Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([NH:35][C:36]([N:16]2[CH2:15][C:14]3[CH:13]=[N:12][C:11]4[NH:10][N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[CH3:21])[C:20]=4[C:19]=3[CH2:18][CH2:17]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCN(C(=O)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the crude 1-o-tolyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine hydrochloride salt obtained from step 2 was added anhydrous tetrahydrofuran (1.5 mL) and triethylamine (50 μL) followed by 400 mM solution of phenyl isocyanate (0.25 mL) in tetrahydrofuran. The reaction mixture was shaken at room temperature for 6 hours. The solvent was then removed under reduced pressure and the crude product was purified using reverse phase HPLC to give the pure desired product, N-phenyl-1-o-tolyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide. LCMS [M+H]: 384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][N:22]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:20])=[CH:23][CH:24]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 53 mg of the title compound (57%) as a orange powder in 93% purity by HPLC (Rt: 4.11, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 2-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (9.6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].CC#N.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Br)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
A 12 L four-necked round-bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser with nitrogen inlet was charged with 2-bromo-5-methoxyphenol (615 g, 2.98 mol), CH3CN (6 L), K2CO3 (671 g, 4.77 mol), benzyl chloride (363 mL, 3.14 mol), and KI (6 g, 0.036 mol). The mixture was heated to reflux for 3 h, cooled to room temperature, and H2O (3 L) added to form a biphasic mixture. The aqueous layer was separated, CH3CN (3 L) removed in vacuo and EtOAc (4 L) added to extract the product. After a wash with H2O (3 L) and 10% NaCl solution (1.8 L), the organic layer was concentrated to dryness to afford 1-bromo-4-methoxy-2-(phenylmethoxy)benzene as a light yellow oil (895.5 g, 99%): bp 110° C. (2.5 mm Hg); 1H NMR δ 7.55-7.25 (m, 6 H), 6.55 (d, J=2.7 Hz, 1 H), 6.35 (dd, J=8.5 Hz, 1.5 Hz, 1 H), 5.1 (s, 2 H), 3.75 (s, 3 H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:21]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH2:19][CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: CCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCOC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from propyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained propyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 402 (5), 359 (14), 194 (100), 123 (51);
Reaction SMILES: C([O:5][C:6]([C:8]1[N:16]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:15]2[C:10](=[N:11][C:12]([N:26](C(OC(C)(C)C)=O)[NH:27][C:28](OC(C)(C)C)=O)=[CH:13][CH:14]=2)[CH:9]=1)=[O:7])(C)(C)C.[CH3:42]C(O)=O>>[CH3:42][C:28]1[N:11]2[C:10]3[CH:9]=[C:8]([C:6]([OH:5])=[O:7])[N:16]([S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])[C:15]=3[CH:14]=[CH:13][C:12]2=[N:26][N:27]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OC(C)(C)C)n2S(=O)(=O)c2ccccc2)n1
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3S(=O)(=O)c3ccccc3)n12

Procedure:
A solution of di-tert-butyl 1-[2-(tert-butoxycarbonyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.430 g, 0.730 mmol, from Step 2) in AcOH (7 mL) was heated in the microwave to a temperature of 180° C. for 3 minutes. The solid product was isolated by filtration and air dried, and used without further purification. Yield: (0.106 g, 41%). LCMS (M+H)+: 357.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccc(F)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(F)c(Cl)c2)cc1
Yield: 52.9 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-chloro-4fluorophenyl)ethanol (prepared as described in Preparation 40), 4.22 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.31 g of the title compound were obtained having an Rf=0.22 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [O:1]=[C:2]([C@@:16]1([OH:57])[CH2:33][C@H:32]([O:34][C@@H:35]2[O:49][C@@H:48]([CH3:50])[C@H:38]3[O:39][C@H:40]4[N:45]([C@H:37]3[CH2:36]2)[CH2:44][CH2:43][O:42][C@@H:41]4[O:46][CH3:47])[C:31]2[C:18](=[C:19]([OH:56])[C:20]3[C:21](=[O:55])[C:22]4[C:27]([C:28](=[O:52])[C:29]=3[C:30]=2[OH:51])=[C:26]([O:53][CH3:54])[CH:25]=[CH:24][CH:23]=4)[CH2:17]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O[N:59]1[C:63](=[O:64])[CH2:62][CH2:61][C:60]1=[O:65].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]=[C:2]([C@@:16]1([OH:57])[CH2:33][C@H:32]([O:34][C@@H:35]2[O:49][C@@H:48]([CH3:50])[C@H:38]3[O:39][C@H:40]4[N:45]([C@H:37]3[CH2:36]2)[CH2:44][CH2:43][O:42][C@@H:41]4[O:46][CH3:47])[C:31]2[C:18](=[C:19]([OH:56])[C:20]3[C:21](=[O:55])[C:22]4[C:27]([C:28](=[O:52])[C:29]=3[C:30]=2[OH:51])=[C:26]([O:53][CH3:54])[CH:25]=[CH:24][CH:23]=4)[CH2:17]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([O:15][N:59]2[C:63](=[O:64])[CH2:62][CH2:61][C:60]2=[O:65])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)ON2C(=O)CCC2=O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the acid intermediate 46 (4 mg, 0.005 mmol) in dry Dichloromethane (2 mL) kept at +5° C., N-hydroxysuccinimide (2 mg, 0.017 mmol) and N,N′-dicyclohexylcarbodiimide (2 mg, 0.01 mmol) were added. The solution was stirred at room temperature for 6 h, the solvent evaporated under vacuum and the residue treated with ethyl ether (5 mL). The suspension was stirred for 30 minutes, the solid removed by filtration and organic solution concentrated in vacuo. Purification of the crude by flash chromatography (DCM/Acetone 80:20) yield 1.5 mg (y=33%) of 47 as a red solid. MS (ESI): 895 [M+H]+. Retention time=3.22 min. Method 1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](O)([CH3:14])[CH3:13].S(=O)(=O)(O)O>CCCCCC>[CH:12]([O:1][C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5])([CH3:14])[CH3:13]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
210 g mixture of 2,5-dihydroxy benzoic acid and isopropanol was added to 1201 g of 80% sulfuric acid and stirred for 8 hours at 75° C. The solution was allowed to cool, and was added with 2 liters of ice water and 140 ml of hexane and was stirred in an ice bath. Resultant crystal deposit was filtrated, and the residue was washed with hexane. Then, it was dispersed in a mixture liquid consisting of methanol and water in a ratio of 6:4, and filtration was conducted. The substance was dried for 48 hours at 60° C., and 65.4 g of isopropyl-salicylic acid intermediate was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([CH:18]=O)[CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([C:22]1[CH:23]=[C:24]([C:28](O)=O)[N:25](C)[CH:26]=1)=O.[Li].Cl.Cl.C(N1CCNCC1)(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([CH2:18][N:25]3[CH2:26][CH2:22][CH2:23][CH2:28][CH2:24]3)[CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2cc(C=O)cn2C)CC1
Reactant: Cn1cc(C=O)cc1C(=O)O
Agent: CC(C)N1CCNCC1
Agent: Cl
Agent: [Li]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2cc(CN3CCCCC3)cn2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Isopropyl-piperazine-1-carbonyl)-1-methyl-1H-pyrrole-3-carbaldehyde. 4-Formyl-1-methyl-1H-pyrrole-2-carboxylic acid, lithium salt, (1.08 g.) was diluted with thionyl chloride (20 mL) and heated at reflux under nitrogen for 1.5 h. The reaction mixture was carefully concentrated. The residue was co-evaporated with toluene (3×) to remove residual HCl, and then was kept under vacuum for 2 h. Separately, a solution of 1-isopropyl-piperazine dihydrochloride (1.21 g, 6.00 mmol) in DCM (50 mL) was cooled to 0-5° C. TEA (2.23 mL, 24.0 mmol) was added slowly, followed by the above acid chloride solution in DCM (50 mL). The resulting mixture was allowed to stir overnight at rt. The mixture was concentrated to yield the crude product (3.78 g), which was purified on silica gel column using 2-6% 2 M NH3 in MeOH/DCM to yield the title compound (0.20 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.97 g), triethylamine (1 ml) and tetrahydrofuran (60 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 89%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 194–196° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:40])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:40][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Acryloyl chloride (1M in THF, 0.225 mL, 0.22 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine (Intermediate 35, 105 mg, 0.21 mmol) and DIPEA (0.041 mL, 0.24 mmol) in CH2Cl2 (3 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.5 h, washed with brine and then concentrated in vacuo. Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (60 mg, 52%) as a pale yellow solid; 1H NMR: 1.77-1.81 (1H, m), 1.95-2.16 (5H, m), 2.24-2.35 (1H, m), 2.38-2.48 (1H, m), 2.86-2.90 (1H, m), 3.18-3.22 (1H, m), 3.37-3.45 (1H, m), 3.76 (3H, s), 4.33-4.37 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.51 (1H, dd), 6.66 (1H, s), 7.10 (1H, dt), 7.33-7.41 (1H, m), 7.65 (1H, s), 8.3-8.4 (2H, m), 8.56 (1H, s), 8.81 (1H, d), 8.94 (1H, s), 9.38 (1H, s); m/z: ES+, MH+ 545.57.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].[F-].[Cs+]>C(#N)C>[F:21][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
Procedure EE: In a microwave reactor vessel, add (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (1.0 mmol), 4-methanesulfonylphenyl boronic acid (2.5 mmol), dichloropalladium di-triphenylphosphine (0.2 mmol), cesium fluoride (9.0 mmol) and acetonitrile (0.20M) and run in a CEM microwave reactor for 10 minutes at 120° C. with 75W power and cooling on. After this time, wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 431.2 (M+1)
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[C:20]([CH:23]=1)[C:21]#[N:22].[H-].[Na+].Cl>CN(C)C=O>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:12]=[C:6]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (31 mg, 0.153 mmol) and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (49.4 mg, 0.168 mmol) in N, N-dimethylformamide (DMF) (1.5 mL), was added NaH (18.36 mg, 0.459 mmol). The reaction mixture was stirred at rt for 30 min. Aqueous HCl solution was added to adjust pH to ˜7. Purification by Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (35 mg, 50% yield).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][CH:2]1[N:7]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methylpiperazine-1-carboxylate (1.00 g, 4.99 mmol, 1.00 equiv), 4-phenylbenzaldehyde (1.00 g, 5.49 mmol, 1.10 equiv), sodium triacetoxyborohydride (3.18 g, 15.0 mmol, 3.01 equiv), 1,2-dichloroethane (30 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was washed with water (1×120 mL) and extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to yield 1.71 g (93% yield) of tert-butyl 3-methyl-4-[(4-phenylphenyl)methyl]piperazine-1-carboxylate as a light yellow solid. LCMS (ESI, m/z): 367 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[C:34]([C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2)#[N:35]>>[ClH:4].[ClH:1].[ClH:4].[NH2:33][C:17]1[C:16]([C:39]2[N:40]=[CH:41][C:42]3[C:43]([F:46])=[CH:44][CH:45]=[C:36]([C:34]#[N:35])[C:37]=3[CH:38]=2)=[CH:21][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)=[CH:19][N:18]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: N#Cc1ccc(F)c2cnc(OS(=O)(=O)C(F)(F)F)cc12
Agent: Cl
Product: N#Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc12

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 5-cyano-8-fluoroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.26-2.42 (m, 4H), 3.20-3.29 (m, 2H), 3.55-3.63 (m, 2H), 4.55-4.67 (m, 1H), 7.54 (dd, J=9.7, 8.2 Hz, 1H), 7.95 (s, 1H), 8.15 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.35 (dd, J=8.1, 5.1 Hz, 1H), 8.39 (s, 1H), 9.70 (d, J=1.0 Hz, 1H). MS (ES+): m/z=414.13 [MH+]. HPLC: tR=1.70 min (ZQ2, polar—5 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (37.4 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([C:31]([O:33][CH3:34])=[O:32])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Alternatively, to a solution of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (220 mg, 0.71 mMol) in tetrahydrofuran (5 mL) at -78° C. was added a solution of n-butyl lithium in hexane (1.6 M, 1 mL, 1.6 mMol), and the solution was stirred for two hours at -78° C. The solution was then cannulated into a solution of methyl chloroformate (0.5 mL, 6.5 mMol) in tetrahydrofuran (10 mL) at -78° C., and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was then extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated in vacuo to give a greenish-yellow oil. Purification by flash chromatography (3:1 hexane:tetrahydrofuran+tr. NH4OH) gave the title compound as a colorless glass (130 mg, 63%). The hydrochloride salt was formed and recrystallized (acetone/diethyl ether) to give colorless crystals (m.p.=132° C.).