Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)C.[OH-].[Na+].Cl>C(OCC)(=O)C.C(O)C.[C].[Pd]>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]=1[O:14][CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(F)c(OC)c1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)O)ccc1F
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
To a solution of 3-(4-fluoro-3-methoxyphenyl)acrylic acid ethyl ester (4.54 g) in ethyl acetate (20 mL)-ethanol (20 mL) was added 10% percent palladium-carbon (450 mg). After stirring under hydrogen gas atmosphere for 2.5 hours, the metal catalyst was removed by filtration, the solvent was removed by evaporation, and an oily substance (4.64 g) was obtained. This was dissolved in a solution of ethanol (40 mL), an aqueous solution of 5N sodium hydroxide was added, and the solution was stirred at room temperature for 30 minutes. After the solution was acidified by adding 5N hydrochloric acid (21 mL), the solid precipitated. After diluting with water, the solid was collected by filtration, dried by aeration, and a colorless solid (3.4 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])[NH2:14]
Reactant: NN
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)cc1C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A mixture of 3,6-dichloro-4-carboxy-pyridazine (20 g; 0.103 mole) and 22 ml of 98% hydrazine hydrate in 200 ml of 50% ethanol was refluxed, under stirring, for one hour. After cooling at 5° C., the solid precipitate was collected, washed with 20 ml of anhydrous ethanol. The solid was suspended in 100 ml of water, the mixture was brought to pH 1-2 with 23% HCl, after cooling at 5° C. the solid was filtered, dried under vacuum at 80° C. to give 18.29 g (93.4%) of the title compound, m.p. 198°-201° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][C@@H:14]1[C@@H:9](/[CH:8]=[CH:7]/[C@@H:6]([O:26][C:27](=[O:29])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH:10]=[CH:11][C:12]1=[O:13]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C/CCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC[C@@H](/C=C/[C@H]1C=CC(=O)[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Temperature: 35 °C
Reaction time: 40 h

Procedure:
A mixture of 2.4 g of PGE2 methyl ester, 30 ml of acetic anhydride and 6 ml of pyridine was stirred at 35° C. for 40 hours. After concentration under reduced pressure, the residue was dissolved in diethyl ether, washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 2.56 g of (5Z,13E)-(15S)-9-oxo-15-acetoxyprosta-5,10,13-trienoic acid methyl ester having the following physical characteristic:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]([C:17]3[NH:25][C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>O1CCCC1.CO.[Pd]>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]([C:17]3[NH:25][C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(c1cccc(-n2cccn2)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.5 %

Procedure:
A solution of 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.4 g, 4.3 mmol) in tetrahydrofuran (20 mL) and methanol (40 mL) was treated with 10% palladium on carbon (285 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 3 d. At this time, the reaction mixture was filtered and was washed with tetrahydrofuran (2×15 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 25% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridine (1.03 g, 71.8%) as a white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.62 (s, 1H), 8.48 (d, 1H, J=1.8 Hz), 8.10 (d, 1H, J=4.5 Hz), 7.89 (s, 1H), 7.81 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.65 (d, 1H, J=8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 6.97 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.54 (s, 1H), 6.33 (s, 1H), 4.28 (t, 1H, J=8.1 Hz), 2.17-2.10 (m, 1H), 1.97-1.90 (m, 1H), 1.45-1.36 (m, 1H), 0.93 (d, 3H, J=2.4 Hz), 0.91 (d, 3H, J=2.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:13]=1)[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]3[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N+:14]([O-:16])=[O:15])[CH2:24]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(OC2CCNC2)cc1
Reactant: COc1ccc([N+](=O)[O-])c(OCC2CO2)c1
Product: COc1ccc([N+](=O)[O-])c(OCC(O)CN2CCC(Oc3ccc(Cl)cc3)C2)c1

Procedure:
The subtitle compound was prepared in analogy of Example 253 ii) from 2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (320 mg, 1.6 mmol) and 3-(4-chlorophenoxy)pyrrolidine (365 mg, 1.6 mmol). The crude product was obtained as a yellow oil (580 mg) and was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:30])[CH:24]([Br:29])[CH2:25][CH2:26][CH2:27]Br)[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:9]([O:8][CH2:7][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([Br:29])[C:23]2=[O:30])[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 9a (32.5 g, 29.1 mmol) in dimethylacetamide (250 ml), was added powdered potassium carbonate (25.2 g, 116.5 mmol). After stirring for 4 hours, the mixture was filtered. The filtrate was freed of the solvent in vacuo at 45° C. and the resulting solid was redissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with water (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to obtain a white solid (29.5 g) which, upon crystallization from ethyl acetate (1.2 L), furnished analytically pure N,N'-bis[2-acetyloxy)-1-[(acetyloxy) -methyl]ethyl]-5-(3-bromo-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide as a white crystalline solid (23.95 g, 79.5% yield), m.p. 231°-3°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 67 %

Procedure:
A suspension of 4-(benzyloxy)-1-chloro-2-nitrobenzene (5.00 g, 19.0 mmol), 2-ethylhexyl 3-sulfanylpropanoate (4.55 g, 20.9 mmol) and potassium carbonate (3.93 g, 28.4 mmol) in DMF (20 mL) was stirred under heating at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by 15 silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (5.67 g, yield 67%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-:11].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:5]([CH3:6])([CH3:4])[C:8]([OH:10])=[O:11])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
2-(p-Acetylphenoxy)-2-methylpropionic acid was prepared from 545 g. of p-hydroxyacetophenone, 960 g. of sodium hydroxide and 715 g. of chloroform in 11 liters of acetone according to the procedure described above in Example 1, part (d). The product was recrystallized from carbon tetrachloride and from isopropyl acetate to give 2-(p-acetylphenoxy)-2-methylpropionic acid as a pale cream solid, m.p. 108°-110°C.
Reaction SMILES: [F:1][C:2]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]#[C:17][CH2:18][OH:19])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].CN(C)CC#CC1NC2=NC=C(NC(=O)C3C(F)=CC=C(NS(CCC)(=O)=O)C=3F)C=C2C=1>>[F:1][C:2]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C#CCO)c3c2)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCN(C)C)cc3c2)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(CCCO)c3c2)c1F
Yield: 77 %

Procedure:
2,6-Difluoro-N-(3-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (77%) was prepared according to the general procedure for Example 95 substituting 2,6-difluoro-N-(3-(3-hydroxyprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide for N-(2-(3-(dimethylamino)prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide. 1H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 10.83 (s, 1H), 9.79 (br s, 1H), 8.47-8.38 (m, 2H), 7.51-7.57 (m, 1H), 7.24-7.28 (m, 2H), 4.45-4.48 (m, 1H), 3.44-3.49 (m, 2H), 3.11-3.15 (m, 2H), 2.68-2.72 (m, 2H), 1.75-1.81 (m, 4H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=451.2.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([N+:38]([O-:40])=[O:39])[CH2:34][CH:33]3[C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([N+:38]([O-:40])=[O:39])[CH2:34][CH:33]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN([N+](=O)[O-])CC3C(=O)OCc3ccccc3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN([N+](=O)[O-])CC1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
130 ml of trifluoroacetic acid and 4.6 ml of trifluoromethanesulfonic acid were added dropwise to a solution of 13.8 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-nitrobenzyloxycarbonyl -1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 28.3 ml of anisole, and the resulting mixture was stirred for 30 minutes, whilst ice-cooling. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was washed with hexane and ether, in that order, by decantation to give 13.9 g of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:6]2[C:7]([NH:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nccc2scc(Br)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Brc1csc2ccnc(NCc3ccccn3)c12
Temperature: 25 °C
Yield: 4.5 %

Procedure:
3-Bromo-4-chloro-thieno[3,2-c]pyridine (409 mg, 16.5 mmol) was dissolved in anhydrous EtOH (20 ml), and 2-picolylamine (184 μl, 17.9 mmol) and triethylamine (241 μl, 17.3 mmol) were added. The reaction was heated to reflux and this was maintained for 24 h. The reaction was then allowed to cool to room temperature. The solvent was removed in vacuo and the residue partitioned between DCM (20 ml) and a saturated sodium, chloride solution (20 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was subjected to flash column chromatography (eluent petroleum spirit 40-60° C.:EtOAc, 3:1, Rf 0.3). This afforded the title compound as a yellow solid (236 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)([CH3:28])[CH3:27]>>[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)([CH3:28])[CH3:27]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: CC(C)Oc1ccccc1B(O)O
Product: CC(C)Oc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-isopropoxyphenylboronic acid (CAS RN 138008-97-6). Black solid (25%). MS (ESI): m/z=483.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na+].[I-:10].[OH-].[Na+].[O-]Cl.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:10])[CH:3]=1
Reactant: [I-]
Reactant: Oc1ccc(F)cc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(F)cc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To a stirred solution of 16.8 g (150 millimoles (mmol) of 4-fluorophenol in 300 mL of methanol at 0° C., add 22.5 g (150 mmol) of NaI and 6.00 g (150 mmol) of NaOH. To the resulting mixture add 258 mL of 5% aqueous NaOCl solution (commercial bleach) over a one hour period. Stir the resulting slurry for one more hour at 0° C. Add 90 mL of 10% aqueous Na2S2O3 solution, and acidify the resulting reaction mixture by adding dilute hydrochloric acid. Extract the resulting mixture with methylene chloride, wash the resulting organic layer with brine and dry it over anhydrous magnesium sulfate. Remove solvent, dissolve the residue in hot hexanes, and allow the resulting solution to stand in a freezer for two hours. A dark colored material oils out. Decant the solution away therefrom and allow the resulting colorless decanted solution to stand in a freezer for 18 hours. Filter off the resulting white crystals and dry them under reduced pressure to yield 18.00 g (50%) of pure 4-fluoro-2-iodophenol (P7) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:6][CH:5]=1
Reactant: O=C1OCCN1CCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A mixture of 3-[2-(6-Nitro-indazol-1-yl)-ethyl]-oxazolidin-2-one (200 mg, 0.72 mmol), iron powder (400 mg, 7.1 mmol), and ammonium chloride (20 mg, 0.37 mmol) in a 4:1 ethanol/H2O solution (5 mL) was heated to reflux for 3 hours, cooled to room temperature, concentrated under reduced pressure. The resudue was stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (120 mg, 67%). 1H NMR (300 MHz, DMSO-d6) ppm 4.03 (s, 3H), 4.42 (d, J=6.10, 1H), 6.04 (m, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.38 (m, 1H), 7.48 (m, 2H), 7.69 (m, 1H), 7.79 (m, 1H), 8.44 (m, 1H), 9.12 (s, 1H); MS (DCI/NH3) m/z 247 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[I-].C[N+]1C=CN(C)C=1.[H-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:15]([C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)=[O:16])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1C(=O)c1cccc(C(F)(F)F)c1
Yield: 32.5 %

Procedure:
2,4-Dichloro-5-methylpyrimidine (3.6 g, 18.4 mmol) was dissolved in dichloromethane (50 mL) and treated sequentially with 3-trifluoromethylbenzaldehyde (3.3 g, 18.4 mmol), and 1,3-dimethylimidazolium iodide (1.37 g, 6.2 mmol). Sodium hydride (0.74 g, 18.4 mmol) was added and an exotherm was noted. After being heated at reflux for 3 h, the reaction was quenched with water and the layers were separated. The dried (magnesium sulfate) organic layer was purified by chromatography on silica gel using hexanes/ethyl acetate 85:15 as eluent. The title compound of Step A (1.8 g) was isolated as a white solid melting at 113-116° C. 1H NMR (CDCl3/200 MHz) 2.39 (s, 3H), 7.66 (m, 1H), 7.90 (d, 1H), 8.07 (s,1H), 8.69 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([N:13]2[C:29]3[C:16](=[CH:17][C:18]4[O:19][CH2:20][C:21]5[N:26]([C:27]=4[CH:28]=3)[C@H:25]([CH3:30])[C:24](=[O:31])[NH:23][N:22]=5)[C:15]([CH2:32][CH3:33])=[CH:14]2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[ClH:34]>>[ClH:34].[CH2:32]([C:15]1[C:16]2=[CH:17][C:18]3[O:19][CH2:20][C:21]4[N:26]([C:27]=3[CH:28]=[C:29]2[N:13]([C:10]2([CH3:12])[CH2:9][NH:8][CH2:11]2)[CH:14]=1)[C@H:25]([CH3:30])[C:24](=[O:31])[NH:23][N:22]=4)[CH3:33]
Reactant: CCc1cn(C2(C)CN(C(=O)OC(C)(C)C)C2)c2cc3c(cc12)OCC1=NNC(=O)[C@@H](C)N13
Agent: Cl
Product: CCc1cn(C2(C)CNC2)c2cc3c(cc12)OCC1=NNC(=O)[C@@H](C)N13
Yield: 39 %

Procedure:
A solution of 3-((R)-8-ethyl-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.04 g, 0.088 mmol) in HCl (4M in EtOAc, 3 mL) was stirred at −5-0° C. for 2 h. The solvent was removed in vacuo to give (R)-8-ethyl-1-methyl-10-(3-methyl-azetidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloride (0.0122 g, 39%) as a yellow solid. 1H NMR (400 MHz, methanol-d4): δ 7.22 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 4.95 (m, 1H), 4.75 (m, 2H), 4.63-4.50 (m, 4H), 2.72 (q, J=7.6 Hz, 2H), 1.85 (s, 3H), 1.46 (d, J=6.8 Hz, 3H), 1.33 (t, J=7.6 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.591 min.; MS m/z: 354 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(=O)CC>[CH2:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:23]=[CH2:22]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 6.5 h

Procedure:
4-hydroxybenzophenone (186.7 g, 940 mmol, Fluka Chemical) was dissolved in 2-butanone (700 mL, Fisher Scientific) in a 2 L four-necked flask equipped with a mechanical stirrer, reflux condenser, addition funnel and internal temperature probe. K2CO3 (195 g, 1.41 mol, Aldrich Chemical) was added to the reactor, and the contents was placed under a slow N2 purge. Allyl bromide (123 mL, 1.41 mol, Aldrich Chemical) was charged to the addition funnel. The pot temperature was raised to 65° C., at which point the allyl bromide was added over the course of 30 minutes. The reaction was stirred for 6.5 h at 65° C. after the addition was completed. At this point no starting material was present as determined by GC analysis.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]C)=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(CCc3ccccc3)csc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: Oc1ccc2c(CCc3ccccc3)csc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred, −10° C. solution of the product from Step D (5.483 grams; dry methylene chloride; 60 mL) was treated with 1M boron tribromide solution (methylene chloride; 20.81 mL). After 2 hours, the reaction was momentarily warmed to ambient temperature. It was partitioned between isopropyl acetate and aqueous sodium bicarbonate, washed once with water and dried over magnesium sulfate. Filtration and evaporation produced a semi-solid. Chromatography over silica gel (2.5:1 hex/ethyl acetate) resulted in the isolation of the title compound, a pale yellow solid.