Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:7]=1[OH:14].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(O)(=O)C>ClCCl>[F:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([NH:5][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:7]([OH:14])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(N)c(O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Temperature: 100 °C
Yield: 106.9 %

Procedure:
Polymer supported sodium cyanoborohydride (794 mg, 3.41 mmol) was added to a solution of commercially available 2-amino-5-fluoro-4-methylphenol (241 mg, 1.71 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (350 mg, 1.76 mmol) and acetic acid (0.489 mL, 8.53 mmol) in dichloromethane (10 mL). The mixture was heated by microwave at 100° C. for 30 min before being filtered and concentrated by rotary evaporation to give a green oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (593 mg, 73% purity, 78% yield) as a brown oil.
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=O)[O:4][CH2:5][O:6][C:7](=[S:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=[S:36])[O:4][CH2:5][O:6][C:7](=[S:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCP(=O)(OCOC(=S)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=S)(OCOC(=S)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, 2,2-dimethyl(thiopropionyl)oxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate is reacted with phosphorus pentasulfide to yield O-[2,2-dimethyl(thiopropionyl)oxymethyl] P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)nc1Oc1ccccc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a cooled solution of phenol (0.07 mL, 0.80 mmol) in dry DMF (5 mL), sodium hydride (NaH) (0.02 g, 0.80 mmol) was added and the resulting mixture was cooled at 5-10° C. and stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.25 g, 1.00 mmol) was added and the mixture refluxed for 20 h, cooled and extracted with EtOAc. The organic layer was washed with water, anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using dichloromethane-EtOAc (70:30 v/v) as eluent, to obtain 0.13 g of the title compound 18q as a pink solid (mp 129-131° C., 62% yield). 1H-NMR (CDCh): 5.04 (br s, 2H), 7.28-7.43 (m, 8H), 7.69-7.73 (m, 2H), 8.18 (s, 1H). MS (ESI): m/z 264 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:18])[CH:8]=2)[O:3]1.Cl.[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:24][CH3:25])[CH3:22]>CN(C=O)C.CC(=O)OCC>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:19])([CH3:1])[CH2:11][CH:10]2[N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:22]
Reactant: CN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: CCN(CC)CCCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)CC(C)(C)O2
Temperature: 100 °C
Yield: 48.2 %

Procedure:
0.7g (2.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-methylmethanesulfonamide (Example 15b) was stirred at RT for 1 h with 1.6 g (5.2 mmol) of phosphazene base [tert-butylimino-tri(pyrrolidino)phosphorane] in 2.5 ml of DMF. 0.48 g (2.6 mmol) of diethylaminopropyl chloride hydrochloride was then added and the mixture was heated to 100° C. for 8 h. After stripping off the solvent in vacuo, the residue was taken up in EA and the mixture was washed with water. After drying over magnesium sulfate and chromatography through a short silica gel column, 0.48 g of N-[6-(3-diethylaminopropoxy)-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide was obtained as a glassy solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].CCOC(C)=O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CNC
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dimethylamine (42 mL, 84 mmol) in THF at 0° C. is added 2,6-dimethoxybenzoyl chloride (5.58 g, 27.8 mmol) and it is warmed to RT and stirred for 18 h. The mixture is poured to EtOAc, washed with water, 1 N HCl solution and brine. The solvent is removed and concentrated to give the title compound and it is used in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([OH:17])=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate and NaOH in ethanol was stirred at 50° C. for 3 h after which it was cooled to RT and neutralized with conc. HCl. The solvent was removed under reduced pressure to obtain crude 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(Br)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl-ester (0.500 g, 2.75 mmol) in MeCN (3.78 mL) was added N-bromosuccinimide (0.492 g, 2.76 mmol) at room temperature. The reaction was stirred for 1 h at room temperature and concentrated. Chromatography (silica gel, gradient elution, 0-40%, EtOAc in petrol 40-60) gave the title compound (356 mg), 1H NMR (Me-d3-OD): 7.80 (1H, s), 7.43 (1H, s), 3.73 (2H, s), 1.66-1.51 (9H, m), 1.32 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C.N1C=CC=CC=1>[C:25]1([S:31]([NH:1][C:2]2[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 54.7 %

Procedure:
To a stirred solution of benzoic acid 3-amino-4-benzyloxy-phenyl ester (5.91 g, 18.5 mmol) (which was obtained in Example 16) in ethyl acetate (100 mL) and pyridine (20 mL) at 0° C. was added dropwise phenyl sulfonyl chloride (3.26 g, 18.5 mmol) in 50 mL of ethyl acetate. After one hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature over night. The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (4.65 g, 61%); 1H NMR (300 MHz, CDCl3) δ 4.93(s, 2 H), 6.90–7.80(m, 15 H), 8.12(d, J=8.5 Hz, 2 H), 9.81(s, 1 H); MS (ES) m/z: 458.9 (MH+, 100%); HRMS Calcd. for C26H22NO5S(MH+): 459.1141. Found: 459.1151.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(N(C)C)=O.C([SiH](CC)CC)C>O1CCCC1.C([Pd]Cl)C=C.O>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C#Cc2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: C=CC[Pd]Cl
Agent: CC[SiH](CC)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a flask was successively added N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (20 g; 42.60 mmol); allylpalladium(II) chloride (0.39 g; 1.06 mmol); triphenylphosphine (1.12 g; 4.26 mmol) and a solution of dimethylacetamide (80 ml)/water (2.3 ml) previously purge with nitrogen. The solution was heated at 70° C. for 30 minutes. To the reaction mixture was then added over 3 hours triethylsilane (7.42 g; 63.90 mmol). The mixture was stirred for 12 hours at 70° C. The reaction was cooled at 23° C. then diluted with tetrahydrofuran (180 ml) and successively washed with a solution of 1% Cysteine/2.5% NaHCO3/7% NaCl and a solution of 2.5% NaHCO3/7% NaCl. The organic layer was treated with activated carbon and the filtrate was concentrated down and solvent switched to methanol. The slurry was mixed at 62° C. for 60 minutes, cooled down to 25° C., mixed for 2 hours, filtered, and washed with methanol to give the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H) MS (APCI) m/z 470.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:32]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 3 ml of methylene chloride, cooled to 0° C., under argon, is added 346 μl of triethylamine followed by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 2 N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetatehexane to give 295 mg of the desired product as a white solid, m.p. 170-180° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisopropylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].C(O)(C(F)(F)F)=O.CO>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1cc(F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-5-fluorobenzonitrile (3.0 g, 15.00 mmol) and NaBH4 (1.419 g, 37.5 mmol) in THF (30 mL) was slowly added TFA (3.47 mL, 45.0 mmol) over a period of 20 min. The resulting mixture was stirred at rt for 16 hours, then MeOH (10 mL) was added and the mixture was stirred for another 30 min. It was then diluted with EtOAc (200 mL), washed with water, dried over Na2SO4 and evaporated. The residue was purified on an 80 g Thompson silica cartridge (3% to 100% B in Hexanes, 1200 mL, B: 10% MeOH in EtOAc). The desired product was obtained as a colorless oil (1.70 g, 8.33 mmol, 55.5% yield). LC/MS (0.647 min, MH+: 205.92). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.59 (1H, dd, J=8.85, 5.49 Hz), 7.43 (1H, dd, J=10.07, 3.05 Hz), 7.05 (1H, td, J=8.47, 3.20 Hz), 3.72 (3H, s), 2.00 (2H, br. s.).
Reaction SMILES: [Br:1][C:2]1[C:15]2[CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:28][CH2:27][NH:26][C@H:25]([C:29]([OH:31])=[O:30])[C@@H:24]1[C:32]([OH:34])=[O:33].[OH-].[Na+]>O1CCOCC1.C1C=CC=CC=1>[Br:1][C:2]1[C:15]2[CH:14]=[C:13]([C:16]([N:23]3[CH2:28][CH2:27][NH:26][C@H:25]([C:29]([OH:31])=[O:30])[C@@H:24]3[C:32]([OH:34])=[O:33])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)cc1ccccc12
Reactant: O=C(O)[C@H]1NCCN[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=C(O)[C@H]1NCCN(C(=O)c2ccc3c(c2)c(Br)cc2ccccc23)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
10-Bromophenanthrene-2-carboxylic acid (2, 0.663 g, 2.2 mmol) was added to benzene (50 ml) containing excess thionyl chloride and the mixture heated under reflux overnight. The following day, the mixture was evaporated under reduced pressure and the resulting acid chloride (3) used without further purification. (_)-Cis-piperazine-2,3-dicarboxylic acid (4, 0.46 g, 2.6 mmol) was added to 0.991 M aqueous sodium hydroxide (8 ml, 8 mmol) and dioxan (10 ml) and the mixture was cooled to 0° C. A solution of the crude acid chloride (3) in dry dioxan was then added and the mixture was stirred at 0° C. for 5 min and then at room temperature overnight. The following day, the reaction mixture was reduced to˜ half the volume by evaporation under reduced pressure and was then acidified with 6 M aqueous hydrochloric acid. The resulting precipitate was collected by filtration, heated in dioxan (50-100 ml) and filtered. This procedure was then repeated twice. The resulting solid was added to water just below the boiling point and stirred in order to dissolve water soluble by-products. The insoluble material was collected by filtration, washed with dioxan and dried to give (±)-cis-1-(10-bromophenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (5) as a white solid. 1H NMR (270 MHz, D2O/NaOD):—2.5-3.4 (m, 4H), 4.3 (d, 0.5 H), 5.5 (d, 0.5 H), 7.2-7.6 (m), 7.65-7.8 (m), 7.75 (s) 7.95-8.2 (m), 8.1 (s) and 8.25-8.5 (m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)([OH:13])[CH3:12])=[CH:9][N:10]=2)[N:7]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+].Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:11]([C:8]1[N:6]2[N:7]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([OH:13])[CH3:12]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoro-quinolin-6-yl)-ethanol (Stage 174.1, 200 mg, 0.584 mmol) was dissolved in DME (4 mL) under argon atm. 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 282 mg, 0.875 mmol) was added, followed by 2 M K2CO3 (0.79 mL) and PdCl2(PPh3)2 (20.5 mg, 0.029 mmol). The RM was stirred at 90° C. for 1.5 h. It was then taken into a mixture of EtOAc and 1 M Na2CO3 and extracted. The organic phase was dried on Na2SO4, filtered and evaporation of the solvent. The residue was dissolved in DCM (16 mL), 4 M HCl (dioxane, 0.438 mL, 1.751 mmol) were added at 10° C. The mixture was stirred at rt for 1 h. The solvent was evaporated and the residue was diluted with EtOAc/MeOH (95:5) and washed with 1 M Na2CO3 (1×). The aqueous phases were further extracted with EtOAc (1×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized in DCM/Et2O to afford the title compound as a slightly yellow solid (tR 2.37 min (conditions 13), MH+=419). 1H-NMR in DMSO-d6: 8.86 (m, 1H), 8.64 (m, 2H), 8.02 (d, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.58-7.50 (m, 2H), 7.45-7.40 (m, 2H), 6.25 (s, 1H), 4.86 (t, 1H), 4.00 (m, 2H), 3.60 (m, 2H), 2.15 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OO)(=[O:21])C>O>[C:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N+:11]([O-:21])=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnccc1-c1ccccc1
Reactant: CC(=O)OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c[n+]([O-])ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenylnicotinic acid hydrochloride (2.4 g, 0.01 mol) is dissolved in water (50 ml) and the pH is adjusted to pH 10-11 by the addition of 5N aqueous NaOH solution. A solution of peracetic acid (40% w/v, 15.2 g) is added cautiously at ambient temperatures. When the addition is complete, the reaction mixture is stirred at ambient temperature for 15 min and then heated at 50° for 4 h. After this period, the mixture is allowed to cool and evaporated in vacuo to dryness. The residue is slurried in hot ethanol (20 ml), then filtered, and the filtrates are evaporated to dryness in vacuo to yield 4-phenylnicotinic acid N-oxide.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:27]([N:46]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2[CH:64]=[CH:63][C:60]([CH2:61]Br)=[CH:59][CH:58]=2)=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[N:8]([CH2:61][C:60]2[CH:59]=[CH:58][C:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[C:50]3[N:46]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:47]=[N:48][N:49]=3)=[CH:64][CH:63]=2)[C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([CH3:4])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78.1 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 189 mg of propyl 4-(1-hydroxy-1-methylethyl)-2-propoxymethylimidazole-5-carboxylate [prepared as described in Preparation 45(iii)], 78 mg of potassium t-butoxide and 445 mg of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide as starting materials and then purifying the product by column chromatography through silica gel using a 1:1 mixture of hexane and ethyl acetate as the eluent, 395 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Br:1][CH:2](Br)C.[Li+].CC([N-]C(C)C)C.CO[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23].C([Li])CCC.Cl>C1COCC1.CCCCCC>[Br:1][CH2:2][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23])=[O:24]
Reactant: CCc1ccccc1C(=O)OC
Reactant: CC(Br)Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccccc1C(=O)CBr
Yield: 41.8 %

Procedure:
To a solution of 15.2 g (88 mmol) dibromethane in 120 ml THF at −75° C. was added 44 ml (88 mmol) of a 2M solution of LDA in THF and subsequently 6.57 g (40 mmol) ethyl-benzoic acid methyl ester in 80 ml THF. 37.5 ml of a 1.6 M n-butyl lithium solution in n-hexane was added and after 30 min the mixture was treated carefully below −65° C. with 35 ml HCl (37%). The mixture was washed with water and NaHCO3 aq. and the organic phase was dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/hexane 1:9 twice to afford 3.8 g (41%) of the title compound as yellow oil. MS (m/e): 227.1 (M+H, 100%).