography using a mixture of hexanes in ethyl acetate (9:1) to provide 4-(3-bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[N:21]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][CH2:25][C:23]1[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=1)=[O:7]
Reactant: Cn1cc(CN)cn1
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2cnn(C)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a 100 mL round bottom flask containing 3-bromo-4-methoxybenzoic acid (500 mg, 2.16 mmol) and DCM (5 mL) was added oxalyl chloride (0.23 mL, 2.60 mmol) and DMF (0.1 mL, 0.13 mmol). The reaction mixture was stirred at RT for one hour and concentrated in vacuo. The resulting colorless oil was taken up in DCM (2.5 mL) and added to a mixture of (1-methyl-1H-pyrazol-4-yl)methanamine (241 mg, 2.16 mmol), TEA (0.60 mL, 4.33 mmol) and DCM (2.5 mL) at 0° C. The reaction mixture was stirred at RT for 0.5 hours then concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% MeOH in DCM) to afford 3-bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (702 mg) MS [M+H+]=325.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1c(=O)sc2cnc(N)nc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 88 (0.22 g, 0.44 mmol) in THF (5 mL) in a plastic vial was added HF/pyridine (0.70 mL). The reaction was stirred for 2 h, concentrated and purified by flash column chromatography (silica, MeOH/CHCl3: gradient=5-10%) to afford 0.17 g (100%) of the title compound as a white solid: mp 109-111° C.; 1H (400 MHz, d6-DMSO) δ 8.37 (s, 1H), 6.91 (s, 2H), 6.00 (m, 2H), 5.48 (t, J=6.0 Hz, 1H), 4.91 (t, J=6.0 Hz, 1H), 4.04 (dd, J=10.4, 6.0 Hz, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ m/z 385.3. Elemental Analysis calc'd for C14H16N4O7S.0.5 CH3OH.0.2 CHCl3: C, 41.61; H, 4.32; N, 13.21; S 7.56. Found: C, 41.73; H, 4.29; N, 12.86; S, 7.33.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:37]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])=[O:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 529.8.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: Nc1cccnc1N
Product: N#CCc1nc2cccnc2[nH]1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.5 eq) and 2,3-diaminopyridine (1 eq) were heated at 185° C. for 30 minutes. The reaction mixture was cooled to room temperature and the black solid was triturated with ether. The desired product was thus obtained as a dark brown powder. LC/MS m/z 159.1 (MH+), Rf 0.44 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH2:80])=[CH:78][CH:77]=1>CN(C=O)C>[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH:80][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:29])=[CH:78][CH:77]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 4-methoxyaniline (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with DCM/ethanol/ammonia (400:8:1 then 300:8:1), which, after evaporation of the solvents under vacuum, gave N-{4′[(4-methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (16 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4N(CC(F)(F)F)N=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.[NH:44]([CH2:46][CH:47]([OH:49])[CH3:48])[NH2:45]>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:44]([CH2:46][CH:47]([OH:49])[CH3:48])[N:45]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CC(O)CNN
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with 1-hydrazino-propan-2-ol to give 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol. MS (ESI+) 407.0/409.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14](Cl)[C:13]3=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][N:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13]3=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][N:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc2c(Cl)nc(-c3ccc([N+](=O)[O-])cc3)nn2c1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(N3CCOCC3)nc(-c3ccc([N+](=O)[O-])cc3)nn2c1

Procedure:
Compound 8 (4.6 g, 13.8 mmol) was suspended in 150 mL of tetrahydrofuran, 3.6 mL of morpholine was added dropwise and reacted for 5 hours at room temperature. 3.9 g of solid was obtained by filteration, and the filtrate was separated through a column chromatography with dichloromethane to give 1.1 g of yellow compound 9a (94.3%). m.p. 296-300° C. 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J=8.7 Hz, 2H), 8.29 (d, J=8.7 Hz, 2H), 8.14 (d, J=1.3 Hz, 1H), 7.23 (d, J=1.3 Hz, 1H), 4.17 (t, J=4.8 Hz, 4H), 3.91 (t, J=4.8 Hz, 7H). LC-MS: 384 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:24][CH2:25]4)=[CH:13][C:14]([CH:21]=[O:30])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1cc(C2CC2)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-vinylbenzoate (0.22 g) in a mixed solvent of acetone (4.40 ml)-acetonitrile (4.40 mL)-water (4.40 mL) were added osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.65 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.22 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][CH:4]=[O:5].[OH-:14].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][C:4]([OH:14])=[O:5]
Reactant: [OH-]
Reactant: CC(C=Cc1ccccc1)=CC=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C=Cc1ccccc1)=CC(=O)O
Reaction time: 5 h
Yield: 14.7 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-2,4-pentadienal (16.5 g) in ethanol (330 mL) was added dropwise a solution of silver nitrate (19.28 g) in water (160 mL) followed by dropwise addition of an aqueous sodium hydroxide (25 g, 80 mL) solution. The resulting mixture was allowed to stir for an additional five hours and then filtered. The solid was washed with ethanol. The combined filtrate was concentrated in vacuum. The residue was dissolved in water (200 mL). The aqueous solution was extracted with ether (300 mL) twice and acidified with 6 N hydrochloric acid (74 mL). The solid formed was filtered and recrystallized from methanol (40 mL) to yield 2.65 g of the desired 3-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.60 (d, 2H), 7.35 (m, 3H), 7.06 (m, 2H), 6.02 (broad s, 1H), 2.50 (s, 3H).