Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12.[H-].[Na+].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:7]=[N:6][C:5]=2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12
Reactant: ClCc1ccc(Cl)cc1
Reactant: CN1C(=O)c2[nH]cnc2N2C1=N[C@@H]1CCC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(ncn2Cc2ccc(Cl)cc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 50 °C

Procedure:
Add a solution of cis-5,6a,7,8,9,9a-hexahydro-5-methylcyclopenta[4,5]imidazo[2,1-b]purin-4-one (0.5 g=2.2 mmol)in DMF drop-wise to a slurry of 60% NaH (0.1 g=2.4 mmol) in DMF at 30° C. When gas evolution ceases, add 4-chlorobenzyl chloride (0.5 g=2.4 mmol) in 2 ml DMF. Heat at 50° C. two hours. Remove DMF and partition between EtOAc and water. Dry, solvent strip, and recrystallize from CH3CN to give the title compound, a white solid. CI MS: M+ =356.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)C>CO>[CH2:13]([NH:21][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCN
Solvent: CO
Solvent: CCO
Product: CCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 65 °C

Procedure:
54 g of glucose (0.3 mol) are added to a solution of 40 g of octylamine (0.3 mol) in 50 ml of absolute methanol. The reaction mixture is heated to 65° C. for 20 min and then 50 ml of 95% hot ethanol are added. The N-octyl-β-D-glucopyranosylamine which precipitates on cooling (complete precipitation after 2 hours) is filtered off on a Buchner and then recrystallized from absolute ethand (1.5 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21]([O:23]CC)=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21]([NH:27][CH3:26])=[O:23])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Solvent: CO
Product: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of ethyl 5-[(3-bromophenyl)thio]-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (687 mg) in methanol (8 mL) was added 40% methylamine-methanol solution (1.6 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 600 mg, yield 90%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:35].[CH3:36][Mg]Br>C1COCC1.C(OCC)C>[F:29][C:26]([F:27])([F:28])[C:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:3]1[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[CH3:36])=[CH:13][CH:14]=3)[O:6][C:2]=1[CH3:1])[C:17]([CH3:35])=[CH:18]2)([OH:34])[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1oc(-c2ccc(C=O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(C)O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 50 mg (0.1 mmol) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-benzaldehyde in 1 ml of THF was cooled to 0° C. and treated with 0.13 ml (0.4 mmol) of a 3M methylmagnesium bromide solution in diethylether. The mixture was stirred and allowed to reach RT within 1 hr. Distribution of the crude between a saturated aqueous solution of NH4Cl and EtOAc, drying of the combined organic phases over Na2SO4, evaporation of the solvent, and chromatography on silica gel with heptane/EtOAc 4:1 gave 44 mg (85%) of 1,1,1,3,3,3-hexafluoro-2-(1-{2-[4-(1-hydroxy-ethyl)-phenyl]-5-methyl-oxazol-4-ylmethyl}-2-methyl-1H-indol-5-yl)-propan-2-ol, off-white solid, MS: 513 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[NH3:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:19])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: CC1=Cc2cc(Br)cc(S(=O)(=O)Cl)c2OS1(=O)=O
Reactant: N
Solvent: C1CCOC1
Product: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 180 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl chloride in 500 ml of tetrahydrofuran is added dropwise over 30 minutes to 307 ml of a 30% aqueous solution of ammonia. The mixture is stirred for 30 minutes at 20° C. and concentrated under reduced pressure at 45° C. The residue is triturated with 200 ml of ether. The precipitate is isolated, washed with water and dried at 45° C., affording 63.2 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 243°-245° C. (crystallisation from ethanol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:16][C:17]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:18]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[O:15][CH2:18][C:17]([F:31])([F:16])[C:27]([F:30])([F:29])[F:28]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1OCC(F)(F)C(F)(F)F
Yield: 55.9 %

Procedure:
A solution of methyl 5-(methanesulfonyl)salicylate [101371-44-2] (0.50 g), trifluoro-methanesulfonic acid 2,2,3,3,3-pentafluoro-propyl ester (0.67 g) and potassium carbonate (0.60 g) in acetone was stirred at 60° C. for 5 hours. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a white solid (0.44 g). MS (m/e): 363.1 (M+H+, 100%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1.O>C1COCC1>[Cl:25][C:18]1[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([F:3])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (0.124 g, 5.18 mmol) was added to a chilled (0° C.) solution of 4-fluoro-2-(trifluoromethyl)aniline (0.464 g, 2.59 mmol) in THF (1 mL) and stirred for 30 min. 2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol) was then added and the reaction mixture stirred at 80° C. for 18 h. Water was added to quench excess sodium hydride and volatile solvents were removed under reduced pressure. The product was then extracted into DCM, solvent removed under reduced pressure, and the residue purified by preparative HPLC to give the title compound (0.624 g). LCMS m/z=336.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (d, J=8.6 Hz, 1H), 7.34 (td, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.43 (dd, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=5.0 Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 10.26 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH:10](O)[CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[C:17]([F:26])[CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].C(C1C=CC(OCCCSC2C=CC(CC(OC)=O)=C(Cl)C=2Cl)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH:10]=[CH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([F:26])[CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)CS(=O)(=O)c2ccc(CC(=O)OC)c(F)c2)ccc(C(C)=O)c1O
Agent: CCCc1c(OCCCSc2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Product: CCCc1c(OCC=CS(=O)(=O)c2ccc(CC(=O)O)c(F)c2)ccc(C(C)=O)c1O

Procedure:
By following Step H of Example 1, but substituting the product of Step A of this example for the ester of Step G of Example 1, a mixture was obtained. After recrystallization from diethyl ether, 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneacetic acid, mp 119°-120° C., was obtained. The mother liquors were purified by chromatography on silica gel to yield 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-propenyl-sulfonyl)-2-fluoro-benzene acetic acid, mp 249°-251° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=2)[O:9][C:8]1([CH3:19])[CH3:18])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:18][C:8]1([CH3:19])[CH:7]([CH2:6][CH2:4][OH:3])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=2)[O:9]1
Reactant: CCOC(=O)CC1Cc2cc(F)ccc2OC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)Oc2ccc(F)cc2CC1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.4 g (12.7 mmol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-chroman in 40 ml of absolute diethyl ether is added dropwise within a period of 30 minutes, while cooling with ice, to a suspension of 0.97 g (25.5 mmol) of lithium aluminium hydride in 30 ml of absolute diethyl ether. The reaction mixture is then stirred for 2 hours at room temperature and then carefully decomposed with 1 ml of water, 1 ml of sodium hydroxide solution (15%) and 3 ml of water. The resulting precipitate is filtered off with suction and the filtrate is dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 2.75 g (96% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chroman in the form of a light-yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and benzyl alcohol. Colorless crystals (278 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:40])[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:40]=[C:29]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=4)[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: COc1cc(OC)cc(C(N)=NO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2noc(-c3ccc(-n4nc(-c5c(F)cccc5Cl)[nH]c4=O)cc3OC)n2)c1
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using Methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-20, 0.077 g, 0.529 mmol), sodium hydride (0.006 g, 0.39 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1H NMR (DMSO-d6): δ 3.84 (s, 611), 3.99 (s, 3H), 6.73 (s, 1H), 7.19 (s, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.67 (t, J=8.7 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 12.61 (br s, 1H); MS (m/z): 523.89 [M+]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([O:25]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\C3CC3)CS[C@H]12
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(/C=C\C3CC3)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.5 g (0.0227 mmol) of benzhydryl 7-phenylacetamido-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylate are dissolved in 23 ml of methylene chloride with the addition of 7.2 ml of anisole, the solution is cooled to 0° C. and 23 ml of trifluoroacetic acid are added. The mixture is stirred at 0° C. for 30 minutes and 46 ml of water are then added. 400 ml of diisopropyl ether are subsequently added to he reaction solution and the mixture is stirred at 0° C. for 30 minutes. The product which has crystallized out is filtered off with suction and washed with diisopropyl ether.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([OH:5])=[O:4].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br.Cl>C1COCC1>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:2]([Cl:6])([Cl:1])[C:3]([OH:5])=[O:4]
Reactant: BrCCCCCCCCCCBr
Reactant: O=C(O)C(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCBr
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 6.41 g (49.7 mmol) dichloroacetic acid in 20 ml THF is added dropwise at -70° C. within 30 minutes to a solution of lithium diisopropylamide under a nitrogen atmosphere prepared at 0° C. in 150 ml tetrahydrofuran from 11.2 g (110 mmol) diisopropylamine and 66.0 ml (105 mmol) butyllithium (1.6 M in hexane). It was allowed to stir for a further 30 minutes at -70° C. and the clear yellow solution was admixed with 15.0 g (50.0 mmol) 1,10 dibromodecane dissolved in 30 ml THF and the temperature was kept for 6 hours between -50 and -35° C. The concentration precipitate that first formed dissolved again in this process. For the processing 200 ml 3 N HCl was added and it was extracted with 200 ml ethyl acetate. The organic phase was washed with 3 N HCl and saturated NaCl solution and the aqueous phase was again extracted with 200 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed by distillation. Flash chromatography of the residue on silica gel (mobile solvent: petroleum ether/ethyl acetate 4:1, 1% glacial acetic acid) yielded 8.3 g (48%) 1, melting point 49-51° C. (isohexane).
Reaction SMILES: [F:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1C(=O)N([I:18])C(=O)C1>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([I:18])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc2cc[nH]c12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cncc2c(I)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 7-fluoro-pyrrolo[3,2-c]pyridine (Preparation 62, 5 g, 36.76 mmol) in anhydrous DMF (35 mL) was added NIS (9 g, 40.44 mmol), and the reaction stirred at room temperature for 4 hours. The reaction was diluted with water and EtOAc. The organic layer was collected, washed with saturate aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50-100% EtOAc in heptanes followed by 5% MeOH in DCM to afford the title compound (5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CCOC(C)=O.Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)C3CCOCC3)cc2)OC1(C)C
Reactant: Nc1ncc(Br)nc1C#Cc1cccc(O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCOCC3)cc2)nc1C#Cc1cccc(O)c1
Temperature: 60 °C
Yield: 18.7 %

Procedure:
3-[2-(3-Amino-6-bromo-pyrazin-2-yl)ethynyl]phenol (50 mg, 0.1723 mmol), 4,4,5,5-tetramethyl-2-(4-tetrahydropyran-4-ylsulfonylphenyl)-1,3,2-dioxaborolane (85.70 mg, 0.2068 mmol) and K3PO4 (73.15 mg, 0.3446 mmol) were combined in MeCN (2 mL)/water (0.5 mL) and Pd[P(tBu)3]2 (4.403 mg, 0.008615 mmol) was added. The reaction was heated at 60° C. for 15 hours. The reaction was cooled to ambient temperature and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, dry loaded) followed by purification by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (14 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.30-1.41 (m, 2H), 1.56 (d, 2H), 3.07-3.12 (m, 2H), 3.34-3.40 (m, 2H), 3.71 (dd, J=3.9, 11.4 Hz, 1H), 6.67-6.70 (m, 1H), 6.94 (br s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.07 (t, 1H), 7.70 (d, 2H), 8.05 (d, 2H), 8.55 (s, 1H) and 9.57 (s, 1H) ppm; MS (ES+) 436.1.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:3]=1[C:16]([O:18]C)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[NH2:24]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[C:3]=1[C:16]([NH:24][C:23]1[CH:22]=[C:21]([Cl:20])[CH:27]=[C:26]([Cl:28])[CH:25]=1)=[O:18]
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Yield: 95.8 %

Procedure:
Prepared from 2.00 g (5.81 mmol) of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate and 2.82 g (17.41 mmol) of 3,5-dichloroaniline following the experimental procedure described in Preparation 44a. The product was purified by flash chromatography (0% to 40% hexane/AcOEt) to give 2.64 g (96% yield) of the title compound as a beige solid.
Reaction SMILES: Br[CH2:2][CH:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Ba+2]>C(O)C>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:9]2[CH:3]([CH2:2][O:21][CH2:20][CH2:19][Cl:18])[O:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: OCCCl
Reactant: COc1cc2c(cc1OC)C(CBr)OCCC2
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(COCCCl)OCCC2
Reaction time: 46 h

Procedure:
A mixture of 10.33 g (0.343 moles) of 1-bromomethyl-1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin, 10 ml of 2-chloroethanol, and 6.77 g of barium carbonate is stirred at 90° for 46 hours. The reaction mixture is then cooled, ethanol is added, and the solids are removed by filtration. The filtrate is taken to dryness in vacuo and the resulting oil is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is then taken to dryness and chromatographed on silica gel using 10 ethylacetate:Skellysolve B as eluent to give 4.18 g (41d) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl chloride, m.p. 90°-91°.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CCc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (415 mg, 11.0 mmol, prepared in Synthetic Example 9) in DMF (10 ml) was added hydrazine monohydrate (80%, 160 μl, 3.99 mmol, 4.0 eq.), and the mixture was then stirred at 100 to 110° C. for 7 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (389 mg, 94%).