Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:27]=1[OH:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[O:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Cl)ccnc21
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Oc3ccc(N)cc3F)ccnc21
Temperature: 185 °C
Yield: 7.4 %

Procedure:
A mixture of 4-chloro-2-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (3.2 g, 8.9 mmol), 2-fluoro-4-nitrophenol (2.79 g, 17.8 mmol), and DIPEA (3.5 mL, 20 mmol) in NMP (15 mL) was heated in a sealed tube at 185° C. for 3 days. The mixture was diluted with EtOAc and filtered through a short pad of Celite® (EtOAc). The filtrate was washed with 5% aq. Na2CO3 solution and dried over MgSO4. The title compound was purified by flash column chromatography (silica gel, 100% CH2Cl2 to 50% EtOAc/CH2Cl2) to afford the desired product (295 mg, 7.4%) as a light brown solid. LC/MS(ESI+) m/z 451 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C(#N)C.CCOCC.N1C2C(=CC=CC=2)C=CC=1>[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](=[O:9])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccccc1CCl
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Solvent: CC#N
Product: N#CC(=O)c1ccccc1CCl
Temperature: 60 °C
Yield: 97.5 %

Procedure:
A mixture of acetonitrile (100 ml), 95% sodium cyanide (6.19 g), 95% cuprous iodide (2.00 g) and quinoline (0.13 g) was stirred at 60° C. A solution of 2-chloromethylbenzoyl chloride (19.0 g) in acetonitrile (100 ml) was added dropwise to the reaction mixture over 3 hours. After completion of the addition, the mixture was stirred at 60° C. for 5 hours. After the reaction mixture was cooled by allowing it to stand, the reaction mixture was diluted with ether, and washed successively with water, a saturated aqueous solution of sodium bicarbonate and water. The ether layer thus obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude title compound (17.6 g, purity: about 72% determined by 1H-NMR analysis).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[CH3:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:24][CH:23]3[CH3:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1CNCCN1c1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCN(c2ccc3ncc(Br)n3n2)C(C)C1
Reaction time: 17 h

Procedure:
Hunig's base [7087-68-5] (2.1 mL, 12.1 mmol) was added to an ambient temperature, stirred suspension of 3-bromo-6-(2-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine dihydrochloride (1.1 g, 3.0 mmol) in ethyl acetate (150 mL). The suspension was stirred for 1.5 h then a 1.0M solution of isopropyl chloroformate in toluene (3.0 mL) was slowly added and the reaction allowed to proceed for 17 h then washed with brine. The ethyl acetate phase was dried (MgSO4) and evaporated. Product was purified by preparative RP-HPLC to provide 52.1 mg of racemic isopropyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-3-methylpiperazine-1-carboxylate as a light yellow solid, mp. 52-54° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.57 Hz, 3H) 1.15-1.25 (m, 6H) 2.51 (dt, J=3.73, 1.80 Hz, 2H) 3.15 (dd, J=12.88, 2.78 Hz, 2H) 3.86 (d, J=13.39 Hz, 1H) 3.98 (d, J=13.39 Hz, 2H) 4.47 (br. s., 1H) 4.78-4.87 (m, 1H) 7.23 (d, J=10.10 Hz, 1H) 7.64 (s, 1H) 7.91 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.53, 21.90, 42.71, 48.04, 68.05, 99.42, 110.59, 126.00, 131.15, 136.33, 154.41, 154.71. LRMS (ESI) m/z 382.0/384.0 [(M+H)]+, calc'd for C16H20BrN6O2: 382.26.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[C:22]([F:29])[CH:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:26][C:24]1[CH:25]=[C:20]([C:18]#[C:17][CH:16]=[C:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)[CH:21]=[C:22]([F:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1c(F)cc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1F
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A mixture of Compound 1c (50 mg, 0.206 mmol), 4-bromo-2,6-difluoroanisole (45.9 mL, 0.206 mmol), bis(triphenylphosphine)palladium(II)dichloride (7.23 mg, 0.012 mmol), CuI (3.92 mg, 0.206 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 10:90) affording the title product (22 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:36])[N:13]2[CH2:25][C:24]3[C:23](=[O:26])[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH:14]2[C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[O:36]=[C:12]([N:13]1[CH2:25][C:24]2[C:23](=[O:26])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:15]=2[CH:14]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)/[CH:11]=[CH:10]/[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1

Procedure:
(E)-4-[3-oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoic acid methyl ester (149 mg, 0.30 mmol), (prepared as in Example 30) was suspended in a 1:1 mixture of 1N aqueous sodium hydroxide:methanol (10 mL) and heated to reflux for 8 h. The reaction mixture was treated with aqueous HCl to pH 1, resulting in a white precipitate. The precipitate was collected by filtration and washed with water (30 mL) and diethyl ether (160 mL) to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: OCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCNc1cccc(Br)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 3-bromo-aniline (0.037 mol), 2-bromo-ethanol (0.074 mol) and triethylamine (0.0555 mol) in toluene (35 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature and the precipitate was filtered off. The solvent of the filtrate was evaporated until dryness. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 4.8 g of 2-(3-bromo-phenylamino)-ethanol (60%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acid tert-butylester (1.0 g; 3.22 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid), were added to the reaction mixture, until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.62 g of (2R)-3-(4-fluorophenyl)-N-methyl-2-methylaminopropionamide.
Reaction SMILES: Br[CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[C:17]1(=[O:27])[N:21]([CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]2[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C(=O)c1cnc(OCC(O)CBr)s1
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc(OCC(O)CN2C(=O)c3ccccc3C2=O)s1

Procedure:
By a procedure analogous to Example 2 the product from Example 7 can be reacted with potassium phthalimide in N,N-dimethylformamide to give the solid title compound.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=O)C.[CH3:27]O>>[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:27])=[O:19])=[CH:9][CH:8]=1
Reactant: CC(=O)NCCc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Reactant: CO
Product: COC(=O)CCCC=C(c1ccc(CCN)cc1)c1cccnc1

Procedure:
Prepared by hydrolysis of 6-(4-(2-acetylaminoethyl)-phenyl)-6-(3-pyridyl)hex-5-enoic acid and subsequent esterification with methanol analogously to Example 8b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:11]=[C:12]([CH2:23][OH:24])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:11]=[C:12]([CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCc1c(COS(C)(=O)=O)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) and triethylamine (65.9 mg) in dichloromethane (2 mL) was added methanesulfonyl chloride (54.7 mg) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL). The mixrure was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (5 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as an yellow gum (247 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@:6]([OH:26])(/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:13]([OH:24])[CH2:12][C@H:11]1[OH:25])[CH3:7].O=O.C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.CCOC(C)=O.CCCCCC.C1(C)C(C)=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@:6]([OH:26])(/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:13]([OH:24])[CH2:12][C@@H:11]1[OH:25])[CH3:7]
Reactant: CCCCC[C@](C)(O)/C=C/[C@@H]1[C@@H](C/C=C/CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CCCCC[C@](C)(O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@@H]1O
Reaction time: 2.5 h

Procedure:
A solution of 15-methyl-PGF2α (185 mg.) in 2.5 ml. of an anhydrous, oxygen-free xylene containing 2,2'-dipyridyl disulfide (165 mg.) and triphenylphosphine (196 mg.) is stirred under nitrogen for 2.5 hr. at 25° C. The mixture is diluted with 150 ml. of xylene and heated at reflux for 3 hr. TLC (80 percent EtOAc/hexane) shows essentially a single, less polar product. The xylene is removed by evaporation at reduced pressure to afford a residue which is diluted with ice/water/sodium bicarbonate and ethyl acetate and extracted thoroughly with ethyl acetate. The ethyl acetate extract is washed with brine, dired over anhydrous sodium sulfate and concentrated to afford a residue of (15S)-15-methyl PGF2α, 1,9-lactone. The residue is purified by chromatography on 50 g. of neutral silica packed with 10 percent acetone/methylene chloride and eluted (5 ml. fractions) with 200 ml. of 10percent acetone/methylene chloride, 1500 ml. of 20 percent acetone/methylene chloride and 1000 ml. of 35 percent acetone/methylene chloride.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[N:19]1([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:9]=[C:10]4[C:2]([C:28]5[CH:29]=[N:25][NH:26][CH:27]=5)=[N:3][NH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=2)=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Reactant: OB(O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(c1cccc(-c2cnc3[nH]nc(-c4cn[nH]c4)c3c2)c1)N1CCOCC1
Yield: 28.6 %

Procedure:
A mixture of [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone (25 mg, 58 μmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (5 mg, 6 μmol) and 1H-pyrazol-4-ylboronic acid (11 mg, 98 μmol) in acetonitrile (2 mL) and 2 M solution of sodium carbonate (1 mL) was irradiated in a Personal Chemistry Optimizer at 175° C. for 30 min. The crude reaction mixture was diluted with water (1 mL) and ethyl acetate (3 mL) and the organic phase separated, filtered and concentrated. The resulting crude mixture was then purified by mass-triggered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford morpholin-4-yl-{3-[3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone (6.2 mg, 29% yield) of as a colorless powder. 1H-NMR (500 MHz, d6-DMSO) δ 13.59 (s, 1H), 13.17 (s, 1H), 8.87 (d, 1H), 8.73 (d, 1H), 8.60 (s, br, 1H), 8.17 (s, br, 1H), 7.95 (ddd, 1H), 7.89 (t, 1H), (t, 1H), 7.59 (t, 1H), 7.43 (ddd, 1H), 3.80-3.35 (m, 8H). MS: m/z 397 [MNa+], 375 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CC(N(C)C)=O>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[N:9]([CH3:16])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)oc(=O)c2ccc(F)cc21
Reaction time: 1.25 h

Procedure:
A stirred solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (9.0 g) in dimethylacetamide (100 ml) at 18.5° was treated portionwise with sodium hydride (80% dispersion in mineral oil, 1.65 ) during 10 minutes. The mixture was stirred for a further 75 minutes. Methyl iodide (7.81 g) was then added dropwise to the stirred mixture during 5 minutes and the mixture was stirred for a further 18.5 hours at ambient temperature. Solvent (60 ml) was removed by distillation in vacuo. The residue was cooled to 3° and poured into ice-water. The resulting precipitate was collected, dried in vacuo and recrystallised from dichloromethane to give 7-fluoro-1-methyl-1H-3,1-benzoxazine-2,4-dione m.p. 158°-159.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3C(OC(C)(C)C)=O)=[N:11][C:7]=1[CH:6]=[CH:5]2.Cl.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH3:30])[CH:39]([CH3:41])[CH3:40])=[N:11][C:7]=1[CH:6]=[CH:5]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
(1R,3S,4S)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 0.45 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 1 h, after which the solvent was removed. The intermediate (154 mg, 0.45 mmol) was dissolved in DMF (5 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (79 mg, 0.45 mmol), HATU (171 mg, 0.45 mmol), and DIPEA (0.39 mL, 2.25 mmol) were added sequentially. After stirring o/n, the solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The mixture was purified by silica gel chromatography to yield product (122 mg).
Reaction SMILES: C([N:8]([CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[ClH:34]>CO.[Pd]>[ClH:34].[OH:19][CH:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][NH:8][CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)COc1ccc(CCNCC(O)COc2ccccc2)cc1
Reaction time: 16 h

Procedure:
The starting material was prepared by dissolving methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate (3.0 g) (see Example 8) in methanol (150 ml), adding ethereal hydrogen chloride dropwise to give a pH of 3, followed by 10% palladium on carbon (250 mg). The mixture was stirred under an atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated to give methyl 4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]phenoxyacetate hydrochloride (3.0 g) in the form of a gum, which was used directly and without further purification
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:11]1([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCN(C(=O)Nc3ccc(C)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 2.7 %

Procedure:
A solution of 1-isocyanato-4-methyl-benzene (0.051 mol) in DCM p.a. (75 ml) was added dropwise to a solution of 4-(1-piperazinyl)-benzoic acid, ethyl ester (0.043 mol) and triethylamine (0.051 mol) in DCM p.a. (75 ml) while stirring at 0° C. (ice) for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour and was then extracted with water. The organic layer was extracted with a saturated NaCl-solution and again with water, then separated, dried (MgSO4), filtered off and the filtrate was evaporated. The residue was stirred in DIPE and the formed precipitate was filtered off, washed with DIPE and dried. A part (0.5 g) of the residue (14.3 g, 90%) was crystallized from 2-propanol (10 ml) and the formed precipitate was filtered off and dried, yielding 0.42 g of 4-[4-[[(4-methylphenyl)amino]carbonyl]-1-piperazinyl]-benzoic acid, ethyl ester (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36]C(=O)C)[CH:10]=1>Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:36])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCN(C)CC5)nn4)ccc32)c1
Agent: Cl
Product: CN1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cc(N)cc(-c4ccc(F)cc4F)c3)nn2)CC1
Yield: 27 %

Procedure:
A solution of the compound of Example 164 (0.48 g, 0.91 mmol) in 6 N HCl (10 ml) was heated at 70° C. for 3 h. The mixture was quenched with NaHCO3 solution and extracted as in Example 1(d). The solvent was distilled off to afford the product in 27% yield (0.12 g).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:34])[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12]C.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:34])[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Boron tribromide (44.8 mL of a 1 M solution in methylene chloride; 44 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (6.8 g, 14.7 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature 60 mL of water was added dropwise. The reaction was then partitioned between additional amounts of methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (4.7 g, 71%) as a solid, mp 237-239° C. Elemental Analysis for C24H21BrN2O2. Calc'd: C, 64.15; H, 4.71; N, 6.23. Found: C, 62.15; H, 4.63; N, 5.97.