Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:43]3[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][CH:42]=3)(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 4-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 114 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (86 mg, 50%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].[K].CC(C)([O-])C.Br[CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=1)=[O:21]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)=[O:21])[CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: CC(C)(C)n1cc(C(=O)CBr)cn1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)cn1CC(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 229 mg (1.50 mmol) 4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 3.7 ml DMF is added 185 mg (1.65 mmol) potassium-tertbutoxide portionwise under nitrogen. The mixture is stirred for 30 minutes at room temperature and cooled to 0° C. Then 367 mg (1.50 mmol) 2-bromo-1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone is added. The mixture is stirred for 1 hour at 0° C. and for 30 minutes at room temperature. The reaction mixture is partitioned between dichloromethane and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate to afford 1-[2-(1-tert-butyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as yellow oil; HPLC/MS 2.82 min (B), [M+H] 318.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][C:8]([I:15])=[CH:7][CH:6]=2.[N+](C1C=CC=CC=1)([O-])=O.CCN(C(C)C)C(C)C>>[I:15][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([OH:1])=[CH:11]2
Reactant: O=C(O)c1c(O)cnc2ccc(I)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1cnc2ccc(I)cc2c1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g, 70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed by adding Hunig's base (25 mL)—the suspension was completely dissolved. The resulting mixture was heated to reflux (210° C.) under N2. After 3 h, LC/MS showed no sign of starting material mass. The reaction mixture was cooled to rt; solvent was removed as much as possible in vacuo. The crude product was redissolved in DCM/MeOH and the solid was collected by filtration. The solid was rinsed with hexane and either and dried as brownish solid. The filtrate was removed excess solvent and purified using SiO2 chromatography (TELEDYNE ISCO REDISEP®, P/N 68-2203-058, 330 g SiO2, solvent system: hexanes:acetone=80%:20%, Flow=100 mL/min) to afford the desired product as brown solid. MS m/z: 272.3 (M+H). Calc'd. for C9H6INO−271.05.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[F:28])[N:18]=[C:17]3[N:29](C4CCCCO4)[N:30]=[C:31]([CH3:32])[C:16]=23)[CH2:10][C:9]1([CH3:40])[CH3:39])=O)(C)(C)C.Cl>ClCCl>[CH3:39][C:9]1([CH3:40])[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[F:28])[N:18]=[C:17]3[NH:29][N:30]=[C:31]([CH3:32])[C:16]=23)[CH2:10]1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)c12
Agent: Cl
Solvent: ClCCl
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCNC(C)(C)C3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.6 %

Procedure:
274 mg of 4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 5 ml of dichloromethane, and 1 m of hydrochloric acid (4N in 1,4-dioxane) was added. After stirring at r.t. for 16 h the volatiles were removed in vacuo and the resulting residue was purified by HPLC to obtain 12 mg (7%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2].CN(C)C=O.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C1C(=O)N(C(=O)OCC)c2ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)(C(=O)OCC)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl-5-chloro-2-oxoindoline-1,3-dicarboxylate, intermediate 50, (5.0 g, 16.04 mmol) in anhydrous N,N-dimethylformamide (80 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.64 mmol) was added dropwise at ambient temperature at such a rate that the internal temperature remained below 30° C. After continuous stirring at ambient temperature for one hour the solution was treated with tert-butyl bromoacetate (2.73 ml, 18.45 mmol) and stirring was allowed to continue for 72 h. Water (100 ml) was added, the product was extracted with tert-butyl methyl ether (2×50 ml), the combined extracts were washed with brine (50 ml) and dried (MgSO4) to give a red solid (7.11 g). Purification by flash chromatography (n-heptane/ethyl acetate=15%; increased up to 20%) yielded the title compound (4.00 g, 59%) as colorless solid (HPLC purity: 99%).MS (ESI+): 426.3
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]([CH3:25])[CH:22]([OH:24])[CH3:23])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:6]=1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:37]([O:36][C:32](=[O:35])[CH2:33][CH2:34][O:24][CH:22]([CH3:23])[CH:21]([O:20][C:18]1[C:19]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=3)=[C:12]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:13][C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:25])([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)C(C)O)c23)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)C(C)OCCC(=O)OC(C)(C)C)c23)cc1
Reaction time: 1 h

Procedure:
Add 2.2 ml of 45% sodium hydroxide solution to a mixture of 900 mg (2.31 mmol) 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}butan-2-ol, 1477 mg (11.53 mmol) tert.-butyl acrylate and 157 mg (0.46 mmol) tetra-n-butylammonium hydrogensulphate in 10 ml dichloromethane at 0° C., and stir at this temperature for one hour. After a further 16 hours at room temperature, filter the reaction mixture, and concentrate the filtrate by vacuum evaporation. Purify the raw product by preparative RP-HPLC (gradient: water/acetonitrile). 690 mg (57% of theor.) of the desired product is obtained as (R,S/S,R) racemate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[Cl-]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:24](=[O:23])[CH:25]([CH3:30])[CH3:26])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Agent: [Cl-]
Product: CC(C)C(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isobutyramide is prepared as described in Example 50 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and isobutyril chloride (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.95 min (Grad 2); ES-MS: m/eo=470.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]1=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]3=[O:13])[CH2:25][CH2:26]2)=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: Cc1c[nH]c(=O)n(CCCCl)c1=O
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Product: COc1cc(Cl)ccc1N1CCN(CCCn2c(=O)[nH]cc(C)c2=O)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (223 mg, 0.98 mmol), prepared as in Example 19, and 1-(4-chloro-2-methoxyphenyl)piperazine (200 mg, 0.98 mmol), prepared as in Example 12, was heated 2 hours with stirring at 180° to 190° C., allowed to cool to 25° C. and then purified by preparative thin layer chromatography on silica gel eluting with methylene chloride/(methylene chloride/methanol/ammonium hydroxide-60:10:1) (7:3) to give 3-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione. The free base was recrystallized from a solution of hydrogen chloride in methanol to give 3-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 182°-184° C. Anal.: Calcd. for C19H25ClN4O3.(HCl)2 : C, 48.25; H, 5.92; N, 11.84%; Found: C, 48.55; H, 5.81; N, 11.85%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2.[N+](=[CH2:17])=[N-]>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:17])=[O:13])[CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cccc(O)c2n1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
8-Hydroxyquinoline-2-carboxylic acid (2.08 g) and tetrahydrofuran (200 ml) were combined and stirred with ice bath cooling. Diazomethane (approx. 16.6 mmol in solution in diethyl ether) was then added and the whole stirred for 1.5 h as it slowly warmed to room temperature. Nitrogen was blown through the reaction mixture to purge any excess diazomethane and the solution was evaporated in vacuo to give the title compound (1.6 g).
Reaction SMILES: CS(O/[N:6]=[C:7]1\[CH2:8][CH2:9][C:10]2[C:15]\1=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=O)=O.B(F)(F)F.CS(Cl)(=O)=[O:24].C(Cl)Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:6][C:7]2=[O:24])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To the solution of intermediate 17 (7.76 g, 30.4 mmol) in 1,2-dichloroethane (150 mL) was added BF3 (5.52 mL, 48.7 mmol, in MeOH), MsCl (3.8 mL, 48.7 mmol) and TiCl4 (5.35 mL, 48.7 mmol). The mixture was stirred at rt for 5 h. CH2Cl2 (150 mL) was then added to the reaction mixture. The solution was washed with water and brine. The water layer was neutralized by aqueous Na2CO3 to pH=7 and was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/EtOAc=4:1) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate 18) (5.1 g, 95%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (290 mg, 56%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[C@@H:14]([O:29]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].Cl>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[C@@H:14]([OH:29])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C1CCCCC1
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of (cyclohexylcarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (44c) (0.79 g, 1.4 mmol), 0.4 g of 10 wt.-% of palladium on activated carbon in 20 mL of methanol (MeOH), and 30 μL of one molar (1.0 M) of hydrochloric acid (HCl) was stirred overnight under a hydrogen atmosphere. Upon the completion of reaction and following aqueous work-up, 0.62 g (94% yield) of the title compound (44) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, DMSO-d6, both diastereomers): δ=0.92-0.94 (2s, 3H), 0.97-0.98 (2s, 3H), 1.20-1.42 (br. m, 5H), 1.46-1.48 (2d, J=5.6, 5.6 Hz, 3H), 1.55-1.62 (br. m, 1H), 1.66-1.70 (br. m, 2H), 1.80-1.87 (m, 7H), 2.33-2.40 (m, 1H), 3.14-3.19 (m, 2H), 3.34-3.37 (m, 2H), 3.92-3.96 (m, 2H), 4.09-4.12 (2d, J=9.2, 9.6 Hz, 1H), 5.50-6.87 (2d, J=5.2, 5.6 Hz, 1H), 6.81-6.87 (m, 1H), 7.95-7.98 (br. m, 1H) ppm. MS (ESI) m/z: 466.10 (M+H)+, 488.07 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To the suspension of 4-(4-fluoro-phenyl)-1H-indole (2.28 g, 10.79 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (147 mL) was added pyridinium tribromide (90% purity from Aldrich, 11.51 g, 32.38 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (108 mL). Zinc dust (10.52 g, 162 mmol) was added to the reaction mixture portionwise, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated and the syrupy residue was suspended in water for 4 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (2.40 g, 98%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[CH:27][CH:26]=[CH:25][C:24]=1[B-](F)(F)F)(=[O:20])[CH3:19].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[C:18]([O:21][CH2:22][C:23]1[C:24]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]1[N:38]=[CH:37][C:36]2[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:41])([CH3:40])[CH3:42])[CH:35]=2)[C:30]1=[O:44])(=[O:20])[CH3:19]
Reactant: Cc1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 80.6 %

Procedure:
In a 50 mL test tube, 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 394 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (224 mg, 473 μmol, Eq: 1.2) were combined with BuOH (4.00 ml) to give a orange solution. Water (1.00 ml) was added. X-PHOS (18.8 mg, 39.4 μmol, Eq: 0.1) and potassium phosphate tribasic (167 mg, 788 μmol, Eq: 2) were added. Bis(dibenzylideneacetone)palladium (11.3 mg, 19.7 μmol, Eq: 0.05) was added. The reaction mixture was purged with argon. The solution warmed in a oil bath at 100° C. for 1.5 hours. The solution was allowed to cool to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with DCM. The organic layer was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 30% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a solid. The solid was triturated with Et2O to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (186 mg, 81%). LC/MS-ESI observed [M+H]+ 586.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[OH-].[Na+].[CH:13](Cl)(Cl)Cl.C(Cl)Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([N+:9]#[C-:13])[CH2:5][CH2:4]1
Reactant: ClC(Cl)Cl
Reactant: NC1CCC(F)(F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4,4-Difluoro-cyclohexylamine hydrochloride (1.0 g, 5.8 mmol, 1 equiv.) was added to a mixture of NaOH (1.5 g, 37 mmol, 6.3 equiv.) and tetrabutylammonium hydrogen sulfate (40 mg, 0.12 mmol, 0.02 equiv.) in water (2.5 ml), chloroform (3 ml, 37 mmol) 6.3 equiv.) and DCM (5 ml). The mixture was stirred at room temperature for 72 h and the crude extracted with DCM. The product was isolated via Kieslgel chromatography.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>C(OCC)C>[CH2:23]([O:22][C:16]([CH:17]([CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12)[C:18]([CH3:20])=[O:19])=[O:21])[CH3:24]
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C(C)=O)C1NC(=O)c2sccc2-n2cccc21
Yield: 47 %

Procedure:
Using the procedure described in Example 26, starting with 1 g of 6-hydroxy-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine and 2 ml of ethyl acetoacetate, 0.7 g of 6-[1-(ethoxycarbonyl) -acetonyl]-5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]thieno -[2,3-f][1,4]diazepine was obtained in the form of white crystals, melting point 196° C. (ethyl ether).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[O:22])[CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][CH3:31])=[CH:26][CH:25]=2)=[O:22])[CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CSc1ccccc1B(O)O
Reactant: CCCN(C(=O)Nc1ccc(I)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCN(C(=O)Nc1ccc(-c2ccccc2SC)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
1.5 g (2.883 mmol) of 405 and 0.968 g (5.766 mmol) of 2-(methylthio)-phenylboronic acid are dissolved in 100 ml of ethylene glycol dimethyl ether, treated with 63 mg (0.086 mmol) of PdCl2(dppf) and 20.0 ml of 2N sodium carbonate solution and then stirred at 110° C. under a nitrogen atmosphere for 3 h. After customary work-up, 1.28 g (75.9%) of 409 are thus obtained as crystals having a melting point of 184-185° C.; MS(FAB)=517.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(C(N)=O)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-2-nitrobenzamide 2 (1.0 g, 0.005 mol) in 20 mL dichloromethane cooled in an ice-bath was added aluminum chloride (2.0 g, 0.015 mol) portion wise. The resulting mixture was gradually warmed to room temperature and then refluxed for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was added to water. The aqueous layer was separated and evaporated to dryness. The residue was dissolved in methyl tert-butyl ether, filtered and the filtrate was evaporated to give 4-hydroxy-2-nitrobenzamide 3. Colorless oil (0.7 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.07 (dd, J=2.4, 8.4 Hz, 1H); 7.32 (d, J=2.4 Hz, 1H); 7.45 (d, J=8.4 Hz, 1H).