Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=2.CCN(C(C)C)C(C)C.[C:28]1([C:34]2[N:39]=[N:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([NH:41][NH:40][C:37]1[N:38]=[N:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[O:16])=[CH:8][CH:7]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(C(C)(C)C(=O)O)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc2ccc(C(C)(C)C(=O)NNc3ccc(-c4ccccc4)nn3)cc2c1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid (92 mg, 375 μmol), DIEA (66 μl, 375 μmol), and o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uronium hexafluorophosphate (143 mg, 375 μmol) in DMF was stirred for 2 h at 23° C. To the solution was added 1-(6-phenylpyridazin-3-yl)hydrazine (70 mg, 375 μmol) and stirred for 72 h at 23° C. Reaction partitioned between 9:1 CHCl3/IPA (25 mL) and 1M NaOH (5 mL). Organic dried over MgSO4 the concentrated to a solid from toluene under reduced pressure. Solid triturated with ACN (2 mL) and collected by filtration. 2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide isolated as a white solid. MS (ESI pos. ion) m/z: 414 (MH+). Calc'd exact mass for C24H23N5O2: 413.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:20].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH3:28][S:29]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[C:3]1=[O:20])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](O)C2=O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(R)-tert-Butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (20.5 g, 72.1 mmol) was dissolved in THF (500 mL) and triethylamine (20.1 mL, 144 mmol) and methanesulfonyl chloride (6.74 mL, 86.5 mmol) were added to the reaction and stirred at ambient temperature for 1 hour. The reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel to afford (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 25.5 g, 70.4 mmol, 98% yield) as a white solid. 1H NMR CDCl3 5.2 ppm (t, 1H), 4.3 ppm (m, 2H), 4.1 ppm (m, 1H), 3.4 ppm (m, 1H), 3.3 ppm (m, 1H), 3.3 ppm (s, 3H), 2.8 ppm (m, 2H), 2.6 ppm (m, 1H), 2.3 ppm (m, 1H), 1.7 ppm (m, 2H, 1.6 ppm (m, 2H), 1.5 ppm (s, 9H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:49]1[CH:50]=[CH:51][C:52]2[C:53](=[O:69])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:55](=[O:62])[C:56]3[C:61]=2[C:60]=1[CH:59]=[CH:58][CH:57]=3.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.[Cu]I>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:59]5[CH:58]=[CH:57][C:56]6[C:55](=[O:62])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:53](=[O:69])[C:52]7[C:61]=6[C:60]=5[CH:49]=[CH:50][CH:51]=7)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCN1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCN1C(=O)c2cccc3c(-n4nc5c(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)ccc(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)c5n4)ccc(c23)C1=O
Temperature: 160 °C

Procedure:
A mixture of Intermediate D (1.00 g, 1.65 mmol), 6-bromo-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (720 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol), CuI (382 mg, 2.0 mmol), and dimethylformamide (12 mL) was stirred under argon and heated at 160° C. for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/dichloromethane 1:1) and washing with ethanol to give 6-(4,7-bis(4-(N,N-diphenylamino)phenyl)-2H-benzo[d][1,2,3]triazol-2-yl)-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (Example 18), brown-violet crystals, 445 mg (30%). 1H NMR (400 MHz, CDCl3): δ 9.08 (dd, J=8.4 and 1.1 Hz, 1H, naphthalene), 8.74 (d, J=7.6 Hz, 1H, naphthalene), 7.69 (dd, J=7.3 and 1.1 Hz, 1H, naphthalene), 8.43 (d, J=8.1 Hz, 1H, naphthalene), 8.07 (d, J=8.8 Hz, 4H, p-phenylene), 7.85 (dd, J=8.4 and 7.3 Hz, 1H, naphthalene), 7.74 (s, 2H, benzotriazole), 7.28 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.18 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=381 nm. Fluorimetry (dichloromethane): λmax=481 nm.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[CH3:19][O:20][CH2:21][C:22](Cl)=O>O1CCOCC1>[CH3:19][O:20][CH2:21][C:22]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: COCC(=O)Cl
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Solvent: C1COCCO1
Product: COCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
To a mixture of 0.02 mole of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine in 50 ml. of dioxane is added 0.01 mole of methoxyacetyl chloride. The mixture is heated at reflux temperature for 4 hours, then is filtered. The filtrate is evaporated and the residue is crystallized from dichloromethane-hexane to give the product of the Example, m.p. 149°-150° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1([CH2:17][NH:18][S:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][NH:18][S:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=3)[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=S(=O)(NCc1ccccc1)C1CCNCC1
Product: Nc1ccc(N2CCC(S(=O)(=O)NCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-25 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-((phenylmethylamino)sulfonyl)piperidine as starting materials. MS (M+1): 347.
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.Br[C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15].C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[C:14]([C:13]1[CH:16]=[C:9]([B:3]([OH:6])[OH:2])[CH:10]=[CH:11][C:12]=1[F:17])#[N:15]
Reactant: COB(OC)OC
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc(B(O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Trimethylborate (1.37 mL, 12 mmol) was added to a solution of 5-bromo-2-fluorobenzonitrile (2.0 g, 10 mmol) in toluene (16 mL) and THF (4 mL) at −78° C. n-Butyl lithium (2.5M in hexane; 4.8 mL) was slowly added over 1 h and the solution was stirred for 30 min after which it was warmed to rt for 1 h. The reaction was cooled to 0° C. and quenched with 20 mL of 1 N HCl. The product was extracted with ethyl acetate (2×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 5% methanol/methylene chloride afforded 0.33 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)=[O:15]>COCCOC.O.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>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:14]=[O:15]
Reactant: Clc1cnccn1
Reactant: O=Cc1ccccc1B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccccc1-c1cnccn1

Procedure:
A solution of Pd(PPh3)4 (330 mg, 0.28 mmol) and chloropyrazine (987 μL, 11.0 mmol) in anhydrous DME (60 mL) was stirred for 20 min at room temperature under N2 atmosphere. The resulting red-orange mixture was treated with a solution of Na2CO3 (1.05 mg, 3.30 mmol) in H2O (15 ml), followed by 2-formylbenzene boronic acid (1.50 mg, 9.90 mmol), resulting in a white precipitate. The mixture was heated to reflux for 1.5 h. The DME was then removed in vacuo and the residual suspension was extracted twice with CH2Cl2. The combined organic extracts were dried (anhydrous Na2SO4) and concentrated to give the title compound as a red-orange solid which was dried in vacuo for 16 h and used without further purification. LCMS (M+H): 185.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.S(Cl)(Cl)=O.C(OC([N:25]1[CH2:29][CH2:28][CH:27]([NH:30][CH2:31][C:32]([CH3:42])=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[CH2:26]1)=O)(C)(C)C>C(N(CC)CC)C>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[CH:33]=[C:32]([CH3:42])[CH2:31][N:30]([CH:27]1[CH2:28][CH2:29][NH:25][CH2:26]1)[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CC(=Cc1ccc(F)cc1F)CNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N(CC(C)=Cc2ccc(F)cc2F)C2CCNC2)cc1OC
Yield: 35 %

Procedure:
Experimental condition analogous to Example 18 were used with 3,4-dimethoxybenzoic acid 0.12 g (0.68 mmol), thionyl chloride 2 ml (1.68 mmol). The obtained acyl chloride was reacted with 3-[3-(2,4-difluoro-phenyl)-2-methyl-allylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester 0.2 g (0.56 mmol), triethylamine 0.2 ml. The reaction yielded the free amine, which was converted to the HCl salt 90 mg as an off-white solid: Yield: 35%.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][CH2:35][O:36]C2CCCCO2)=[C:26]1[C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(O)C.[Cl-].[Na+].O>[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][CH2:35][OH:36])=[C:26]1[C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:54])[F:55])[CH:44]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(CCOC2CCCCO2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(CCO)c2ccccc21
Temperature: 50 °C

Procedure:
PPTS (95 mg) was added to a stirred solution of 1-tert-butoxycarbonyl-2-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (2.1 g) in ethanol (50 ml) and warmed to 50° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into brine (80 ml) and extracted into diethyl ether. The organic layers were separated, dried over MgSO4, filtered and the solvent removed under reduced pressure to give a clear oil which crystallized on standing (1.67 g). 1H NMR (CDCl3) δ1.23 (s, 9H), 2.79 (t, 2H, J=7.2 Hz), 3.86 (m, 2H), 7.27 (t, 1H, J=7.0 Hz), 7.34 (t, 1H, J=7.0 Hz), 7.60 (d, 1H, J=10.0 Hz), 7.90 (s, 3H), 8.28 (d, 1H, J=10.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:17]1=[O:26])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:37](=[O:38])[CH:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:40][C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:17]1=[O:26])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCNC(CC2CC2)C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 10 h
Yield: 71 %

Procedure:
To a solution of 2-(3-cyclopropylmethyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 14, (528 mg, 1.44 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (489 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (951 mg, 1.83 mmol) and triethyl amine (174 mg, 1.72 mmol). The reaction mixture is stirred for 10 hours, quenched with 10% NaHCO3 aqueous solution and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a crude residue which is purified over silica gel (silica gel, hexanes/ethyl acetate, 1:1) to afford 651 mg (71% yield) of the desired product. 1H NMR (300 MHz, CDCl3, Rotamers) δ 7.66–7.85 (m, 3H), 7.55 (s, 1H), 7.39–7.53 (m, 2H), 7.28–7.38 (m, 1H), 7.04–7.18 (m, 2H), 6.86–7.01 (m, 2H), 5.63 (dd, J=11.4, 5.4 Hz, 0.5H), 5.47 (dd, J=11.4, 5.4 Hz, 0.5H), 5.28–5.38 (m, 0.5H), 4.82–4.98 (m, 1H), 4.56–4.80 (m, 1H), 4.30–4.43 (m, 0.5H), 3.75–3.91 (m, 4H), 3.50–3.62 (m, 1H), 2.92–3.36 (m, 4H), 2.64–2.88 (m, 2H), 1.38 (s, 5H), 1.35 (s, 4H), 0.91–1.18 (m, 2H), −0.64–0.17 (m, 5H); 13C NMR (75 MHz, CDCl3, Rotamers) δ 170.69, 170.54, 169.37, 168.55, 167.10, 155.09, 154.84, 134.05, 133.71, 133.53, 133.49, 132.60, 132.41, 131.79, 131.28, 131.17, 130.89, 130.79, 128.74, 128.66, 127.94, 127.86, 127.73, 127.63, 127.50, 127.03, 126.63, 126.57, 126.14, 115.94, 115.66, 115.56, 115.28, 80.34, 79.87, 58.82, 57.26, 56.42, 52.76, 51.66, 51.32, 44.08, 42.79, 41.36, 39.92, 38.75, 37.43, 36.72, 36.58, 34.92, 34.54, 28.44, 7.12, 4.74, 4.69, 4.34, 4.31; MS (ESMS) m/z 632.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C@H:15]([OH:18])[CH2:16][OH:17]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C@H:15]([OH:18])[CH2:16][OH:17]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c([C@H](O)CO)c1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)c([C@H](O)CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
Ethyl (2E)-3-{4-chloro-3-[(1S)-1,2-dihydroxyethyl]phenyl}acrylate (1.90 g, 7.02 mmol) was dissolved in EtOH and then degassed (3×) with N2. Rh/Al2CO3 was added and then the solution was degassed again and then a H2 balloon was attached. After 16 h of stirring at rt, the solution was filtered through celite, concentrated, and purified by Biotage chromatography (0%-25% EtOAc/hexanes) to afford 1.41 g of product as an oil (74%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.45 (d, J=2.02 Hz, 1 H) 7.25 (d, J=8.08 Hz, 1 H) 7.08 (dd, J=8.08, 2.27 Hz, 1 H) 5.21 (dd, J=7.83, 3.03 Hz, 1 H) 4.13 (q, J=7.16 Hz, 2 H) 3.90 (dd, J=11.37, 3.28 Hz, 1 H) 3.56 (dd, J=11.37, 7.83 Hz, 1 H) 2.94 (t, J=7.71 Hz, 2 H) 2.62 (t, J=7.83 Hz, 2 H) 1.24 (t, J=7.20 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: OB(O)c1cn[nH]c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3cn[nH]c3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 5, using Intermediate C instead of Intermediate B and pyrazol-4-ylboronic acid instead of pyridin-4-ylboronic acid. 1H NMR (CDCl3) δ: 8.23 (broad, 2H), 7.85 (s, 1H), 4.63 (m, 1H), 4.33 (m, 1H), 3.36 (s, 3H), 1.95 (m, 1H), 1.75 (m, 1H), 1.44 (dd, 6H) and 0.87 ppm (t, 3H); LCMS: 301.2 m/z (M+H)+; ret. Time: 1.30 min (Analytical Method E).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:26])=[CH:2][CH:3]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1ccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-p-tolyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][C:37]=1[C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([O:13][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:43])[NH2:44])=[CH:38][C:37]=2[C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a mixture of 3.1 g of 4-acetyloxycinnamic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DCC. To the mixture, after having been stirred for 30 minutes, was added 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate. The mixture was stirred overnight at room temperature. The insolubles precipitated from the reaction mixture were collected by filtration and mixed with DMF. Ethyl ether was added to the supernatant to precipitate an insoluble substance which was recrystallized from ethanol, yielding 4.7 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamate methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC(C)([O-])C.[K+].[NH2:17]Cl>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH2:17])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 5-fluoro-1H-indole (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl. in ether (169.2 mL) is added drop-wise for 15 minutes at rt. The reaction mixture is stirred at rt for 2 h, then quenched with 10% Na2S2O3 aqueous solution and extracted with ether. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60-80% EtOAc in heptane to afford 5-fluoro-indole-1-ylamine (751 mg, 30%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.80 (br, 2N—H), 6.38 (d, H), 7.00 (m, H), 7.19-7.43 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2C=C[CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.[Li].C(C1N=C(C([O-])=O)[S:34]C=1)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[S:34][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1
Reactant: CC(C)c1csc(C(=O)[O-])n1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Agent: [Li]
Product: COCCOc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-methoxy-ethoxy)-quinoline was prepared in a similar fashion as 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that the lithium salt of 4-isopropyl-thiazole-2-carboxylate was used instead of 6-isopropyl-pyridine-2-carboxylic acid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1>C1COCC1>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:2][C:1]#[N:3])=[N:11][CH:12]=1
Reactant: CC#N
Reactant: Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(CC#N)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 234.3 %

Procedure:
To a solution of anhydrous acetonitrile (10.1 mL, 191.83 mmol, 3.3 eq) in dry THF (500 mL) was added dropwise n-BuLi (2.5 M in Hexane, 69.8 mL, 174.39 mmol, 3 eq) at −78° C. under N2 atmosphere. The resulting white suspension was stirred at −78° C. for 1 hr, and then a solution of 2-bromo-5-methylpyridine (10.0 g, 58.13 mmol, 1 eq) in dry THF (30 mL) was added. The reaction mixture was kept at −78° C. for 1 hr then warmed up slowly to r.t and stirred for another 1 hr. Ice/water was added and the layer was separated. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to give 18 g of crude 2-(5-methylpyridin-2-yl)acetonitrile. Since the product is very volatile, it was not dried under high vacuum and still contains some solvent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([S:28]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])=[O:29])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([CH2:31][S:28]([C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:30])=[O:29])[CH:33]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: CC(C)(C)S(=O)(=O)Cc1cccc(N)c1
Product: CC(C)(C)S(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1

Procedure:
Example 4 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(tert-butylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.