Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH2:69]>CN(C=O)C>[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH:69][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:31])[CH:28]([CH3:29])[CH3:30])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reactant: Nc1ccccc1F
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@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and HATU (50.9 mg, 134 μmol, Eq: 1.2) were combined in DMF to give a colorless solution. Diisopropylethylamine (23.4 μL, 134 μmol, Eq: 1.2) and 2-fluoroaniline (14.9 mg, 134 μmol, Eq: 1.2) were added. The reaction was stirred at rt for 1 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (39 mg), m/z=542 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.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.Cl.[F:48][C:49]([F:62])([F:61])[C:50]1[NH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([CH2:59][NH2:60])=[CH:54][CH:53]=2>C(#N)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[N:7][C:6]([C:9]([NH:60][CH2:59][C:55]2[CH:56]=[C:57]3[C:52](=[CH:53][CH:54]=2)[NH:51][C:50]([C:49]([F:62])([F:48])[F:61])=[CH:58]3)=[O:11])=[CH:5][CH:4]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nn1
Reaction time: 18 h

Procedure:
A solution of 6-(trifluoromethyl)-3-pyridazinecarboxylic acid (Intermediate 9, 60 mg, 0.312 mmol), HATU (131 mg, 0.344 mmol) and DIPEA (0.164 ml, 0.937 mmol) in acetonitrile (3 ml) was stirred at room temperature under argon for 15 mins and then treated with {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 78 mg, 0.312 mmol). The reaction mixture was stirred for 18 hrs and evaporated under reduced pressure to remove the acetonitrile. The residue was dissolved in DCM and washed with water. The organic solution was dried over MgSO4 and evaporated under reduced pressure to afford the crude product which was purified by MDAP the title compound (39 mg) as a pale solid;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=1.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@:35]([NH2:39])([CH3:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@:35]([CH3:38])([NH:39][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one ((Preparation #1, Step E, 2.184 g, 5.12 mmol) and (S)-3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.977 g, 4.88 mmol) in toluene (5 mL) was added Pd(OAc)2 (0.110 g, 0.488 mmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.464 g, 0.976 mmol) followed by cesium carbonate (3.18 g, 9.76 mmol) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give (S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 38%). 1H NMR (400 MHz, CDCl3) δ 6.85 (m, 1H), 6.34-6.28 (m, 2H), 5.11 (m, 2H), 4.70-4.52 (m, 3H), 3.68 (m, 2H), 3.70-3.35 (m, 4H), 2.20 (m, 1H), 1.88 (m, 1H), 1.46 (m., 12H), 1.05 (m, 2H), 0.03 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2CNCCO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
(R)-2-(6-Methoxy-pyridin-3-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester (194 mg, 0.63 mmol) was dissolved in dichloromethane (2 mL), cooled to 0° C. and treated with TFA (1 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was taken up in dichloromethane and extracted with 1M NaOH. The mixture was extracted 3 times with dichloromethane. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to afford (R)-2-(6-methoxy-pyridin-3-ylmethyl)-morpholine (130 mg, 99%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.52-2.63 (m, 2H) 2.65-2.75 (m, 1H) 2.75-2.81 (m, 1H) 2.81-2.91 (m, 2H) 3.49-3.63 (m, 2H) 3.85 (ddd, J=11.28, 3.22, 1.34 Hz, 1H) 3.91 (s, 3H) 6.68 (d, J=8.33 Hz, 1H) 7.44 (dd, J=8.60, 2.42 Hz, 1H) 7.99 (d, J=2.15 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:17]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:10]3[C:15]([N:16]=2)=[CH:14][N:13]=[CH:12][N:11]=3)[CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: N#CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Yield: 87.5 %

Procedure:
A mixture of 18.2 parts of 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrile and 240 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at a temperature below 20° C. with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 16 parts (87.5%) of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine; mp. 146.1° C. (compound 155).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]2[CH2:34][O:35][CH2:36][CH:30]2[CH2:29]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:21][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH:31]5[CH2:34][O:35][CH2:36][CH:30]5[CH2:29]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: ClCCCN1CCC2COCC2C1
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(O)cc23)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CCC5COCC5C4)cc23)ccc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
A mixture of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (220 mg, 0.71 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (174 mg, 0.44 mmol, 1.2 eq) and K2CO3 (197 mg, 1.42 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight, and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (110 mg, 32.50%), HPLC: 97.45%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 477.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (2H, m), 2.68-2.71 (3H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.07 (1H, s), 4.24-4.27 (2H, m), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CC(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
80 mg (151 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoyl}amino)benzoate (racemate) in 2 ml of methanol/water (4/1) were reacted with 326 mg (302 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 18 mg (23% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[F:14][C:15]1[CH:25]=[C:24]([C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[O:34][C:33]([CH3:39])([CH3:38])[CH:32]=[C:31]3OS(C(F)(F)F)(=O)=O)[CH:23]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[F:14][C:15]1[CH:25]=[C:24]([C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[O:34][C:33]([CH3:38])([CH3:39])[CH:32]=[C:31]3[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:23]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1F
Temperature: 25 °C

Procedure:
A solution of 4-methylbromobenzene (140.0 mg, 0.80 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (102.5 mg, 1.60 mmol, 0.94 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (174.0 mg, 1.28 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 2-fluoro-4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-ylethynyl)-benzoate (Compound 271, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 86.0 mg (62%), was isolated by column chromatography (5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.88 (1H, d, J=7.8 Hz), 7.35 (1H, d, J=7.8 Hz), 7.35 (1H, dd, J=2.0, 8.4 Hz), 7.28-7.19 (7H, m), 6.88 (1H, d, J=8.3 Hz), 5.64 (1H, s), 4.40 (2H, q, J=7.1 Hz), 2.43 (3H, s), 1.51 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:25])[N:11]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]2=[CH:5][CH:4]=1.Cl>CO.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:25])[N:11]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2c(n1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c(n1)[nH]c(=O)n2C1CCNCC1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
5-Methoxy-2-oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (100 mg, 0.287 mmol) was dissolved in methanol (2.5 mL) and a solution of 2N hydrochloric acid in ether (3 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (61 mg). MS 249.1 (M+1).
Reaction SMILES: C1(P(CCCC)C2C=CC=CC=2)C=CC=CC=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[N:23][C:24]=1Br.[CH2:30]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[Cl:44])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.[Pd].C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.C(O)C>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[N:23][C:24]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:39]=1
Reactant: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Reactant: COC(=O)c1cnc(N)c(Br)n1
Agent: [Pd]
Agent: CCCCP(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: N#Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnc(N)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Yield: 50.3 %

Procedure:
Stir a suspension of 137 mg (0.36 mmol) of (bis-benzonitrile)-palladium II dichloride and 183 mg (0.43 mmol) of diphenylphosphinobutane in 7 mL of toluene under argon for 30 min at room temperature. Then add, while bubbling with argon, 1.66 g (7.15 mmol) of methyl 5-amino-6-bromopyrazine-2-carboxylate, 1.97 g (7.51 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid, 2.4 mL of ethanol and 3.58 mL (7.15 mmol) of a 2N aqueous solution of sodium carbonate. Reflux the reaction mixture for 5 h 30 min and then distribute in 100 mL of a water/EtOAc 1:1 mixture. Wash the organic phase with 50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue, obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 50 to 100% of EtOAc. After concentration under reduced pressure, we obtain 1.33 g of methyl 5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate in the form of yellow wax.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:27]([NH:26][CH3:25])=[O:28])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:13][CH2:14]2)=[CH:23][CH:22]=1
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2

Procedure:
1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) was dissolved in dichloromethane (140 ml) and methylisocyanate (0.53 g) was added. The solution was refluxed for 4 hours. Dichloromethane was evaporated and the remaining crude title compound was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethyl acetate). The pure title compound 5a crystallized from diethyl ether. Yield: 0.8 g, mp: 170-173° C. 1H NMR (CDCl3): δ 1.70-1.90 (m, 5 H); 2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H); 2.35-2.55 (m, 2 H); 2.60 (dd, 1 H); 2.80 (d, 3 H); 2.75-2.95 (m, 2 H); 3.05 (broad d; 2 H); 3.30 (qui, 1 H); 4.95 (q, 1 H); 6.55 (s, 1 H); 6.90-7.00 (m, 3 H); 7.10-7.25 (m, 3 H); 7.35 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[Li+].[OH-].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (245 mg, 0.99 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.00 mL, 2.00 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (284 mg, 0.99 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave, after evaporation, 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 62 as a beige solid (46 mg, 9% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:39])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:35])[CH3:36])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)C(C)(C)O)c(F)cc43)c(C)c2C1=O
Yield: 62.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 9b as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide 9 (39 mg, yield 62.4%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:3]2[C:4]3[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 13 %

Procedure:
A suspension of methyl 1H-benzimidazole-5-carboxylate (10.4 g, 58.8 mmol), (4-methoxyphenyl)boronic acid (17.9 g, 118 mmol), copper(II) acetate (16.0 g, 88.2 mmol), pyridine (9.54 mL, 118 mmol) and molecular sieves 4A (24.0 g) in dichloromethane (240 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered, and the filtrate was washed with 5% aqueous ammonia and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=5/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.15 g, yield 13%) as colorless crystals.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])([CH3:3])[CH3:2].[NH2:17][OH:18]>CCO>[OH:18]/[N:17]=[C:9](\[NH2:10])/[C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Reactant: NO
Solvent: CCO
Product: CC(C)Oc1ccc(/C(N)=N/O)cc1C(F)(F)F
Yield: 33.7 %

Procedure:
Under an atmosphere of nitrogen, 4-isopropoxy-3-(trifluoromethyl)benzonitrile (6.5 g, 28.4 mmol) and 50% aqueous hyroxylamine (5.21 mL, 85 mmol) in EtOH (20.0 mL) was heated at 60° C. for 18 hr. Solvents removed in vacuo and the residue was azeotroped with MeOH. The residual solid was purified by precipitation from an ethyl acetate/30-600 C pet/ether mixture (1:2) to give (Z)-N′-hydroxy-4-isopropoxy-3-(trifluoromethyl)benzimidamide (2.51 g, 33.8%) LCMS (Table 1, Method b) Rt=1.89 min, m/z 263.13 (M+H)+.