Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(CC[O:12][C:13](=[O:66])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[S:34]([CH2:36][C:37]3[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:40]=[CH:39][N:38]=3)=[O:35])(=[O:24])=[O:23])=[CH:18][C:17]=2[O:50][CH2:51][C:52]([O:54]CCS(C2C=CC=CC=2)(=O)=O)=[O:53])(=O)=O)C=CC=CC=1.C([O-])(O)=O.[Na+:71]>C1COCC1.O>[Na+:71].[Na+:71].[C:52]([CH2:51][O:50][C:17]1[CH:18]=[C:19]([S:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[S:34]([CH2:36][C:37]2[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])[CH:40]=[CH:39][N:38]=2)=[O:35])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([O-:66])=[O:12])([OH:54])=[O:53].[C:52]([CH2:51][O:50][C:17]1[CH:18]=[C:19]([S:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[S:34]([CH2:36][C:37]2[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])[CH:40]=[CH:39][N:38]=2)=[O:35])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([O-:66])=[O:12])([OH:54])=[O:53]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)OCCS(=O)(=O)c2ccccc2)c(OCC(=O)OCCS(=O)(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)[O-])c(OCC(=O)O)c1
Yield: 88.3 %

Procedure:
A solution of (2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 30, 500 mg, 0.50 mmol) and NaHCO3 (90 mg, 1.10 mmol, 2.2 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 2 h. Thereafter volatile materials were removed by evaporation under reduced pressure and the residual semi-solid was briefly treated with MeOH-CH2Cl2 (1:1). The resulting solid was collected by filtration to give Compound 12 (300 mg, 74%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(N)ccc1O
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Temperature: 100 °C

Procedure:
4-Amino-2-methyl-phenol (84 mg, 0.68 mmol), Cs2CO3 (665 mg, 2.04 mmol) and NMP (2.5 mL) were combined. The mixture was heated for 5 minutes at 100° C., cooled to RT and [4-(2-chloro-pyridin-3-yl)-pyrimidin-2-yl]-methyl-amine (150 mg, 0.68 mmol) was added. The mixture was heated in the microwave to 210° C. for 20 minutes, cooled, filtered through a plug of cotton and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=308 [M+1]+. Calc'd for C17H17N5O: 307.36.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:9][CH:8]=1>>[O:20]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:8][CH:9]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 43.3 %

Procedure:
In a manner similar to that described in Example 3, propionyl chloride (0.029 g, 0.00032 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.027 g of 4-oxo-4-[4-(propionylamino)-phenyl]-butyric acid as an off-white solid; MS-(AP+) MH+250.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:13]=2)[C:8]1=[O:26])[CH3:6])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:13]=2)[C:8]1=[O:26])([CH3:28])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Temperature: -78 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
The 2-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid ethyl ester (Example 10b, 365 mg, 0.983 mmol) was solved in THF (3.5 ml) and at −78° C. was added potassium bis(trimethylsilyl)amide (7.8 mL, 3.9 mmol), followed 15 min later by methyl iodide (0.368 mL, 5.89 mmol). The reaction mixture was stirred at −78° C. for 5 hours. Ammonium chloride was added and the reaction extracted with dichloromethane. The organic phases were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (hexane to hexane/ethyl acetate 1:1) to give 288 mg (76%) of the product. MS: m/e=386.2 (M+H+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Mg].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.S(=O)(=O)(O)O.[CH2:20]([Mg:23][Br:24])[CH:21]=[CH2:22]>O1CCCC1.CCOCC>[CH2:20]([Mg:23][Br:24])[CH:21]=[CH2:22].[OH:10][C:8]([C:7]([F:6])([F:13])[F:14])([CH2:22][CH:21]=[CH2:20])[CH2:1][CH:2]=[CH2:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C=CCBr
Agent: C=CC[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)(CC=C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Allylmagnesium bromide was prepared from 140 g (1.16 mole) of allyl bromide, 35 g (1.44 mole) of magnesium and 640 ml of ether. The product was titrated and found to be 1.2 molar in allylmagnesium bromide. To a 230 ml (0.276 mole) aliquot of the reagent was added 17.4 g (0.122 mole) of ethyl trifluoroacetate in 60 ml of dry tetrahydrofuran at a drop rate of 2-3 drops/second. The reaction temperature was held near -40° during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was heated at reflux for two hours, then stirred for an additional 24 hours. The reaction mixture was poured into 300 ml of ice and 20% sulfuric acid was added to bring the pH to about 1. The phases were separated and the aqueous phase extracted with 3×70 ml of ether. The combined organic phases were dried over magnesium sulfate, filtered and the solvent evaporated. The liquid product was distilled in vacuo to give 15.2 g (70%) of 4-hydroxy-4-trifluoromethyl-1,6-heptadiene, bp 54.5-58.5° C./30 torr.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.C(O)(=O)C.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>CO.O.ClCCCl>[CH2:33]([N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M) (50 mg, 0.120 mmol) was added DCE (479 n1), acetic acid (10.28 μl, 0.180 mmol) and benzaldehyde (18.24 μl, 0.180 mmol). The mixture was shaken at room temperature for 10 min prior to the addition of sodium triacetoxyborohydride (76 mg, 0.359 mmol). The mixture was shaken at rt overnight yielding product (PMB protected) as the major species. To the mixture was added TFA (100 n1) and the mixture shaken at room temperature for 1 hr then at 80° C. for 1 hr. The mixture was concentrated under reduced pressure and purified with a 25 g HP spherical silica column (15 nm spherical, Interchim) ramping DCM:MeOH (90:10) in DCM (0-50%), monitoring at 215 nm providing product which had coeluted with minor impurities (51 mg). The material was repurified with Gilson RP-HPLC dissolving in DMSO/MeOH ramping ACN in H2O (10-90%, 0.1% TFA throughout). The product containing eluents were filtered through a 2 g SCX-2 column washing with MeOH, then 2 M NH3 in MeOH. The basic wash was dried under reduced pressure and lyophilized from MeOH/H2O providing product as an off-white solid, 4-benzyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (6 mg, 0.015 mmol, 12.93% yield). 1H NMR (500 MHz, DMSO-d6) ppm 3.45-3.50 (m, 2 H) 4.23 (t, J=4.33 Hz, 2 H) 4.56 (s, 2 H) 6.68 (d, J=8.55 Hz, 1 H) 6.75 (d, J=4.49 Hz, 1 H) 7.03 (d, J=2.24 Hz, 1 H) 7.14 (dd, J=8.49, 2.08 Hz, 1 H) 7.19 (d, J=4.49 Hz, 1 H) 7.26 (d, J=7.37 Hz, 3 H) 7.31-7.36 (m, 2 H) 12.48 (br. s., 1 H). m/z (ESI) 388.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].CON(C)[C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4](=[O:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:21]
Reactant: CON(C)C(=O)CCCCOc1ccccc1
Reactant: CCN(CC)C(=O)Oc1ccc(Cc2ccccc2)cc1
Product: CCN(CC)C(=O)Oc1ccc(Cc2ccccc2)cc1C(=O)CCCCOc1ccccc1

Procedure:
The title compound was prepared from 4-(phenylmethyl)phenyl diethylcarbamate and N-methoxy-N-methyl-5-phenoxypentanamide following the same procedure used in Example F. NMR (CDCl3) δ1.18 (t, 3H), 1.26 (t, 3H), 1.83 (m, 4H), 2.92 (t, 2H), 3.35 (q, 2H), 3.45 (q, 2H) 3.99 (m, 4H), 6.86-7.31 (m, 12H), 7.49 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:19]([OH:21])=[O:20])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A solution of 8.00 g (33.8 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 75 ml of dry THF was cooled to -78° C. and 36 ml (1.8M in pentane, 65 mmol, Aldrich) of t-butyllithium was added over 30 minutes. The reaction mixture was stirred for 30 minutes at -78° C. then warmed to -20° C. for 30 minutes. The mixture was recooled to -78° C. and 8.00 g (180 mmol) of crushed dry ice was added to the slurry, and then this was allowed to warm to room temperature over 2 hours. The mixture was concentrated in vacuo, 100 ml of 1N HCl was added to the residue and this was extracted with 100 ml of hot EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo to give a solid. Purification via recrystallization (EtOAc/petroleum ether) afforded 5.80 g (85%) of the title compound as small white needles: m.p. 198°-200° C.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11]([Br:13])=[CH:10][C:5]=2[C:6](=O)[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:16])=O>>[Br:13][C:11]1[S:12][C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([Cl:16])[C:5]=2[CH:10]=1
Reactant: N#Cc1c[nH]c(=O)c2cc(Br)sc12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)c2cc(Br)sc12
Reaction time: 1 h

Procedure:
2-Bromo-7-cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (99) (2.0 g, 7.84 mmol) was dissolved in phosphorus oxychloride (60 mL) and the resulting solution heated at reflux for 2 h. After this time the mixture was poured into ice and stirred for 1 h. The precipitated solid was filtered, washed with water and dried (50° C., P2O5, in vacuo), affording a brown solid (1.99 g). 1H NMR (300 MHz, d6-DMSO) δ 9.05 (s, 1H), 8.21 (s, 1H)
Reaction SMILES: Cl[B:2]([C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[F:24])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].Cl[SiH](C)C.B>>[F:20][C:19]1[C:14]([BH:2][C:3]2[C:4]([F:13])=[C:5]([F:12])[C:6]([F:11])=[C:7]([F:10])[C:8]=2[F:9])=[C:15]([F:24])[C:16]([F:23])=[C:17]([F:22])[C:18]=1[F:21]
Reactant: Fc1c(F)c(F)c(B(Cl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: B
Agent: C[SiH](C)Cl
Product: Fc1c(F)c(F)c(Bc2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.9 g (20 mmol) of chlorobis(pentafluorophenyl)borane are cooled to −78° C., and 8.9 g (100 mmol) of chlorodimethylsilane are slowly added dropwise. On warming to room temperature, the borane dissolves and a white precipitate is formed. The mixture is subsequently stirred for 1 hour and the precipitate is filtered off and washed with 20 ml of pentane.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:6]=[CH:5][NH:4]1>O1CCOCC1>[N:6]1[C:7]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[C:3](=[O:2])[NH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=CNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NC=NC12CCNCC2
Reaction time: 18 h

Procedure:
Hydrochloric acid (4.0 N in dioxane; 4 mL, 16.0 mmol) was added to a solution of tert-butyl 4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (60 mg, 0.24 mmol) in dioxane (6 mL). After 18 h, the reaction mixture was concentrated to give the hydrochloride salt of the title compound. MS 154.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]4[CH:20]=[C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:22]=[CH:23][C:14]=4[C:13]=3[C:12]3[C:30]([CH3:42])=[N:31][N:32](CC4C=CC(OC)=CC=4)[C:11]=3[N:10]=2)=[CH:5][C:4]=1C(F)(F)F.C(OC(C)C)(C)C.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]4[CH:20]=[C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:22]=[CH:23][C:14]=4[C:13]=3[C:12]3[C:30]([CH3:42])=[N:31][NH:32][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OC)c(C(F)(F)F)c5)nc32)c(=O)[nH]c2cc(N3CCNCC3)ccc24)cc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)[nH]c2cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3 g (4.77 mmol) of 5-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(4-methoxybenzyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one dissolved in 25 ml of trifluoroacetic acid is carried at 70° C. for 4 hours and then cooled to room temperature before the addition of isopropyl ether (50 ml). The reaction medium is stirred at room temperature for 30 minutes and then the precipitate obtained is filtered to yield 5-(4-methoxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one trifluoroacetate. The solid is dissolved in 40 ml of anhydrous dichloroethane. The reaction medium is cooled to 0° C. before the slow addition of 30.3 ml (30.3 mmol) of a 1 M solution of boron tribromide in dichloromethane. The reaction medium is carried at reflux for 20 hours with the regular addition of a cold 1 M solution of boron tribromide in dichloromethane (30.3 ml, 30.3 mmol additional in total) until the reaction is quenched. Methanol (roughly 100 ml) is added and then the reaction medium is stirred for 2 hours. The solvents are concentrated. Saturated aqueous NaHCO3 solution is added and the aqueous phase is washed with ethyl acetate. The aqueous phase is evaporated and then purified by silica gel chromatography (eluent: 60:14:24:2 dichloromethane/methanol/cyclohexane/ammonium hydroxide to pure methanol) to yield 150 mg (12.5%) of 2-hydroxy-5-(1-methyl-6-oxo-9-(piperazin-1-yl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-5-yl)benzoic acid hydrochloride in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
A solution of 2-bromo-1-fluoro-4-nitrobenzene (0.1 g, 0.45 mmol) and tert-butyl piperazine-1-carboxylate (85 mg, 0.45 mmol) in N,N-dimethylformamide (0.9 mL) was treated with potassium carbonate (94 mg, 0.68 mmol) and stirred at 20° C. for 23 h and at 60° C. for 3.5 h. The reaction mixture was diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellow oil. This material was purified by flash column chromatography to give the desired product (0.15 g, 87%) as a yellow solid. LCMS for C15H20BrN3O4Na (M+Na)+: m/z=407.9, 410.1.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]2[C:28]([CH3:33])=[N:29][CH:30]=[C:31]([CH3:32])[C:20]=12>C(Cl)(Cl)Cl>[CH3:33][C:28]1[N:21]2[C:22]3[C:27]([C:19]([CH2:18][CH2:17][N:13]4[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12]4)=[C:20]2[C:31]([CH3:32])=[CH:30][N:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: Cc1cnc(C)n2c1c(CCCl)c1ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C)n2c1c(CCN1CCC(NC(=O)c3ccccc3)CC1)c1ccccc12
Yield: 48.7 %

Procedure:
An intimate mixture of powdered 4-benzoylaminopiperidine (4.08 g) and 5-(2-chloroethyl)-1,4-dimethylpyrimido[1,6-a]indole (5.18 g. described in Example 12) is heated at 150°-160° C. for 30 minutes. After cooling, the melt is dissolved in chloroform, washed with 10% sodium hydroxide and repeatedly with water. The organic phase is dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform-methanol (35:1). The eluates are evaporated and the residue is crystallized from ethanol-diethyl ether to give 4.15 g of the title compound, mp 233°-234° C. The title compound is coverted to the dihydrochloride salt and crystallized from methanol; mp 247° C.; ir (nujol) 3255, 2450 and 1625 cm-1 ; uv(MeOH) λmax 256, 297, 309 and 322 nm; ε=33700, 6000, 9050 and 10880, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B#B>O1CCCC1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: B#B
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(C)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
2,4 dimethylbenzoic acid (10 g; 66.6 mmol) in dry tetrahydrofuran (250 ml) was cooled to 0° C. and treated with a solution of diborane in tetrahydrofuran (135 ml of a 1.0M solution). The reaction mixture was stirred overnight before quenching with 1N HCl and extraction of the product into ethyl acetate. The organic phase was dried (MgSO4) and freed of solvent. The crude product was filtered through a plug of silica, eluting with 10% ethyl acetate in hexane, to obtain 8.62 g (95%) of the alcohol as a clear oil. 1H NMR (CDCl3): δ2.30, 2.32 (s, 6H total); 4.63 (d, 2H); 6.99 (m, 2H); 7.23 (d, 1H). IR (neat): 3338, 2921, 1504, 1453, 1378, 1240, 1039, 1005, 820 cm-1.
Reaction SMILES: Br.[Br:2][CH:3]1[C:14](=[O:15])[C:7]2[N:8]3[N:13]=[CH:12][N:11]=[C:9]3[S:10][C:6]=2[CH2:5][CH2:4]1.N1C=NC(S)=N1>C(O)C>[BrH:2].[N:13]1[N:8]2[C:9]([S:10][C:6]3[CH2:5][CH2:4][CH2:3][C:14](=[O:15])[C:7]=32)=[N:11][CH:12]=1
Reactant: O=C1c2c(sc3ncnn23)CCC1Br
Agent: Br
Agent: Sc1nc[nH]n1
Solvent: CCO
Product: O=C1CCCc2sc3ncnn3c21

Procedure:
2-Bromo-1,3-cyclohexadione (4.4 g) prepared in Example 1, Route 1 (A) and 1H-1,2,4-triazole-3-thiol (2.32 g) were dissolved into absolute ethanol (50 ml), and the reaction mixture was heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled and filtered to give 5,6-dihydro[1,2,4]triazolo[5,1-b]benzothiazole-8(7H)-one hydrobromide (2.84 g, compound (IIc) of Reaction Scheme II). The hydrobromide was dissolved into anhydrous acetic acid (20 ml) and an equivalent amount of bromine was added dropwise thereto at a temperature of 100° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to give the titled compound (95%) as solids.
Reaction SMILES: Cl[CH:2](Cl)[CH3:3].FC1C=CC=CC=1C1C2C=C(N=C=O)C=CC=2N2C(C)=NN=C2CN=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([NH:48][C:49]([NH:51][CH2:52][CH2:53][OH:54])=[O:50])[CH:46]=[CH:47][C:42]=2[N:41]2C=[N:56][N:57]=[C:40]2[CH2:39][N:38]=1.NC1C=CC2N3C(C)=NN=C3CN=C(C3C=CC=CC=3F)C=2C=1.C(=O)([O-])[O-].[Na+].[Na+].C(CN)O>C(#N)C>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([NH:48][C:49]([NH:51][CH2:52][CH2:53][OH:54])=[O:50])[CH:46]=[CH:47][C:42]=2[N:41]2[C:2]([CH3:3])=[N:56][N:57]=[C:40]2[CH2:39][N:38]=1
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Reactant: CC(Cl)Cl
Agent: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1F)=NC2
Agent: Cc1nnc2n1-c1ccc(N=C=O)cc1C(c1ccccc1F)=NC2
Agent: O=C([O-])[O-]
Solvent: NCCO
Solvent: CC#N
Product: Cc1nnc2n1-c1ccc(NC(=O)NCCO)cc1C(c1ccccc1F)=NC2
Reaction time: 20 h

Procedure:
A dichloroethane solution of [6-(o-fluorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]-isocyanate, prepared as described in paragraph (a) of Example 1 from 5 g (16.3 mmol) of 8-amino-6-(o-fluorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, is added dropwise at room temperature while stirring to a suspension of 6.2 g (58.5 mmol) of sodium carbonate in 3 ml (49.8 mmol) of ethanolamine and 40 ml of acetonitrile. After 20 hours, the mixture is partitioned between 500 ml of water and 500 ml of methylene chloride/ethanol (4:1) at 50° C. The separated aqueous phase is treated again in an analogous manner, the combined organic extracts are dried and concentrated in vacuo. Crystallisation of the residue from ethanol yields 1-[6-(o-fluorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-8-yl]-3-(2-hydroxyethyl)urea of melting point 228°-230° C.
Reaction SMILES: [NH2:1][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.[CH2:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:17][CH3:18].C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 78.4 %

Procedure:
Reaction of 4-aminobenzophenone (99 mg, 0.51 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-propyl-benzamide (136 mg, 0.40 mmol, 78% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95).