Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11](Br)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.[C:36]1([N:42]2[C:54]3[CH:53]=[CH:52][C:51](B4OC(C)(C)C(C)(C)O4)=[CH:50][C:49]=3[C:48]3[C:43]2=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([C:51]4[CH:52]=[CH:53][C:54]5[N:42]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:43]6[C:48]([C:49]=5[CH:50]=4)=[CH:47][CH:46]=[CH:45][CH:44]=6)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc3c(c1)c1ccccc1n3-c1ccccc1)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 73 °C
Reaction time: 5 h
Yield: 45.1 %

Procedure:
The resulting 10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (16.5 g), 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (14.2 g), a toluene/ethanol (4/1, v/v) mixed solvent (250 ml), and a 2M potassium carbonate aqueous solution (48 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (1.9 g), and stirred at 73° C. for 5 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (450 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by crystallization using 1,2-dichlorobenzene (150 ml) and n-hexane (300 ml) was performed to obtain a white powder of 10-(biphenyl-4-yl)-12,12-dimethyl-7-(9-phenyl-9H-carbazol-3-yl)-10,12-dihydroindeno[2,1-b]carbazole (9.8 g; yield 45.2%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 100.1 %

Procedure:
A solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (260 mg, 0.918 mmol) and excess dimethylamine (4.59 mL, 9.18 mmol) in methanol (2 mL) was stirred at rt for 30 min. The solvent was removed in vacuum to afford crude 2-chloro-7-(4-fluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (268 mg, 0.919 mmol, 100% yield). LC-MS (M+H)+=292.3.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 33 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 4-methoxypyridine-3-boronic acid (640 mg, 4.20 mmol) were reacted. After purification the title compound (52 mg, 33% yield) was obtained as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.8 Hz, 1H), 8.57 (bm, 1H), 8.44 (s, 1H), 7.91 (m, 1H), 7.74 (m, 2H), 6.94 (d, J=5.8 Hz, 1H), 3.77 (s, 3H), 2.96 (m, 1H), 0.86 (m, 2H), 0.64 (m, 2H). MS APCI, m/z=336.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Cl[C:24]1[N:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:29]=1>CN(C=O)C.O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[N:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:28][CH:29]=3)=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Clc1ccc(OCCN2CCCC2)nn1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)nn3)nc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 0.11 mL (0.79 mmol) triethylamine, 4 mg (0.01 mmol) chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II) and 1.2 mg (0.01 mmol) CuI are added successively to a solution of 57 mg (0.27 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 61 mg (0.26 mmol) 3-chloro-6-(2-pyrrolidin-1-yl-ethoxy)-pyridazine in 3.0 mL DMF. The mixture is stirred for 20 min at 100° C. and 300 Watt in the microwave. The reaction solution is diluted with 10 mL water and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is extracted with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2ccccn2)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1[nH]nc(-c2ccccn2)c1Cl
Temperature: 70 °C
Reaction time: 14 h
Yield: 53 %

Procedure:
Preparation 2: A solution of 2-(5-methyl-1H-pyrazol-3-yl)pyridine (500 mg, 3.15 mmol) in acetonitrile (912 mL) was treated with N-chlorosuccinimide in 6 portions and the resulting mixture stirred at 70° C. for 14 h. The mixture was cooled and then concentrated in vacuo to yield a residue. The residue was partitioned between EtOAc (8 mL) and H2O (3 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to yield a residue. The residue was purified by flash chromatography on silica gel using 20-80% EtOAc in hexanes to give the title compound (300 mg, 53%).
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][C:11]3[C:12]([O:29][CH3:30])=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:33](C([Sn])=C(CCCC)CCCC)[CH2:34]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([O:29][CH3:30])=[CH:13][C:14]([CH:33]=[CH2:34])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:31][CH:32]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(OC)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.23 g) in DMF (4.50 mL) were added tributylvinyltin (0.22 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithium chloride (0.16 g), and the mixture was stirred at 90° C. for 1 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.16 g).
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.[CH2:16]([C:19]1[C:29]([OH:30])=[C:28]([C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:20]=1[O:21][CH2:22][CH2:23][CH2:24]Br)[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[C:31]([C:28]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]2)=[C:19]([CH2:16][CH2:17][CH3:18])[C:29]=1[OH:30])(=[O:33])[CH3:32]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(C)OCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCCSCC2COC(C)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 36 (1.5 g, 0.006 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (1.9 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.7 g (93%) of the product as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=1.O.NN>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1
Reactant: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)cn1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cn(CCCN)cn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (3.42 mmol, 1 eq.) and hydrazine monohydrate (6.84 mmol, 2 eq.) were dissolved in 20 mL of ethanol and the mixture was stirred for 12 h under reflux. The mixture was kept under reflux over night, then mixture was concentrated down to a volume of 25 mL. After that hydrochloric acid (conc., 55 mL) was added and the mixture was heated up to 50° C. for and kept at this temperature for 30 min. The formed precipitate was filtered off. The filtrate was cooled down to 0° C. and solid NaOH was added until a final pH-value of 10-12 is reached. The aqueous solution was extracted by means of CHCl3 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The product was purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient containing aqueous ammonia (2% v/v).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[O:31]([CH2:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([CH2:38][CH2:39][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc(OCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-phenoxyethane chloride are treated as described in Example 5.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:10][C:11]3=[O:15])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][CH2:27][C:22]1=2
Reactant: O=c1nc(CCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)nc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 135 °C
Yield: 24.4 %

Procedure:
A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol) and Cs2CO3 (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed under reduced pressure for 15 min. CuI (65.0 mg, 0.34 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was heated at 135° C. in a microwave for 150 min. The mixture was then cooled and diluted with ethyl acetate. The resulting mixture was washed sequentially with an aqueous solution of LiCl (5%) and ammonium hydroxide (1%) (2×) and brine. The organic extract was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was dissolved in DCM, treated with charcoal for 20 min and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM to DCM/MeOH 95:5) to give the title compound (34.0 mg, 25%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.67-7.53 (m, 2H), 7.33-7.20 (m, 6H), 7.05-6.98 (m, 1H), 6.22 (d, J=6.5 Hz, 1H), 4.71-4.62 (m, 2H), 3.76-3.68 (m, 2H), 3.66 (s, 3H), 3.15-3.12 (m, 2H), 3.02-2.96 (m, 4H), 2.08-2.02 (m, 2H), 1.49-1.27 (m, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1
Reactant: Cc1cc2nc(CC(C)(C)C)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nc(CC(C)(C)C)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2,2-dimethylpropyl)-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=C[C:5]([N:8]2CCN(CCCC(O)=O)[C:10](=[O:20])[C@@H:9]2C)=[CH:4][C:3]=1OC(F)(F)F.C1C2(CCNC[C@H]2O)C1>>[ClH:1].[CH2:2]1[C:3]2([CH2:4][CH2:5][NH:8][CH2:9][C@H:10]2[OH:20])[CH2:7]1
Reactant: C[C@H]1C(=O)N(CCCC(=O)O)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Agent: O[C@@H]1CNCCC12CC2
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 4-[(S)-4-(4-Chloro-3-trifluoromethoxy-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-butyric acid (22% ee) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after precipitation (Et2O/n-pentane) the titled compound in 63% yield as light yellow foam. MS: 504.19 (MH+, Cl).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:23]1([CH:29]2[CH2:34][CH2:33][N:32]([C:7]3[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]4[C:16]=3[N:15]=[CH:14][CH:13]=[CH:12]4)[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(N2CCCCC2)CC1
Temperature: 65 °C
Yield: 11.1 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.14 g, 0.40 mmol, from Example 47, Step 2), 1,4′-bipiperidine (0.0799 g, 0.475 mmol), palladium acetate (1.8 mg, 0.0080 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.4 mg, 0.012 mmol), and cesium carbonate (0.361 g, 1.11 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated. The resulting residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give the desired product (16.5 mg, 11%). LCMS calculated for C21H27ClN3O (M+H)+: m/z=372.2; Found: 372.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH:19]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](Br)[CH:27]=1)(=[O:25])=[O:24])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:28]1[CH:27]=[C:26]([S:23]([NH:22][CH:19]([CH3:20])[CH3:21])(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NC(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)NC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-isopropyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13](C)C)=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:28]([F:31])([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].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.O>[Cl:17][C:18]1[C:19]([C:28]([F:30])([F:29])[F:31])=[N:20][N:21]([CH2:24][C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
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
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.038 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.067 g, 0.18 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.02 g, 0.048 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.37 (dd, J=8.9, 4.7 Hz, 1H), 7.26 (d, J=0.4 Hz, 2H), 7.18 (dd, J=8.9, 8.1 Hz, 2H), 4.94 (s, 2H), 2.39 (s, 3H), 2.16 (s, 3H); MS: (ES) m/z calculated for C17H14ClF4N5O [M+H]+416.1, found 416.0.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@@H:16]([C:27]([OH:29])=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1>>[C:27]([C@H:16]([NH:15][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)c1cc2ccccc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2-chloroquinoline-3-carboxylic acid is reacted with D-tryptophan to provide the title compound in moderate yield as yellow needles (recrystallization from isopropanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)O1.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCO.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]>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:32])[CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(C3(O)CCC3)cc2)OC1(C)C
Reactant: O=Cc1c[nH]c2cc(F)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)CCC4)cc3)cc12
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (90 mg, 0.37 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (120 mg, 0.44 mmol), 2 N aqueous potassium carbonate (0.75 mL, 1.49 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was degassed with N2 for 3 minutes, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg, 0.041 mmol). The mixture was subjected to microwave irradiation conditions at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into half-saturated aqueous NH4Cl solution (15 mL) and extracted with EtOAc (6×15 mL). The combined organic layer were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (9-50% EtOAc/petroleum ether) to afford the title compound (58.0 mg, 51% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 8.42 (s, 1H), 8.20 (d, J=8.00 Hz, 1H), 7.66 (d, J=8.40 Hz, 2H), 7.59 (d, J=8.40 Hz, 2H), 7.50 (d, J=10.80 Hz, 1H), 2.48 (m, 2H), 2.41 (m, 2H), 2.02 (m, 1H), 1.76 (m, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:18][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Oc1ccc(Oc2cccc(Br)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Oc3cccc(Br)c3)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there is added dropwise a solution of 0.50 g of 2-chloro-4-(3-bromophenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.27 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide is added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture is poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give 2-chloro-5-[4-(3-bromophenoxy)-2-chlorophenoxy]methylpyridine.