Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:36][CH:35]=3)=[CH:3][C:4]=2[F:28])=[CH:9][CH:10]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Sc3ccc(C(F)(F)F)cc3)cc2F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 4-(trifluoromethyl)benzenethiol (89 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 7 hr under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and Xantphos (14.9 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (25 mg) as white crystals.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:20][CH2:19][CH2:18][N:17]3[C:13](=[N:14][C:15]([C:21]4[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=4)=[CH:16]3)[C:12]=2[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]([N:22]1[C:21]([C:15]2[N:14]=[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:30])=[O:5])=[CH:29][C:12]=43)[CH:16]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)OC(C)(C)C)ccc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid tert-butyl ester (930 mg, 2.27 mmol) in DCM (20 mL) was added TFA (10 mL) and the resulting mixture stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was found to be acid and the corresponding methyl ester so was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid as a white solid (164 mg, 21%). LCMS: RT 2.65 min [M+H]+ 354.3
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][C:7]=1[CH3:8]>[Pt]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: CC1=C(C)CC(C(=O)O)CC1
Agent: [Pt]
Product: Cc1ccc(C(=O)c2ccc(C)c(C)c2)cc1C
Yield: 60 %

Procedure:
A more complete dehydrogenation of a crude product mixture of the ketonic decarboxylative coupling of 3,4-dimethyl-3-cyclohexene carboxylic acid was accomplished by passing the crude product mixture over a 0.5 wt % platinum on alumina catalyst at a temperature of 385° C. This resulted in a 60 to 75% yield of 3,3',4,4'-tetramethylbenzophenone. The 3,4-dimethyl-3-cyclohexene carboxylic acid had been contacted with a 19 wt % MnO2 /Al2O3 catalyst at a temperature of about 360° C. and a pressure of about 15 psia for a contact time of about 7 sec.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O.Br[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[N:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:19]=[CH:18][C:17]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]([F:32])[CH:10]=1.[CH3:33][O:34][C:35]1[C:40](B(O)O)=[C:39]([CH3:44])[CH:38]=[C:37]([CH3:45])[N:36]=1>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O1CCOCC1>[F:32][C:11]1[CH:10]=[C:9]([C:40]2[C:35]([O:34][CH3:33])=[N:36][C:37]([CH3:45])=[CH:38][C:39]=2[CH3:44])[C:14]([F:15])=[CH:13][C:12]=1[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:19]=[CH:18][C:17]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1nc(C)cc(C)c1B(O)O
Reactant: CCOC(=O)c1cnn(C2CCOCC2)c1-c1cc(F)c(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C2CCOCC2)c1-c1cc(F)c(-c2c(C)cc(C)nc2OC)cc1F
Temperature: 110 °C
Reaction time: 6 h

Procedure:
Pd(PPh3)4 (50 mg), cesium carbonate (282 mg) and water (0.5 mL) were added to a mixed solution of ethyl 5-(4-bromo-2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 10 (180 mg), (2-methoxy-4,6-dimethylpyridin-3-yl)boronic acid obtained in Preparation Example 27 (90 mg) and 1,4-dioxane (2 mL), and the mixture was stirred at 110° C. for six hours. After cooling the reaction mixture to room temperature, ethyl acetate and brine were added, and the mixture was filtered through a cotton plug. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/n-heptane, 25% to 46% to 53%) to give the title compound (157 mg).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].Cl.[C:47]([N:49]=[C:50]([NH2:52])[NH2:51])#N.C(=O)([O-])O.[Na+]>O>[NH:49]([C:47]1[NH:1][C:2]2[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])=[CH:41][CH:42]=[CH:43][C:44]=2[N:45]=1)[C:50]([NH2:52])=[NH:51]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: N#CN=C(N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nc(NC(=N)N)[nH]c12
Yield: 45.1 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in water (5 ml) was added 1 N hydrochloric acid (1.3 ml) and then dicyandiamide (545 mg) was added to the stirred reaction mixture. The solution was heated under reflux for 24 hours. After cooling, aqueous sodium hydrogen carbonate was added to the mixture and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (SiO2, 30 g, 15% methanol in chloroform) to give 4-[2-guanidinobenzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) as yellow amorphous.
Reaction SMILES: [SH:1][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.ClOC(C)(C)C.[Cl:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][S:1][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)C1=CCOC[C@H]1S
Reactant: Nc1ccc(F)cc1Cl
Agent: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=CCOC[C@H]1SNc1ccc(F)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution (400 mL) of ethyl (3S)-3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (14.5 g) in dichloromethane was added dropwise tert-butyl hypochlorite (10 mL) at −78° C. After stirring for 30 min, 2-chloro-4-fluoroaniline (23 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 hr, and the reaction was discontinued with 5% aqueous sodium sulfite solution (300 mL). After extraction with dichloromethane (300 mL), the extract was washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=15:1→5:1) to give the title compound as a crude product (20.0 g, 96.3% ee). This product was crystallized from diisopropyl ether/hexane (120 mL, 1:5) to give the title compound (12.3 g, 62%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:14]3[N:15]=[C:16]([S:27][CH3:28])[C:17]([N:18]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:19][CH:20]4[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.C([Sn]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:20]1([CH2:19][N:18]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:17]2[C:16]([S:27][CH3:28])=[N:15][N:14]3[C:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([C:44]5[S:45][CH:46]=[CH:47][N:48]=5)=[CH:3][C:4]=4[O:29][CH3:30])=[CH:10][CH:11]=[CH:12][C:13]=23)[CH2:22][CH2:21]1
Reactant: COc1cc(Br)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nccs2)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
After dissolving N-[7-(4-bromo-2-methoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (45 mg) in toluene (0.60 mL), tributylstannylthiazole (52 mg) and tetrakis (triphenylphosphine)palladium(0) complex (9 mg) were added, the mixture was heated and stirred at 120° C. for 2 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to obtain the title compound (30 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:24]([O:26][CH:27]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28])=[O:25])=[C:12]([CH2:16][S:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH2:13][S:14](=O)[C@H:9]12)=[O:6].C(Cl)(=O)C.O.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:24]([O:26][CH:27]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28])=[O:25])=[C:12]([CH2:16][S:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CCOC(=O)OC(C)OC(=O)C1=C(CSc2nc(C)ns2)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC)c3cscn3)C(=O)N12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCOC(=O)OC(C)OC(=O)C1=C(CSc2nc(C)ns2)CS[C@@H]2C(NC(=O)/C(=N\OC)c3cscn3)C(=O)N12
Yield: 31.8 %

Procedure:
Stannous chloride dihydrate (84.6 mg) was added to a solution of 1-ethoxycarbonyloxyethyl 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (96.6 mg) in dimethylformamide (2 ml), and then acetyl chloride (0.38 ml) was added dropwise to the mixture with stirring while cooling with ice. After further stirring in 20° C. for 15 min, the reaction mixture was poured into a mixture of water (20 ml) and ethyl acetate (15 ml). The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate (15 ml). The whole ethyl acetate layer combined was dried over MgSO4, concentrated in vacuo, and the residue was added to petroleum ether (30 ml). The resulting crystals were filtered, washed with petroleum ether, and dried in vacuo to give the title compound (30 mg). ##STR24##
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][CH:13]3[CH:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[O:21][CH2:22][C:23](O)=[O:24]>>[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][CH:13]3[CH:9]([CH:10]([C:23](=[O:24])[CH2:22][O:21][C:20]4[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=4[O:18][CH3:17])[NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c1CCC1CNCC21
Reactant: COc1ccccc1OCC(=O)O
Agent: Cl
Product: COc1ccccc1OCC(=O)C1NCC2CCc3c(OC)cccc3C21
Yield: 86 %

Procedure:
Using the procedure described in example 14, but starting with the product of example 27 and o-methoxyphenoxyacetic acid afforded the desired compound, (86%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([F:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](OCC)=[O:32])=[C:25]([F:36])[C:24]=2[F:37])=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([F:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][OH:32])=[C:25]([F:36])[C:24]=2[F:37])=[CH:13][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(F)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2cc(F)sc2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-fluorothiophen-2-yl)methoxy)-2,3-difluoro phenyl)propanoate to give the desired product as off-white oil. 1HNMR (300 MHz, CD3OD) δ 7.25-7.42 (m, 4H), 6.93 (t, J=8.4 Hz, 1H), 6.73 (t, J=8.4 Hz, 1H), 6.70 (s, 2H), 5.12 (s, 2H), 3.58 (t, J=7.5 Hz, 2H), 2.65-2.78 (m, 4H), 1.76-1.86 (m, 2H), 1.32 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H21F3O2S, 405.1 (M−H). found 405.1.
Reaction SMILES: [NH2:1][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>>[N:1]1[CH:23]=[CH:24][N:7]2[C:2]=1[CH:3]=[C:4]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][CH3:14])=[O:12])[CH:5]=[N:6]2
Reactant: CCO
Reactant: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)c1cccc(-c2cnn3ccnc3c2)c1

Procedure:
3-(6-Amino-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (1 eq, 1.07 mmol, 245 mg) is added to a solution of chloroacetic aldehyde (5 eq, 5.4 mmol, 0.69 ml) in EtOH (15 ml). NaHCO3 (2 eq, 2.15 mmol, 180 mg) is then added and the reaction mixture is heated at reflux for 17 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford 3-imidazo-[1,2-b]-pyridazin-7-yl-N-methyl-benzamide as an orange solid; [M+H]+=253
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]([F:13])([F:14])[F:15])=[C:3]([OH:2])[CH:8]=1)([O-:11])=[O:10]
Reactant: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (5.0 g, 22.6 mmol) in N,N-dimethylformamide (23 mL) was added lithium chloride (2.40 g, 56.5 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction temperature was heated to 155° C., and the mixture was further stirred for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL)/hexane (75 mL), and washed with 1% aqueous citric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL)/hexane (25 mL), and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→90/10). The obtained solution was concentrated under reduced pressure to give the title compound (2.22 g, 47%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[CH2:20][NH:21][C@H:22]([C:24](=[O:26])[NH2:25])[CH3:23]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:9]2[CH:10]=[C:5]3[C:6](=[CH:7][CH:8]=2)[CH2:20][N:21]([C@@H:22]([CH3:23])[C:24]([NH2:25])=[O:26])[C:3](=[O:2])[CH2:4]3)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1CN[C@@H](C)C(N)=O
Solvent: Cc1ccccc1
Product: C[C@@H](C(N)=O)N1Cc2ccc(OCc3ccc(F)cc3)cc2CC1=O

Procedure:
[2-[(1(S)-Carbamoyl-ethylamino)-methyl]-5-(4-fluoro-benzyloxy)-phenyl]-acetic acid methyl ester (0.150 g, 0.401 mmol) is refluxed in toluene at 140° C. with a Deam-Stark trap to remove the methanol formed in the reaction. After 5 h the product is obtained. The toluene is removed by evaporation and the compound is crystallized in ether (0.115 g, 84%). MS: m/e=343.4 (M+H+).
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:22])[C:5]1=[O:23])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[NH2:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccccc2)c2cc(F)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(F)ccc21

Procedure:
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.0826 g, 0.267 mmol) and PS—PPh3 (1.63 g of 1.64 mmol/g, 2.67 mmol) were combined. After workup and purification by “catch and release,” the title compound was obtained as a slightly yellow solid (0.0450 g, 59%). 1H-NMR (CDCl3): δ 7.65-7.60 (m, 2H), 7.51-7.46 (m, 1H), 7.44-7.39 (m, 2H), 7.36 (dd, J=4.8 Hz, J=9.2 Hz, 1H), 7.33-7.26 (m, 1H), 7.03 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 4.48 (s, 1H), 3.45 (s, 3H), 2.30-1.60 (br s, 2H). MS (ESI) (M+H)+=284.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:32]=[CH:31][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)[N:16]=3)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:36]([O:35][C:33]([N:7]1[CH2:8][CH2:9][C:10]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=2)[N:16]=4)=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 25 °C
Yield: 50.5 %

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.629 g, 1.18 mmol) and lithium hydroxide monohydrate (4.8 mmol) in THF (4 mL) and water (2 mL) were heated at 60° C. overnight. The reaction mixture was cooled to RT, THF removed in vacuo and the residue acidified to pH 3 with 1M HCl. The resultant solid was filtered off, washed with water and dried. The resultant solid was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (0.31 g, 51%). 1H NMR 300 MHz (CDCl3) δ: 8.27 (1H, d, J=8.34 Hz), 7.93 (1H, s), 7.17 (1H, s), 7.07 (1H, dd, J=8.31, 1.80 Hz), 6.55 (1H, s), 6.10 (1H, m), 4.40 (2H, m), 4.14 (4H, m), 3.67 (2H, m), 2.50 (2H, m), 1.63 (6H, d, J=6.58 Hz), 1.54 (9H, s).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:13]=[C:14]([OH:23])[C:15]3[CH:16]=[CH:17][N:18]([CH2:21][CH3:22])[C:19]=3[CH:20]=2)=[CH:6][N:5]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[CH:17][N:18]3[CH2:21][CH3:22])=[C:14]([O:23][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])[CH:13]=2)=[CH:6][N:5]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCn1ccc2c(O)cc(Cc3cnc(N)nc3N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CCn1ccc2c(OS(=O)(=O)N(C)C)cc(Cc3cnc(N)nc3N)cc21
Reaction time: 0.25 h
Yield: 8.5 %

Procedure:
Tetrabutylammonium bromide (61 mg, 0.19 mmol) and 50% aqueous sodium hydroxide solution (7.8 mL) were added to a suspension of 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-ol (Example 6; 436 mg, 1.54 mmol) in dichloromethane (130 mL), and the mixture was vigorously stirred for 15 min. Dimethylsulfamoyl chloride (226 mg, 1.57 mmol) was added, then after 2 h another portion of dimethylsulfamoyl chloride (60 mg, 0.42 mmol) was added. After 16 h the reaction mixture was partitioned between dichloromethane (130 mL) and water (50 mL), the organic layer was washed with brine, dried (MgSO4), and evaporated. The crude product was purified by preparative HPLC to afford the title compound (51 mg, 9%). Light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]([CH3:19])[C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Yield: 94 %

Procedure:
A solution of 2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5.0 g, 0.0176 mol) in carbon tetrachloride is treated with bromine (56 g, 0.0351 mol), heated at reflux temperature for 8 hours, cooled, washed sequentially with water, aqueous sodium metabisulfite and water, dried over sodium sulfate and concentrated in vacuo to give a solid residue. The residue is recrystallized from heptane to give the title product as a white solid, 6.0 g (94% yield), mp 126°-129° C.