Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][C:40]([C:43]([O:45]C(C)(C)C)=[O:44])([CH3:42])[CH3:41])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:41])[CH3:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.9 g) and anisole (3.9 ml) was added trifluoroacetic acid (15.6 ml) under ice-cooling, and the mixture was stirred at ambient temperature for an hour. To the reaction mixture was added diisopropyl ether and the precipitated crystals were collected by filtration and then washed with diisopropyl ether. To the crystals were added ethyl acetate and water, followed by adjusting to pH 7.5 with sodium bicarbonate. The separated aqueous solution was washed with ethyl acetate and then adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then dried to obtain 7-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.09 g), mp 173°-177° C. (dec.). The filtrate and the washings were combined and saturated with sodium chloride, followed by extraction with tetrahydrofuran. The extract was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was pulverized with diisopropyl ether and collected by filtration to recover the same object compound (0.59 g). Total yield: 1.68 g.
Reaction SMILES: C(OC([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:30]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(SCCCNCCc2ccccc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor J-01b, 5.5 mg, 0.015 mmol) is dissolved in TFA/dichloromethane (1:1, 1.5 ml) and stirred at rt for 1.5 h. The solvents are evaporated under reduced pressure and the residue is dried under high vacuum, yielding the pure title compound: tR=1.51 min (LC-2), ESI-MS (pos.): m/z 370.39 [M+H]+; ESI-MS (neg.): m/z 368.42 [M−H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH3:13][O:12][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[CH:11][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1c(Br)ccc2c1CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)ccc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a stirred mixture of 6-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene, (15 g, 62.21 mmol) in THF (150 mL) cooled to 0° C. was added n-butyllithium (43.14 mL, 69.03 mmol, 1.6M solution in hexanes) over 5 min. The reaction mixture was stirred for 1 h then cooled to −78° C., and triisopropyl borate (21.72 mL, 17.7 g, 94.14 mmol) was added dropwise over 0.25 h. The mixture was allowed to warm to room temperature with stirring then poured into 1N HCl (100 mL). The product was extracted with ethyl acetate (4×100 mL), the combined organic extracts dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate in vacuo at ambient temperature, the oily yellow residue was partially dissolved in diethyl ether, triturated with hexane, and the resulting precipitate filtered and washed with hexane to afford 1.64 g (13%) of the title compound 1-methoxy-5,6,7,8-tetrahydronaphthalene-2-boronic acid as an off-white crystalline solid (MW 206.05, C11H15BO3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CCC(=O)CC2)cc1
Yield: 32 %

Procedure:
A solution of 4-(4-nitro-phenyl)-cyclohexanone (0.512 g, 2.34 mmol, as prepared in the previous step) in EtOH (50 mL) was hydrogenated under the following conditions on an H-cube apparatus fitted with a 30 mm CatCart™ 5% Pd/C cartridge: 40° C., 40 bar H2, flow rate 1 mL/min. The solvent was evaporated in vacuo. Silica gel chromatography of the residue with 25% EtOAc-hexane on a 20-g Isolute SPE column (FlashMaster system) afforded the title compound (0.140 g, 32%) as a colorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C12H15NO, 190.1 (M+H), found 190.2.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:18][CH:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:17]2[S:18][CH:19]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:16]=2)[CH:21]=1
Reactant: Brc1csc(-c2cccnc2)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(3-pyridyl)thiophene. The title compound (800 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([F:26])=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[CH:9]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl.Cl>C(O)C>[CH:1]1([C:4]2[CH:9]=[C:8]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:7]([NH2:23])=[CH:6][C:5]=2[F:26])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(F)c(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)c(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Yield: 97.1 %

Procedure:
A stirred mixture of N-(5-cyclopropyl-4-fluoro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D81, 0.38 g, 1.05 mmol), tin (II) chloride (0.8 mg, 4.20 mmol) and conc. HCl acid (˜0.9 ml) in abs ethanol (30 ml) was heated at gentle reflux temperature for 18 hrs. After cooling, the majority of solvent was removed by concentration under reduced pressure and the residue treated with dilute K2CO3 solution (50 ml) and extracted with ethyl acetate, filtering the mixture to remove tin residues. The separated organic phase was dried (MgSO4) and concentrated to dryness under vacuum to afford the title compound as a pale brown oil (340 mg, 97%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4CCOCC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added morpholine (240 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (192 mg, yield 83%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 536 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][C:49]([CH3:51])=[CH2:50])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:66]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@:9]2([CH2:48][C:49]3([CH3:51])[CH2:50][O:66]3)[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@]3(CC4(C)CO4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 25 (52 mg, 63 μmol) in anhydrous DCM (1 mL) was added 3-chlorobenzoperoxoic acid (21 mg, 95 μmol, 1.2 equiv). The reaction was stirred overnight, directly loaded onto a preparatory TLC plate, and eluted with 15% EtOAc in petroleum ether to give 50 (41 mg, 77% yield). LC/MS m/z 862 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=O.S(Cl)(Cl)=O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[N:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)NC(C)(C)CO)cc1Br
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(C2=NC(C)(C)CO2)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-4-methylbenzamide (1.7 g, 6.04 mmol, 1.0 eq) was treated with thionyl chloride (0.9 mL, 12.08 mmol, 2.0 eq) and the neat reaction mixture was stirred at room temperature for 12 h. The mixture is diluted with diethyl ether (50 mL) and the precipitated solid was filtered and washed with diethyl ether (20 mL). The solid collected was dissolved in sodium hydroxide solution (1N, 15 mL) and extracted with diethyl ether (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford the 1.0 g of the desired title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.12 (d, J=1.0 Hz, 1H), 7.75 (dd, J=1.0, 8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.09 (s, 2H), 2.42 (s, 3H), 1.37 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)+, Br79,81].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9](O)[C:10]2[CH:15]=[CH:14][NH:13][C:11]=2[N:12]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]2[CH:15]=[CH:14][NH:13][C:11]=2[N:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: Oc1nc(-c2ccccn2)nc2[nH]ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Temperature: 110 °C

Procedure:
2-Pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (1 eq, 5.56 mmol, 1.18 g) is added to POCl3 (10 ml), and the resulting mixture is heated at 110° C. for 18 h. The mixture is concentrated in vacuo and then water is added. The aqueous solution is heated at 40° C. for 15 min, cooled down to r.t., and adjusted to pH 9 with aqueous NaOH solution (8 M). The resulting precipitate is filtered and washed with water and MeOH to give the title compound; [M+H]+=231.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=O.[Na+].[ClH:26]>O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:26])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1ccc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cnc(-n2ncc3cc(Cl)ccc32)c(Cl)c1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-aminoindazole [Compound No. 7] (3.0 g) in conc. hydrochloric acid (30 g), the solution of sodium nitrite (0.6 g) in water (1 ml) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature. After 30 minutes, cuprous chloride (CuCl) (3 g) was added thereto, and the resultant mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-chloroindazole (2.0 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[CH3:8][NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[S:3][C:4]([N:9]([CH3:8])[CH:10]2[CH2:11][C:12]([CH3:18])([CH3:19])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]2)=[N:5][N:6]=1
Reactant: Brc1nnc(Br)s1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (2.975 g, 12.2 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (2.493 g, 14.64 mmol) in dioxane (40 mL) was added DIPEA (10.65 mL, 61 mmol) and the resulting mixture refluxed at 120° C. for 16 hours. The reaction mixture was cooled to room temperature then filtered under vacuum, rinsed with dioxane, and the filtrate concentrated in vacuo to afford the crude product as a pink/red oil. The crude material was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pink/red solid (2.924 g, 72% yield). LC-MS: Rt 0.70 min; MS m/z 335.2 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13-4.03 (m, 1H), 2.92 (s, 3H), 1.57 (dd, J=12.13, 3.54 Hz, 2H), 1.39 (t, J=12.13 Hz, 2H), 1.26 (br. s., 1H), 1.16 (s, 6H), 1.06 (s, 6H). LC-MS: Rt 1.12 min; MS m/z 335.2 [M+H]+ [Method B].
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:5]
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(Br)c1ccccc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(Br)c3ccccc3)CC2)c1

Procedure:
Example 10 was prepared from bromo(phenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 486.1 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(OC(=O)C)(=O)C>CO>[C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2[nH]ccc2n1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Yield: 58.9 %

Procedure:
A solution of 0.477 gm (2.7 mMol) of the 5-(N-acetylamino)pyrrolo[3,2-b]pyridine, 0.54 mg (9.5 mMol) potassium hydroxide, and 0.43 mL (3.5 mMol) 1-methyl-4-piperidone in 15 mL methanol was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in pyridine. To this solution was added 0.20 mL (2.2 mMol) acetic anhydride and the resultant mixture stirred for 1 hour. This reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of ethyl acetate (2-40% methanol). Fractions containing product were combined and concentrated under reduced pressure to provide 0.43 gm (59%) 5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine as an ivory foam. A portion was recrystallized from methanol/ethyl acetate to provide an analytical sample.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH:22]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:27]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:29])=[O:28])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCCC2)c2n(c1=O)CCS2
Yield: 113.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with cyclopentanesulfonyl chloride (106 mg, 0.528 mmol) to afford the crude product. Purification by preparative HPLC afforded 0.03 g of the product (11% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(OC)(C)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[N:23]([C:22]2[CH:25]=[CH:26][C:19]([Br:18])=[CH:20][CH:21]=2)[CH3:24])[CH2:13][CH2:14]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(c1ccc(Br)cc1)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of trans-4-(Boc-amino)cyclohexanecarboxylic acid (148 mg, 0.608 mmol) in DMF were successively added 4-bromo-N-methylaniline (0.084 ml, 0.669 mmol), Et3N (0.170 ml, 1.217 mmol) and HATU (278 mg, 0.730 mmol) at RT. The reaction mixture was heated at 80° C. for 6 h then additional HATU (278 mg, 0.730 mmol) was added and the mixture was further stirred at 80° C. for 14 h. The reaction mixture was cooled to RT, diluted with TBME and washed successively with HCl 2M in water and Na2CO3 2M in water. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by reverse phase prep-HPLC (gradient elution, H2O containing 0.1% TFA/MeCN 8:8→2:8) to yield the title compound (97 mg, 0.236 mmol, 39%) as a brownish solid. HPLC: AtRet=2.38 min; LC-MS: m/z 411.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.99 (m, 2H), 1.35 (s, 9H), 1.32-1.45 (m, 3H), 1.55-1.76 (m, 4H), 1.86-2.15 (m, 1H), 3.11 (br. s., 3H), 6.56 (br. s., 1H), 7.27-7.35 (m, 2H), 7.61-7.69 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][NH2:19])[N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][NH:19][C:30](=[O:32])[CH3:31])[N:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2nc(-c3cccc(CN)c3)n[nH]2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(-c3cccc(CNC(C)=O)c3)n[nH]2)cc1
Reaction time: 1.5 h
Yield: 794.9 %

Procedure:
A solution of 3-[5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzylamine hydrochloride (1:1) (50 mg, 0.016 mmol) and triethylamine (32 mg, 0.032 mmol) in CH2Cl2 (5 ml) was stirred at r.t. for 30 min. Acetyl chloride (12 mg, 0.016 mmol) was then added and the mixture stirred for 1.5 hrs. The reaction mixture was evaporated and chromatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4. This afforded a yellow oil, which was then dried under high vacuum at 50° C. to afford the title compound (41 mg, 72% yield) as a light yellow solid. MS: m/e=323.3 (M+H+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:20])[N:10]([OH:19])[C:11](=[O:18])[C:12]3[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=3>C(O)C>[OH:19][N:10]1[C:9](=[O:20])[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:16]3[C:17]=2[C:12](=[CH:13][CH:14]=[CH:15]3)[C:11]1=[O:18]
Reactant: C[S-]
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 77.1 %

Procedure:
Sodium thiomethoxide (0.9 g, 12.0 mmol) was added to a solution of 6-bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione (1.2 g, 4.0 mmol, from Example 4) in ethanol (200 mL). The mixture was refluxed for 48 hours and concentrated. The solid residue was dissolved in water and acidified with concentrated HCl to pH 4. The resulting precipitate was filtered, washed with water, and dried to give 0.8 g of the title compound, mp 301-206° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:11].[B-](F)(F)(F)F.CN(C(O[N:36]1[C:41](=[O:42])[CH2:40][CH2:39][C:37]1=[O:38])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:38]=[C:37]1[CH2:39][CH2:40][C:41](=[O:42])[N:36]1[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][CH2:8][N:3]1[C:4](=[O:7])[CH:5]=[CH:6][C:2]1=[O:1]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CCCCCCCNC(=O)CCN1C(=O)C=CC1=O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCN1C(=O)C=CC1=O)NCCCCCCCC(=O)ON1C(=O)CCC1=O
Yield: 37 %

Procedure:
To a solution of 8-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]octanoic acid (917 mg, crude) in dry THF (15 ml) was added TSTU (1.07 mg) and DIPEA (0.65 ml). The mixture was stirred under nitrogen over night. The mixture was concentrated. To the residue was added EtOAc and the precipitate was filtered off. The filtrate was extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give an off-white solid. Overall yield 37% (444 mg). LC-MS, M/z: 408.39 (M+1).