Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:8](=[O:10])[CH3:9].[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[C:8]([C:7]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:32])[NH:22][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])[CH3:9]
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCl
Solvent: CCCCO
Product: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1

Procedure:
24 g (79 mmol) 1-chloro-6-(3-nitrophenyl-methylene)-5,7-octanedione and 25 g (0.159 mol) tert-butyl β-amino-crotonate are boiled under reflux in 200 ml 1-butanol for 18 h. The mixture is filtered and concentrated, and the residue is chromatographed over silica gel with toluene/acetone=9/1. The title compound is obtained as a yellow oil. Yield: 19.7 g (57%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[NH:13][C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=4)([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[N:13]([CH2:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.3 %

Procedure:
NaH 60% in oil (0.0023 mol) was added at room temperature to a mixture of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2(1H)-quinolinone (0.0021 mol), obtained in Example B32, in DMF (10 ml). The mixture was stirred for 30 minutes. 4-(Bromomethyl)-benzonitrile (0.0023 mol) was added. The mixture was stirred at room temperature for 18 hours, then at 80° C. for 2 hours, then overnight, cooled and poured out into ice water. The precipitate was filtered, taken up in DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.8 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 90/10; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.1 g) was purified by column chromatography over kromasil (eluent: CH3CN/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.078 g (6%) of 4-[[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2-oxo-1(2H)-quinolinyl]methyl]-benzonitrile, mp. 185° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Product: CC(C)(C)OC(=O)N1CCCC(ON2C(=O)c3ccccc3C2=O)C1
Yield: 57 %

Procedure:
Reaction of tert-butyl 3-hydroxypiperidine-1-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Example 9 gave tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate (2.3 g, 57%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 1.47-1.58 (1H, m), 1.74-1.76 (1H, m), 1.90-1.92 (1H, m), 2.08-2.11 (1H, m), 3.04-3.40 (2H, m), 3.66-3.68 (1H, m), 3.70-4.14 (1H, m) 4.24-4.27 (1H, m), 7.74-7.76 (2H, m), 7.82-7.86 (2H, m).
Reaction SMILES: C(N1C=C2C(C=C([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)C=C2)=N1)C1C=CC=CC=1.Br[C:27]1[CH:28]=[CH:29][C:30]2[C:34]([CH:35]=1)=[N:33][N:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]=2[NH2:42]>>[C:36]1([N:32]2[C:31]([NH2:42])=[C:30]3[C:34]([CH:35]=[C:27]([B:17]4[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]4)[CH:28]=[CH:29]3)=[N:33]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1c2ccc(Br)cc2nn1-c1ccccc1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: CC1(C)OB(c2ccc3c(N)n(-c4ccccc4)nc3c2)OC1(C)C

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-(4,4,5,5-tetramethyl-{1,3,2]dioxaborolan-2-yl)-2H-indazole (Intermediate C, step 2), using 6-bromo-2-phenyl-2H-indazol-3-ylamine in place of 2-benzyl-6-bromo-2H-indazole. 1H-NMR (300 MHz, DMSO-d6) 7.72 to 7.69 (m, 3H), 7.64 (s, 1H), 7.56 (t, 2H), 7.44 (t, 1H), 6.93 (d, 1H), 6.25 (s, 2H), 1.30 (s, 12H); ES-MS m/z 336.2 [M+H]+, RT (min) 2.51.
Reaction SMILES: C(OC([CH:8]([NH2:33])[CH2:9][C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:22][CH:21]=2)[C:13]1=[O:32])=[O:11])=O)(C)(C)C>Cl.C(O)(=O)C>[ClH:31].[NH2:33][CH2:8][CH2:9][C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:22][CH:21]=2)[C:13]1=[O:32])=[O:11]
Reactant: CC(C)(C)OC(=O)C(N)CC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: NCCC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C1=O
Reaction time: 2 h

Procedure:
The 3-(t-butoxycarbonyl-aminopropionyl)-1-{[5-(4-chlorophenyl) furfurylidene]amino}hydantoin (47 g, 0.11 mole) was added to 3% hydrochloric acid/acetic acid (500 ml) and was stirred for 2 hours. The mixture was filtered and the collected solid was washed with nitromethane and ether which yielded 30.5 g (82% overall), m.p. 242°-245°.
Reaction SMILES: C(OC(=O)[CH:5]([N:7]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH3:6])C>N1CCCCC1.CN(C)C=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:6][CH2:5][N:7]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:38]
Reactant: CCOC(=O)CN(C(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C(=O)OCC
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Reaction time: 1 h

Procedure:
3-{(Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-amino}-propionic acid ethyl ester AB (11.5 g, 21.3 mmol) was dissolved in 20% piperidine in dimethylformamide at 0° C. The solution was continued stirring for 1 h. The reaction mixture was concentrated under vacuum, water was added to the residue, and the product was extracted with ethyl acetate. The crude product was purified by conversion into its hydrochloride salt.
Reaction SMILES: S([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][C:21]3[N:37]=[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][N:30]5[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]5)[N:23]4[N:22]=3)[CH:19]=[C:14]2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.BrC1C=C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][C:21]3[N:37]=[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][N:30]5[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]5)[N:23]4[N:22]=3)[CH:19]=[C:14]2[CH:13]=[CH:12]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Nc4nc5cccc(CN6CCNC(=O)C6)n5n4)cnc32)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1CN(Cc2cccc3nc(Nc4cnc5[nH]ccc5c4)nn23)CCN1
Temperature: 100 °C
Yield: 57 %

Procedure:
4-((2-(1-Tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.020 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.023 g, 0.041 mmol) in 1,4-dioxane (1.25 mL) was added to 5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.086 g, 0.244 mmol), 4-((2-amino-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methyl)piperazin-2-one (0.050 g, 0.203 mmol), and cesium carbonate (0.265 g, 0.812 mmol) in a 1 dram vial with a stirbar. Nitrogen was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 2 h 20 min. The resulting mixture was diluted with acetonitrile, filtered, and purified using reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 34 min). Fractions containing the desired product were combined and loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator and dried under high vacuum at 40° C. to give the desired product (0.062 g, 0.116 mmol, 57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.91 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 7.97 (d, J=7.81 Hz, 2H), 7.77-7.88 (m, 2H), 7.56-7.64 (m, 1H), 7.49-7.56 (m, 1H), 7.42 (d, J=7.81 Hz, 2H), 7.10 (d, J=7.03 Hz, 1H), 6.82 (d, J=3.90 Hz, 1H), 4.08 (s, 2H), 3.13-3.27 (m, 4H), 2.77 (br s, 2H), 2.34 (s, 3H); MS (ESI) m/z 517.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1B1OC(C)(C)C(C)(C)O1)[C:9]1=[CH:22][N:23]=[CH:24][N:8]1[CH2:7][CH2:6]2.Cl[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]3[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]3)=[CH:28][CH:27]=1)[C:9]1=[CH:22][N:23]=[CH:24][N:8]1[CH2:7][CH2:6]2
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)-c1cncn1CC2
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)-c1cncn1CC2
Yield: 98 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline (104 mg, 0.32 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 90 mg, 0.32 mmol), afforded 6-(8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (140 mg) MS [M+H+]=447.6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([O:9][CH2:10][CH3:11])[CH2:7][CH3:8].[Mg].Cl[CH:14]1[CH2:18][CH2:17][CH:16]=[CH:15]1>O1CCCC1>[CH2:10]([O:9][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH:18]1[CH2:17][CH2:16][CH:15]=[CH:14]1)[CH3:11]
Reactant: CCOC(CC)CCCCCl
Reactant: ClC1C=CCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(CC)CCCCC1C=CCC1

Procedure:
The procedure followed is the same as that described in Example 8 with the following substitutions made: the starting material prepared in Example 38, 1-chloro-5-ethoxyheptane (162 g, 1.13 moles) dissolved in tetrahydrofuran (162 ml), granular magnesium (50 g, 2.1 moles) in tetrahydrofuran (500 ml), Li2CuCl4 (29.1 mmoles), and 3-chlorocyclopentene (89 g, 0.86 moles) diluted in 100 ml tetrahydrofuran was used. The crude product is distilled under reduced pressure leaving a clear, colorless oil (121 g, 0.575 moles), BP 76° C./0.34 mm.
Reaction SMILES: [F:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:30][C:31]#[N:32])([N:16]3[CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].Cl[C:42]1[C:43]2[CH:50]=[CH:49][NH:48][C:44]=2[N:45]=[CH:46][N:47]=1.C(=O)(O)[O-].[Na+].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.O1CCOCC1>[N:45]1[C:44]2[NH:48][CH:49]=[CH:50][C:43]=2[C:42]([C:19]2[CH:18]=[N:17][N:16]([C:14]3([CH2:30][C:31]#[N:32])[CH2:13][N:12]([CH:9]4[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C:3]5[CH:33]=[CH:34][N:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:2]=5[F:1])[CH2:11][CH2:10]4)[CH2:15]3)[CH:20]=2)=[N:47][CH:46]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CN(C4CCN(C(=O)c5ccnc(C(F)(F)F)c5F)CC4)C3)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6%), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10% of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:9]2[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.NCCCN[C:30]([C@@H:32]1[CH2:36][S:35][C:34](=[O:37])[NH:33]1)=[O:31]>>[CH3:24][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:9]3[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=3[N:11]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C@@H:32]3[CH2:36][S:35][C:34](=[O:37])[NH:33]3)=[O:31])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(Nc2nc(NCCCN)nc3cc[nH]c(=O)c23)c1
Reactant: NCCCNC(=O)[C@@H]1CSC(=O)N1
Product: Cc1cccc(Nc2nc(NCCCNC(=O)[C@@H]3CSC(=O)N3)nc3cc[nH]c(=O)c23)c1

Procedure:
The compound was prepared from 2-[(3-aminopropyl)amino]-4-[(3-methylphenyl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one and (4R)—N-(3-aminopropyl)-2-oxo-1,3-thiazolidine-4-carboxamide using the procedure similar to that described for Example
Reaction SMILES: BrC1C=C(C(O)=O)C=CC=1C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[CH:39]=[C:40]([C:58]([O:60]C)=[O:59])[C:41]([C:44]4[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[C:46]([C:54]([F:57])([F:56])[F:55])[CH:45]=4)=[CH:42][CH:43]=3)=[O:37])[CH2:32]2)[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[CH:39]=[C:40]([C:58]([OH:60])=[O:59])[C:41]([C:44]4[CH:49]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:47]=[C:46]([C:54]([F:55])([F:56])[F:57])[CH:45]=4)=[CH:42][CH:43]=3)=[O:37])[CH2:32]2)[CH:26]=1
Reactant: COC(=O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Br)c1
Product: O=C(O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Compound 7b was prepared following procedures similar to those described for the preparation of compound 3a (example 3, step A), substituting 7a for i-1b. m/z (ES) 509 (MH)+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24](=[O:26])[N:23]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:22][CH2:21][C:20]=2[CH:33]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[C:10]([N:30]2[CH2:29][CH2:28][CH:27]([N:23]3[CH2:22][CH2:21][C:20]4[CH:33]=[C:16]([O:15][CH3:14])[CH:17]=[CH:18][C:19]=4[NH:25][C:24]3=[O:26])[CH2:32][CH2:31]2)[N:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(C)OC)ncn3)CC1)C(=O)N2

Procedure:
0.20 g (0.99 mmol) 6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide, 0.28 g 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.20 mL (1.16 mmol) DIPEA in 1.5 mL THF were heated to 120° C. in the microwave for 30 min. The mixture was diluted with water and extracted with DCM. The combined organic phases were dried on sodium sulphate, filtered and evaporated down i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1.O>CN(C=O)C>[CH3:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[N:18]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=2[CH:20]=[CH:19]1
Reactant: CCC(O)CC
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn(C)c(=O)c2c1ccn2-c1ccc(C)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution 3-pentanol (0.064 ml, 0.60 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 3 hours, then dilated with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 48 mg (94%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>Cl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 65 °C
Yield: 92.5 %

Procedure:
In an appropriate vessel, methyl 3-aminothiophene-2-carboxylate (2.5 g; 15.9 mmol) was combined with 4-tert-butylbenzene sulfonyl chloride (3.70 g; 15.9 mmol) and dissolved by addition of pyridine (5.00 mL; 63.2 mmol). The reaction mixture was heated at 65° C. for 2 hours cooled to room temperature, diluted with aqueous hydrochloric acid (100 mL; 2M) and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with aqueous hydrochloric acid (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude solid was recrystallized from a minimal amount of isopropanol to give the title product as a yellow solid (5.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])([CH3:17])[CH3:14])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(C(C)(C)O)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
(4-Acetyl-thiazol-2-yl)-carbamic acid tert-butyl ester (500 mg, 2.06 mmol) was taken in to dry tetrahydrofuran (8 mL) and cooled in an ice bath. To this was added a 3 M solution of methyl magnesium bromide (2.752 mL, 8.256 mmol) in diethyl ether over 5 minutes. After 30 minutes, more 3 M solution of methyl magnesium bromide (1 mL, 3 mmol) in diethyl ether was added. After 30 minutes, an additional aliquot of 3 M methyl magnesium bromide (1 mL, 3 mmol) in diethyl ether was added. No further change in the reaction mixture composition was observed after an additional 30 minutes. The reaction mixture was diluted with tetrahydrofuran (5 mL) and allowed to warm to room temperature. After 2 hours thin layer chromatography indicated no change in the composition of the reaction mixture. The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride was added slowly. The mixture was diluted with water, extracted with ethyl acetate and washed with brine. The combined organic extracts were dried over sodium sulfate and concentrated to give a viscous oil. The crude product was purified by chromatography over silica gel gradient eluted from 1:19 upto 1:4 ethyl acetate/dichloromethane to give [4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester as a white foam (250 mg, 47%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24](O)[CH3:25])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:44])([F:43])[F:42])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11].C(=O)([O-])O.[Na+]>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([F:7])[CH3:25])=[CH:22][CH:23]=2)=[CH:15][C:14]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:42])([F:44])[F:43])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)O)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (DAST, 0.020 mL, 0.15 mmol, 1.3 equiv) was added to a solution of N-[1-(3-{1-ethyl-5-[4-(1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (62 mg, 0.12 mmol, 1 equiv) in dichloromethane (1.2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then saturated sodium hydrogencarbonate was added. The crude mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(1-fluoroethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (40 mg, 64%). Calcd (M+1)+: 514.2. Found: 514.1.