Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=S)[CH2:10][CH3:11]>C(O)C.O>[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=[O:5])[CH2:10][CH3:11]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: O
Solvent: CCO
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Fumaric acid (2.7 g) is added to a solution of N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (9.5 g) in ethanol (100 cc). The solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The merigue-like yellow residue is taken up with acetic acid (200 cc). Mercuric acetate (7.3 g) is added to the solution obtained, and the mixture is stirred for 16 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with distilled water (200 cc) and filtered. The yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc) and then treated with sodium hydroxide (d 1.33) to pH 13. The aqueous phase is separated after settling has taken place and extracted with ethyl acetate (250 cc). The organic phases are combined, washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (9.2 g) is thereby obtained. This residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (95:5 by volume) of methylene chloride and methanol. The first 1,500 cc are discarded and the next 1,500 cc are concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (7.3 g) in the form of a yellow gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Hydroxyphenyl)cyclohexanone (4.98 g, 26.18 mmol), benzyl bromide (4.92 g, 28.79 mmol), K2CO3 (5.06 g, 36.65 mmol) and 75 mL of acetone were mixed in a reaction flask equipped with a reflux condenser. The mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting solid was recrystallized in ethyl acetate to provide the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.80-2.00 (m, 2 H), 2.13-2.26 (m, 2 H), 2.43-2.55 (m, 4 H), 2.91-3.05 (m, 1 H), 5.05 (s, 2 H), 6.94 (d, J=8.82 Hz, 2 H), 7.16 (d, J=8.82 Hz, 2 H), 7.28-7.48 (m, 5 H); MS (DCI) m/z 298 (M−NH4)+.
Reaction SMILES: N[CH:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:23].Cl>C(N(CC)CC)C>[O:23]=[C:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1

Procedure:
2,2,2-Trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 2,2,2-trichloroethyl 7-oxo-3-methyl-3-cephem-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccccc1F
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1F
Reaction time: 27 h

Procedure:
From 2-fluorobenzyl alcohol (5.7 g; 45 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 27 h at 100° C. The yield was 0.64 g (44%). Mp 91–94° C. (dec.)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:39])[C:9]2[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([O:24]C3CCCCO3)[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1.CC(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:39])[C:9]2[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:20][N:21]([OH:24])[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1
Reactant: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: O
Solvent: CC(=O)O
Product: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Yield: 21 %

Procedure:
[(2R)-3-(2-{6-[[(2-Amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (110 mg, 0.19 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature for 2 days. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide N-[(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino}-2-chloro-5-fluoro-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]-N-hydroxyformamide (20 mg, 21%). LCMS: (M+H)+: 501.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[NH:13][C:12]1=[O:37])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:45]([C:48]1[CH:58]=[CH:57][C:51]([CH2:52][O:53][CH2:54][CH2:55]Cl)=[CH:50][CH:49]=1)([O-:47])=[O:46].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[N:13]([CH2:55][CH2:54][O:53][CH2:52][C:51]2[CH:57]=[CH:58][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=2)[C:12]1=[O:37])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
57.7 mg (0.105 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-([(S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl)-2-azetidinone and 33 mg (0.33 mmole) of triethylamine were dissolved in 3 ml of methylene chloride. To the solution were added 73 mg (0.30 mmole) of p-nitrobenzyloxyethyl chloride, with ice-cooling under a nitrogen atmosphere. The mixture was stirred for 1 hour and then poured into a 0.1M phosphate buffer solution (pH 7.2). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. The solvent was distilled off and the residue was purified by column chromatography through 1.3 g of silica gel, to give 67.8 mg (yield 83%) of the desired product as an oil from the fraction eluted with mixtures of benzene and ethyl acetate in volume ratios from 12:1 to 4:1.
Reaction SMILES: [C:1](O)(=[O:3])C.[CH3:5][N:6]([CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)=[O:21])=[CH:15][CH:16]=2)[NH:11][CH2:10]1)[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[CH3:7][N:6]([CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:21])=[CH:15][CH:16]=2)[N:11]([CH:1]=[O:3])[CH2:10]1)[CH3:5]
Reactant: CC(=O)O
Reactant: CN(C)CC1CNc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CN(C)CC1Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2N(C=O)C1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Anhydrous acetic acid (0.1 ml) was added to formic acid (1 ml), which was stirred at 55° C. for 2 hours. N-[3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydo-7-quinolinyl]-4-biphenylylcarboxamide (80 mg) was added to the reaction mixture under ice-cooling, which was stirred at room temperature for 72 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture to make the mixture alkaline, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using THF-IPE to give the titled compound (80 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([Cl:15])=[C:6]([S:8][C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:7]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[Cl:15][C:5]1[CH:4]=[C:3]([F:16])[C:2]([N:1]2[C:20](=[O:21])[CH:19]3[C:18](=[CH:26][CH2:25][CH2:24][CH2:23]3)[C:17]2=[O:22])=[CH:7][C:6]=1[S:8][C:9]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]1
Reactant: Nc1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Temperature: 0 °C

Procedure:
A mixture of 2.4 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid, 1.5 g of 3,4,5,6-tetrahydrophthalic anhydride and 100 ml of glacial acetic acid is heated under reflux for 18 hours while stirring. The reaction mixture is then introduced into ice-water and the resulting product is extracted with ethyl acetate. Drying over sodium sulfate and concentration of the solution by evaporation yield 1.7 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid having a melting point of from +186° to +188° C.
Reaction SMILES: C([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)C=C.ClC1C=CC=[C:23]([C:27]([O:29]O)=O)[CH:22]=1>CCOCC.C1C=CC=CC=1>[O:29]1[CH2:27][CH:23]1[CH2:22][C:6]1[C:5]2[CH:4]3[CH2:19][CH2:18][CH:11]([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCC12CCC(c3ccccc31)c1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc2c(c1)C1CCC2c2c(CC3CO3)cccc21

Procedure:
A solution of 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene (1.1 g) and m-chloroperbenzoic acid (1.6 g) in ether was stirred at room temperature for 5 days. The solution was diluted with benzene, washed with aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-β,γ-epoxypropyl-9,10-dihydro-9,10-ethanoanthracene as an oil, I.R., 3070, 3040, 3020, 2860, 1263, 1140, 1033, 830, 760, 680, 630 cm-1.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.OC1C=CC=CC=1C#[N:18].C([O-])(=O)C.[NH4+]>CO>[NH2:18][CH:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: N#Cc1cccc2c1OCCC2=O
Reactant: N#Cc1ccccc1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1cccc2c1OCCC2N
Reaction time: 120 h

Procedure:
A mixture of 260 mg of 4-oxo-3,4-dihydro-2H-chromene-8-carbonitrile (made from 2-hydroxybenzonitrile via the procedure described in Example 29), ammonium acetate (1.2 g), and 3 A molecular sieves (1.5 g) in 10 mL of methanol was stirred for 5 days. The mixture was filtered through celite and the filtrate concentrated in vacuo. The crude residue was treated with 100 mL of 1 M HCl and extracted with ethyl ether (3×100 mL). The aqueous layer was made basic to pH 10 with saturated NaOH and extracted with DCM (3×100 mL). The combined DCM layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to provide 150 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[S:48][C:47]([CH3:49])=[N:46][C:45]=1[CH3:50]>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[S:48][C:47]([CH3:49])=[N:46][C:45]=3[CH3:50])=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Cc1nc(C)c(Br)s1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3sc(C)nc3C)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 5-bromo-2,4-dimethyl-1,3-thiazole.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH:14]=[O:15])=[CH:11][C:12]=1[CH3:13])=[O:7])C>CO.O>[CH:14]([C:10]1[NH:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[CH:11]=1)=[O:15]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C=O)[nH]c1C(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
Lithium hydroxide (8.73 g, 36.44 mmol) was added to the 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.32 g, 7.27 mmol) in methanol (27 mL) and water (9 mL). The mixture was stirred at room temperature for over the weekend. The reaction was diluted with water (10 mL), evaporated most of the methanol and washed with ether. The aqueous layer was acidified with 1N HCl (37 mL) to pH=2, extracted with ethyl acetate. Washed with brine, dried and concentrated. The residue was washed with dichloromethane and filtered to give 0.98 g (88%) of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid as a tan solid. 1H NMR (360 MHz, DMSO-d6) δ 12.87 (br s, 1H, COOH), 12.41 (br s, 1H, NH), 9.63 (s, 1H, CHO), 6.74 (s, 1H), 2.26 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:6](=[N:7][NH:8][C:9]2[CH:10]=[C:11](S(N)(=O)=O)[CH:12]=C[CH:14]=2)[C:5]([CH:19]2[CH2:21][CH2:20]2)=[N:4][N:3]=1.[NH2:22]C1C=C(S(N)(=O)=O)C=CC=1>>[CH:19]1([C:5]2[C:6](=[N:7][NH:8][C:9]3[CH:14]=[N:22][CH:12]=[CH:11][CH:10]=3)[C:2]([NH2:1])=[N:3][N:4]=2)[CH2:20][CH2:21]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: NC1=NN=C(C2CC2)C1=NNc1cccc(S(N)(=O)=O)c1
Product: NC1=NN=C(C2CC2)C1=NNc1cccnc1

Procedure:
In a similar manner, 3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]benzenesulfonamide was prepared from 3-aminobenzenesulfonamide (0.51 g, 2.96 mmol) to yield 0.1 g of the product. MS (m/z, ES+): 307 (M+1, 100%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]([C:25]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[O:26])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C:10]1[S:14][C:13]([CH:15]([C:25]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[O:26])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E237) in THF at 0° C. was added TBAF and the solution was stirred for 0° C. for 30 min then warmed to room temperature for 2 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 6% MeOH/CH2Cl2) gave pure tert-butyl 2-(5-(hydroxymethyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E238).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:53])=[C:33]([CH:52]=1)[CH2:34][N:35]1[CH2:51][CH2:50][C:38]2([O:43][CH2:42][CH2:41][N:40]([C:44](=[O:49])[C:45]([F:48])([F:47])[F:46])[CH2:39]2)[CH2:37][CH2:36]1)(C(C)(C)C)(C)C>C1COCC1>[F:48][C:45]([F:46])([F:47])[C:44]([N:40]1[CH2:39][C:38]2([CH2:50][CH2:51][N:35]([CH2:34][C:33]3[CH:52]=[C:29]([CH2:28][CH2:27][OH:26])[CH:30]=[CH:31][C:32]=3[F:53])[CH2:36][CH2:37]2)[O:43][CH2:42][CH2:41]1)=[O:49]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1CCOC2(CCN(Cc3cc(CCO)ccc3F)CC2)C1)C(F)(F)F
Reaction time: 18 h

Procedure:
TBAF (1M in THF, 16.4 mL) was added to a solution of 1-(9-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2,2,2-trifluoroethanone [Example 44, step a] (8.5 g) in THF (100 mL) and the resultant solution allowed to stand at 20° C. for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash silica chromatography, using 2% methanol in dichloromethane containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 4.2 g.
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]3[CH2:12][C@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][N:8]3[C:4]=2[CH:3]=1.[CH2:32]([Sn](CCCC)(CCCC)C=C)[CH2:33]CC>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.O1CCOCC1>[F:21][C:14]1[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=1[C@@H:11]1[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:9][N:8]2[C:4]3[CH:3]=[C:2]([CH:32]=[CH2:33])[N:31]=[CH:30][C:5]=3[N:6]=[C:7]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cnc(Cl)cc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(cn1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Temperature: 25 °C

Procedure:
An oven dried flask charged with 30 mg (0.066 mmol) of tert-butyl [(7R,8R)-3-chloro-8-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,4′:4,5]imidazo[1,2-a]pyridine-7-yl]carbamate, 0.024 mL (0.079 mmol) of tributyl(vinyl)tin, 23 mg (0.020 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.5 mL of dry dioxane was put under nitrogen and heated to reflux for 72 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and the filter cake rinsed with 50 mL of ethyl acetate. The filtrate was evaporated in vacuo and the crude residue was purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 90% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 445.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH2:24])[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:24][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: NCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCC2CCCO2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 34.8 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), tetrahydrofurfuryl amine (Aldrich Chemical Company) (0.212 mL, 2.05 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to obtain crude pink solids. Recrystallization from EtOH/MeOH gave 0.044 g (35%) of the title compound as an off-white solid. Mp: 280° C. 1H NMR (CDCl3; 500 MHz): δ 1.59 (m, 1), 1.87 (m, 2), 2.00 (m, 1), 2.39 (s, 3), 3.48 (m, 1), 3.71 (m, 2), 3.86 (t, 1, J=7.3), 4.06 (m, 1), 6.74 (s, 1), 6.95 (s, 1), 7.38 (t, 1, J=7.1), 7.51 (t, 2, J=7.6), 7.80 (d, 2, J=8.0), 11.41 (s, 1). MS m/z: 309 (M+1). Anal. Calcd for C18H20N4O: C 70.11, H 6.54, N 18.17. Found: C 69.88, H 6.51, N 18.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=3[N:17]=[C:18]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: COc1ccc(Nc2ccc(Br)cn2)c(NC(=O)C(F)(F)F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(Br)cn1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of N-[2-(5-Bromo-pyridin-2-ylamino)-5-methoxy-phenyl]-2,2,2-trifluoro-acetamide (70 mg, 0.18 mmol) in toluene (15 mL) was added (CF3CO)2O (6 mL). The resulting solution was allowed to stir overnight at reflux. The volatile components were then removed under reduced pressure and the residue was purified by SGC using 1:7 EtOAc/petroleum ether as eluents to provide 5 mg (6%) of 1-(5-Bromo-pyridin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (cc) as a white solid. 1HNMR (400 MHz, DMSO-D6) δ 3.84 (3H, s), 7.11-7.13 (1H, d), 7.37 (1H, d), 7.45 (1H, s), 7.81 (1H, d), 8.46 (1H, d), 8.88 (1H, s) ppm.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][OH:38]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCO
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(dimethylamino)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.