Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCCl>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN(c2ccc3ncnc(Cl)c3c2)CC1
Reactant: Clc1ccc2c(c1)NCC2
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc3ncnc(N4CCc5ccc(Cl)cc54)c3c2)CC1

Procedure:
4-Chloro-6-(4-methylpiperazin-1-yl)-quinazoline hydrochloride (537 mg, 1.80 mmol) and 6-chloroindoline (169 mg, 1.10 mmol) were refluxed in 10 mL of 1,2-dichloroethane and pyridine (350 mg, 4.40 mmol) for 48 hours. The product was isolated as the (58%); using the analogous method of Example 120; 267 mg (58%); M.P. 289°-290° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.1, 116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M NaHCO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon, heated to 100° C. in a pressure safe vial and PdCl2(dppf) (9.15 mg, 0.013 mmol) was added. The RM was stirred under argon at 100° C. for 2 h. The RM was cooled to RT, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, EtOAc/(EtOAc/MeOH 98:2), 50% to 100% (EtOAc/MeOH 98:2) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.03 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, tR=24.83 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=10.90, 4.70 Hz, 2H) 3.33-3.43 (m, 1H) 4.20 (d, J=1.96 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[CH2:13][O:12][C@H:11]1[N:34]1[CH:41]=[C:40]([CH2:42][CH2:43][N:44]2[C:48](=[O:49])[C:47]3=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]3[C:45]2=[O:54])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.C[O-].[Na+].O>CO>[C:45]1(=[O:54])[N:44]([CH2:43][CH2:42][C:40]2[C:38](=[O:39])[NH:37][C:35](=[O:36])[N:34]([C@@H:11]3[O:12][CH2:13][C@@H:14]([OH:25])[C@@H:15]([OH:16])[C@H:10]3[OH:9])[CH:41]=2)[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]12
Reactant: O=C(O[C@@H]1[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
15 g (20 mmol) of 34 were dissolved in 500 ml of MeOH in a 1 l round-bottomed flask, treated with 324 mg (6 mmol) of NaOMe and stirred at room-temp. overnight with exclusion of water (TLC checking, AcOEt/n-heptane 1:1). Amberlite IR-120 was added to the resulting suspension until the pH was <7. The solid was dissolved in the presence of heat, filtered off hot from the ion exchanger and washed with MeOH. After removing the solvent, the residue was co-evaporated twice using 150 ml of water each time. This yielded 9 g of crude product, which was heated under reflux in 90 ml of MeOH for 10 min. After cooling to room temp., the mixture was treated with 60 ml of Et2O and stored overnight at 4° C. Filtration, washing with Et2O and drying in an oil pump vacuum yielded 7.8 g (93%) of 35.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[NH2:2].C[O-].[Na+]>CO>[C:22]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[C:1](=[O:3])[NH:2][C:11]([C:13]2([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[N:10]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCC(C)(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)OCC(C)(c2nc3cccc(-c4ccccc4)c3c(=O)[nH]2)CO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution N-(2-carbamoylbiphenyl-3-yl)-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (0.23 g, 0.62 mmol) in methanol was added NaOMe (0.25 mL, 25% in MeOH, 1.2 mmol) and the reaction mixture stirred at 50° C. for 1 h. After this time, the reaction mixture was concentrated and the resulting residue was diluted with ethyl acetate then washed with water. The organic portion was dried and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield pure 5-phenyl-2-(2,2,5-trimethyl-1,3-dioxan-5-yl)quinazolin-4(3H)-one (0.2 g, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.49 (br s, 1H), 7.77 (t, 1H, J=8 Hz), 7.64 (d, 1H, J=8 Hz), 7.36-7.28 (m, 5H), 7.21 (d, 1H, J=8 Hz), 4.27 (d, 2H, J=12 Hz), 3.91 (d, 2H, J=12 Hz), 1.40 (s, 3H), 1.35 (d, 6H, 10.2 Hz). LCMS Method W: retention time 2.01 min; [M+1]=351.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]1([C:24]([O:26][CH3:27])=[O:25])[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]([NH:11][C@:12]1([C:24]([O:26][CH3:27])=[O:25])[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:28]=[CH2:29])=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC[C@@H](c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc([C@@H]2CC[C@](NC(=O)OCc3ccccc3)(C(=O)OC)C2)cc1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
To a 60-mL microwave vial was suspended (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-bromophenyl)cyclopentanecarboxylate (1.1 g, 2.54 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.431 g, 2.80 mmol) and Cs2CO3 (2.487 g, 7.63 mmol) in DME (30 ml) and Water (7.50 ml). The reaction vessel was purged with nitrogen for 5 minutes. PdCl2(dppf) (0.186 g, 0.254 mmol) was added and the reaction vessel was purged with nitrogen one more time. The reaction mixture was heated to 120° C. in microwave for 30 minutes. The product ((1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-vinylphenyl)cyclopentanecarboxylate (705 mg, 1.858 mmol, 73.0% yield)) was isolated by FCC as a lightly colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(=O)O
Reactant: COc1cccc(/C=C/C(C)=O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(/C=C/C(=O)/C=C/C(=O)O)c1

Procedure:
A solution of 14.7 g (83.4 mmol) of (E)-4-(3-methoxyphenyl)but-3-en-2-one and 7.67 g (83.4 mmol) of glyoxylic acid monohydrate in 21.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/ethyl acetate yielded (E,E)-6-(3-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 158°-160°.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@H:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]([CH2:5][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:7]2)[CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][C@H:4]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:7][CH:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]2)[CH2:9]1
Reactant: COC(=O)C1=C[C@H]2CN(C)C[C@@H](C1)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C[C@@H]2CN(C)C[C@H](C1)N2C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of (1R,5S)-9-tert-butyl 7-methyl 3-methyl-3,9-diazabicyclo[3.3.1]non-6-ene-7,9-dicarboxylate (4.69 g, 15.8 mmol) in methanol (50 mL) was added palladium on carbon (10%, 1.684 g, 1.583 mmol) and the resulting mixture was subjected to hydrogenation under 40 psi for three days. After filtration through CELITE® under nitrogen the filtrate was concentrated to give the title compound. LC/MS: (M+1)+: 299.1.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cncc(Br)c1
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cncc(Cl)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=311.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromo-5-chloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]=[C:10]=[O:11])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 119.3 %

Procedure:
To a solution of 4-chlorobenzylamine (0.50 g, 3.5 mmol) in toluene (15 mL) was added phosgene (7.3 mL, 14 mmol, 1.93 M solution in toluene). The resulting mixture was stirred at ambient temperature for 15 minutes, then heated to reflux. After 2 hours at reflux, the mixture was cooled to ambient temperature and concentrated in vacuo to afford 0.70 g (100% yield) of 4-chlorobenzylisocyanate, a compound of formula (Y), as a yellow liquid; NMR (CDCl3) 7.4-7.2 (m, 4), 4.4 (m, 2) ppm.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1ccc(S(=O)(=O)N(CC(=O)OCC)c2ccc(N3CCC(=O)CC3)cc2)cc1

Procedure:
A solution of 0.12 g of 4-butyl-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 247), 0.038 mL of ethyl bromoacetate and 0.047 g of potassium carbonate in 10 mL acetonitrile was refluxed overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (8:1 Hexanes:EtOAc—1:1 Hexanes:EtOAc) to give 0.107 g of the title compound as a yellow gum; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J=7.26 Hz, 3H), 1.19–1.26 (m, 3H), 1.31–1.43 (m, 2H), 1.57–1.66 (m, 2H), 2.52 (t, J=6.03 Hz, 4H), 2.67 (t, J-7.56 Hz, 2H), 3.60 (t, J=6.00 Hz, 4H), 4.14 (q, J=7.14 Hz, 2H), 4.35 (s, 2H), 6.80–6.85 (m, 2H), 7.06–7.12 (m, 2H), 7.24 (m, 2H), 7.59 (d, J=8.28 Hz, 2H); MS (ES) m/z: 473.0 (MH+); HRMS found for C25H32N2O5S: 472.2028.
Reaction SMILES: [CH3:1][Mg]I.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:17])[CH3:1])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methylmagnesium iodide (3.0 M in Et2O, 10 mL, 30 mmol) was added, under nitrogen atmosphere, to a solution of 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.0 mmol) in tetrahydrofuran (15 mL) at 0° C. and the resulting mixture was stirred at room temperature for 1 hour. A second aliquot of tetrahydrofuran (55 mL) was then added. The reaction mixture was quenched by addition of a saturated aqueous solution of ammonium chloride until dissolution of the solids. The volatiles were evaporated under reduced pressure and the residue was extracted twice with dichloromethane. The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.149 of 3-(1-hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. To a portion of this material (875 mg, 4.1 mmol) was added a solution of trifluoroacetic acid (5% in DCM, 10 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then evaporated under reduced pressure to give 1-pyrrolidin-3-yl-ethanol trifluoroacetate which was used without further purifications.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1.[CH:23]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:32]3[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:47])=[CH:30][C:31]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=3)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1
Reactant: CC(C)NC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(CCN(C)C)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn(CCN(C)C)c2ccc(-c3cnc(NC(=O)NC(C)C)cc3-c3nc(C(F)(F)F)cs3)cc2c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A suspension of ethyl 1-(2-(dimethylamino)ethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 29, 250 mg, 0.60 mmol) in dimethoxyethane (4.8 mL) in a microwave vial was stirred with heating to obtain a solution. The solution was then cooled to 30° C., trans-dichlorobis(triphenylphosphine)palladium (II) (55 mg, 0.08 mmol) was added and the mixture was stirred for 10 min at room temperature. 6-(3-isopropylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 89, 294 mg, 0.79 mmol) was added to the mixture followed by an aqueous solution of sodium bicarbonate (163 mg in 1.2 mL of water) and the vial was sealed. The mixture was stirred at 65° C. for 30 min in a heating block then cooled to room temperature. The crude reaction mixture was placed into fridge for a 2 h. The solid precipitate that formed was collected by filtration, washed with a small amount of dimethoxyethane, methyl tert-butyl ether and dried to give ˜270 mg yellowish solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[CH2:32](Br)[CH:33]=[C:34]([CH2:36][CH2:37][CH:38]=[C:39]([CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH3:40])[CH3:35]>C1COCC1>[CH3:35]/[C:34](/[CH2:36][CH2:37]/[CH:38]=[C:39](\[CH3:40])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:33]\[CH2:32][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 9.60 ml (68.5 mmol, 1.5 eq.) of diisopropylamine in 100 ml of THF at -78° C. under argon was added 28.2 ml (45.0 mmol, 1.0 eq.) of 1.6M n-butyllithium in hexanes over 20 minutes. After warming to 0° C. for 15 minutes, the solution was recooled to -78° C. and 6.05 ml (45 mmol, 1.0 eq) of t-butyl acetate was added over 20 minutes. After an additional 15 minutes, 16.0 ml (92 mmol, 2.05 eq.) of hexamethylphosphoramide (HMPA) was added, followed by a solution of 12.53 g (45.0 mmol) of Part A(1) farnesyl bromide in 100 ml of THF over 20 minutes. The reaction was stirred at -78° C. for 2.5 hours, quenched with saturated NH4Cl and allowed to warm to room temperature. After diluting with 400 ml of ethyl acetate, the mixture was washed with four 100 ml portions of water, and 200 ml of brine, dried over MgSO4 and evaporated to provide 12.96 g of crude product as a yellow oil. Purification by flash chromatography on 1 kg of silica gel, eluted with 1:9 ethyl acetate:petroleum ether afforded 9.39 g (65%) of title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[H-].[Na+].[N:23]1[C:30](Cl)=[N:29][C:27](Cl)=[N:26][C:24]=1Cl>O1CCOCC1>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][C:24]2[N:26]=[C:27]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)[N:29]=[C:30]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)[N:23]=2)[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCCCON1C(C)(C)CC(Oc2nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine, sodium hydride, and cyanuric chloride in 1,4-dioxane solvent.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:25][CH:24]=4)[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[NH:9]1[CH:10]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:27][CH:28]=4)[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:12]=[N:8]1
Reactant: c1ccc(Cn2cc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cn2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
[5-(1-Benzyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (1.66 g, 3.46 mmol) and palladium hydroxide (1.6 g) were suspended in methanol (50 mL) and conc. HCl (1 mL) added. The suspension was then stirred under an atmosphere of hydrogen at 50° C. for 18 hours after which the catalyst was removed by filtration and the filtrate concentrated in vacuo. Sodium carbonate (50% sat.) was added, and the precipitate, a pale brown solid, collected by filtration. Yield: 1.22 g, 90%; LCMS method: 2, RT: 2.13 min, MI: 390 [M+1]. 1H NMR (DMSO): 1.75-1.85 (m, 4H), 2.92-2.98 (m, 4H), 3.16 (t, 2H), 4.15 (t, 2H), 6.95 (d, 2H), 7.38 (d, 1H), 7.46 (d, 1H), 7.55 (d, 1H), 7.65 (d, 2H), 8.24 (s, 1H), 8.69 (s, 1H), 9.43 (s, 1H).
Reaction SMILES: CC1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]2[C:8]([CH3:15])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.N>Cl>[CH3:15][C:8]1[C:9]([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:3]
Reactant: Cc1cccc2nc(C)n3ccnc3c12
Agent: Cl
Agent: N
Product: Cc1cccc(N)c1-c1ncc[nH]1
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
6. 13 g of 5,10-dimethylimidazo[1,2-c]quinazoline in 350 ml of 6N hydrochloric acid are stirred at 95° C. and then cooled in an ice bath. The reaction solution is poured into 30 ml of 25% ammonia and stirred in an ice bath for 10 min. The crystals are filtered off, washed with water and dried in a vacuum. 10.1 g of 3-methyl-2-(1H-2-imidazolyl)aniline are obtained. The filtrate is extracted three times with chloroform. The extracts are evaporated in a vacuum. A further 1.4 g of 3-methyl-2-(1H-2-imidazolyl) aniline are obtained. The m.p. lies at 174°-175° C. after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(Br)ccc23)C1(C)C
Yield: 44 %

Procedure:
A mixture of 6-bromoindole (2.0 g. 10 mmol), ethylmagnesium bromide (1.0 M solution in THF, 12 mL, 12 mmol), zinc chloride (1.0 M solution in Et2O, 12 mL, 12 mmol) and the product of Example 1A (15 mmol) in 50 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.4 g, 4.4 mmol, 44% yield). MS (DCI/NH3) m/z 320, 322 (M+H)+.