Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:9])[C:8]2[N:4]([CH:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>ClCC(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:5]2[N:4]3[C:8](=[CH:7][CH:6]=2)[C:1](=[O:9])[CH2:2][CH2:3]3)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCn2cccc21
Agent: ClCC(Cl)(Cl)Cl
Product: O=C1CCn2c1ccc2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred mixture of 12.1 g compound (1) and 8 g AICI3 in 40 ml tetrachloroethane was added dropwise 5.3 g 4-chlorobenzoyl chloride during 1 hour. The mixture was stirred at 40°-45° C. for 2 hours. The reaction mixture was added into 100 g ice-water. The organic layer was dried over MgSO4. Evaporated to dryness, 7 g crude product was obtained. Recrystallized from ethanol, 5.5 g of (3) was obtained as a white solid, mp 165°-166.5° C., yield 72%.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:36][CH:35]([F:37])[CH2:34]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)[CH3:2].[F:39]C1(F)CN(CCN2C=C(C3C=CC(F)=C(C(F)(F)F)C=3)N=C2C2CCNCC2)C1>>[F:37][C:35]1([F:39])[CH2:34][N:33]([CH2:32][CH2:31][N:16]2[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:28])([F:30])[F:29])[CH:21]=3)[N:19]=[C:15]2[CH:12]2[CH2:11][CH2:10][N:9]([C:8]3[N:7]=[CH:6][N:5]=[C:4]([NH2:38])[C:3]=3[CH2:1][CH3:2])[CH2:14][CH2:13]2)[CH2:36]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Reactant: Fc1ccc(-c2cn(CCN3CC(F)(F)C3)c(C3CCNCC3)n2)cc1C(F)(F)F
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine using 4-(1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine instead of 4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1>C1COCC1.CCOC(C)=O.O>[Cl:20][C:13]1[N:12]=[C:11]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of THF and 2.4 g NaH (55% in mineral oil, 55 mmol) is cooled to 0° C., 5.2 ml tetrahydro-pyran-4-ol (55 mmol) are slowly added and the mixture stirred for 30 minutes. 10.0 g (52 mmol) 2,6-dichloro-3-nitro-pyridine in THF are slowly added and the mixture is stirred at RT over night. The reaction mixture is diluted with EtOAc and water. The organic phase is separated and washed with water and brine, dried and evaporated. The residual is purified by FC, giving rise to 7.8 g (58%) 6-chloro-3-nitro-2-(tetrahydro-pyran-4-yloxy)-pyridine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 8 phenyloctanoic acid (19.8 mmoles in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:9]([CH3:10])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: COCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (2.86 ml, 36.9 mmol) was added dropwise to an ice-cooled solution of 1-methoxy-2-propanol (3 ml, 30.7 mmol) and triethylamine (10.27 ml, 73.7 mmol) in dichloromethane (150 ml), and the reaction stirred at room temperature for 18 hours. The mixture was washed with water, then 2M hydrochloric acid, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow oil, 5.24 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16](OC)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:43](=[O:48])[C:44]([O:46]C)=[O:45].[O:49]1CCCC1>>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:43]([C:44]([OH:46])=[O:45])=[O:48])[CH:12]=2)[C:16]([OH:49])=[O:17])([CH3:23])([CH3:24])[CH3:22]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(CNC(=O)C(=O)O)ccc23)cc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 61.2 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in tetrahydrofuran (THF) (1.000 mL) was treated with DIEA (0.015 mL, 0.086 mmol) and methyl 2-chloro-2-oxoacetate (6.35 μL, 0.069 mmol). After stirring for 40 min, the reaction was quenched with sat. NaHCO3, extracted with EtOAc, washed with sat. NaHCO3, Brine, dried with Na2SO4, filtered, and concentrated. The residue was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(7-((carboxyformamido)methyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (13.7 mg, 0.026 mmol, 61.2% yield) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.32 (s, 1 H), 7.61-7.49 (m, 1 H), 7.36-7.22 (m, 2 H), 7.04-7.14 (m, 2 H), 5.26 (s, 1 H), 4.59 (s, 2 H), 3.75-3.68 (m, 3 H), 2.39 (s, 3 H), 2.34 (s, 3 H), 1.04-0.96 (m, 9 H); LCMS (m/z) ES+=495 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2c(OC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 67.1 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-cyclopropoxyisoquinolin (0.24 g, 1.01 mmol) in DMSO (2 ml) was added cesium fluoride (0.38 g 2.52 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.15 g 67%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I.[Br:19]C1C=C(F)C=CC=1N>>[Br:19][C:12]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Nc1ccc(F)cc1Br
Product: COc1ccc(Sc2cc(F)ccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene (prepared from 2-bromo-4-fluoro-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: BrCCCCCBr
Reactant: COc1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc(C2(C#N)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a solution of 4-methoxyphenylacetonitrile (2) (1.002 g, 6.8 mmol) and 1,5-dibromopentane (1.886 g, 8.2 mmol) in dry dimethylformamide (15 ml) at ice bath temperature slowly (ca. 2-3 min.) a 60% suspension of NaH in mineral oil (0.579 g, 14.4 mmol) was added. The obtained reaction mixture was stirred for 15 minutes at ice bath temperature and for 1.5 hours at room temperature, then the content was poured into benzene (75 ml). The mixture was successively washed with water (3×75 ml), brine (25 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (50 g) with petroleum ether-ethyl acetate (5:1) as eluent to give the title compound (0.924 g, 63%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.00-2.28 (10H, m); 3.81 (3H, s); 6.90 (2H, d, J=9.0 Hz); 7.40 (2H, d, J=9.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].C(Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH:24](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]([CH3:24])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:10][C:8]2=[O:9]
Reactant: ClC(Cl)Cl
Reactant: CNc1ccc(OC)cc1C(N)=O
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc2c(c1)c(=O)nc(-c1ccccc1)n2C
Reaction time: 1.5 h

Procedure:
1.00 g (5.55 mmol) 5-Methoxy-2-methylamino-benzamide were dissolved in 25 ml trichloromethane and 2.34 g (1.93 ml, 16.6 mmol) benzoyl chloride were added. The mixture was boiled for 90 min. After filtration the residue was dissolved in trichloromethane and saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:50])[CH:23]([C:25]1[CH:30]=[CH:29][C:28](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:27][CH:26]=1)[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:20][O:21][C:22](=[O:50])[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([C:18]#[C:17][C:9]2[CH:8]=[CH:7][C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:19])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:29][CH:30]=1)[CH3:24]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.116 g, 0.46 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.17 g, 0.59 mmol), triethyl amine (0.75 mL), copper(I)iodide (0.07 g, 0.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) followed by flash column chromatography over silica gel (230–400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the eluent, the title compound was obtained (0.08 g, 42%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:13][CH2:12][CH2:11][NH2:14])[CH:7]=1
Reactant: COc1cc(C)nc(Br)c1
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C)nc(NCCN)c1
Temperature: 120 °C
Yield: 24 %

Procedure:
2-Bromo-6-methyl-4-methoxy-pyridine (202 mg, 1 mmol) was combined with 1,2-ethylenediamine (3 ml) and triethylamin (280 μl, 2 mmol) and heated in a sealed tube at 120° C. for three hours under microwave heating. The mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 2% to 100% acetonitrile) to yield 44 mg of a solid (0.24 mmol, 24%) MS(ESI) m/z=182.1 [M+1]+.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Cl:28][C:20]1[N:19]=[C:18]2[C:23]([C:24](=[O:26])[CH:25]=[C:16]([N:9]([CH3:3])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C)c1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2CO3 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf=0.76 (4:1 Hex:EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:35]=O)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[NH2:37][C:38]([C:40]([NH2:42])=[S:41])=[S:39]>CS(C)=O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:35]4[S:39][C:38]5[N:37]=[C:35]([C:9]6[CH:8]=[CH:7][C:6]7[C:5]8[C:13](=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=8)[C:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=7[CH:10]=6)[S:41][C:40]=5[N:42]=4)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: NC(=S)C(N)=S
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3nc4sc(-c5ccc6c(c5)C(CCCCCCCCCC)(CCCCCCCCCC)c5cc(Br)ccc5-6)nc4s3)cc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
A mixture of 7-bromo-9,9-didecylfluorene-2carbaldehyde (example 2; 6.6 g, 12 mmol), dithiooxamide (rubeanic acid, 0.6 g, 5 mmol) and DMSO (4 mL) was heated in an oil-bath to a bath temperature of 190° C., held 1 hour and poured onto water. The mixture was extracted into toluene (200 mL). The toluene extract was washed with water, dried and concentrated. The resulting residue was chromatographed over alumina to get a mixture of product containing the aldehyde product. The mixture was rechromatographed over silica gel, and elution with toluene gave 0.9 g (15% yield) of the product which was recrystallized from a mixture of heptane and hexanes to get pure product 0.6 g, (10% yield), m.p. 150.8-152.7° C. Mass Spec.(m/z): 1186, 1188, 1190 (M+). Anal. Calcd. for C70H96Br2N2S2: C, 70.68%; H, 8.14%; N, 2.36%; S, 5.39%; Br, 13.44%. Found: C, 70.69%; H, 8.22%; N, 2.07%; S, 5.31%; Br, 13.67%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[O:6][C:2]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN1CCN(Cc2ccc(Br)o2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN2CCN(C)CC2)o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round-bottomed flask was charged with 1-((5-bromofuran-2-yl)methyl)-4-methylpiperazine (1.29 g, 4.88 mmol), and THF (20 mL). The solution was cooled to −78° C. in a dry ice/acetone bath. tert-Butyllithium (6.56 mL, 10.5 mmol; 1.6 M in pentane) was added, and the reaction mixture was stirred for 30 minutes. Tributylchlorostannane (1.12 mL, 4.15 mmol) was added the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by adding pH 7 phosphate buffer (20 mL) and warming to room temperature. The reaction mixture was extracted with EtOAc (50 mL), washed with brine (2×50 mL), dried over sodium sulfate, filter and concentrate. Purify by Biotage 40S (EtOAc). Isolated product (1.20 g, 52%) as a green oil. 1H NMR (CDCl3, 400 MHz) δ 6.47 (d, J=3.1 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 3.62 (s, 2H), 2.50 (br s, 8H), 2.27 (s, 3H), 1.53 (m, 6H), 1.33 (m, 6H), 1.06 (m, 6H), 0.88 (m, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([Br:15])=[C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=12)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:15][C:8]1[C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[C:5]([CH2:3][OH:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)c2oc(C)nc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc2c(CO)ccc(Br)c2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of 7-bromo-2 methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (Example 6.4) (8.64 g) in tetrahydrofuran (250 ml) was added dropwise a solution of diisobutylaluminium hydride (“DIBAL-H”) (1M in hexane) (80 ml) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. Then the ice-bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 40 minutes the mixture was cooled with an ice-bath and the reaction was quenched by the slow addition of water (5.0 ml). The mixture was poured onto aqueous sodium hydrogen carbonate (saturated) (300 ml) and extracted with diethyl ether (400 ml). The aqueous phase was further extracted with diethyl ether (2×300 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated in a mixture of diisopropyl ether and heptane (3:1) to give (7-bromo-2-methyl-benzo[d]oxazol-4-yl)-methanol (4.45 g). 1H-NMR (400 MHz, CDCl3): 7.41 (d, 1H), 7.17 (d, 1H), 4.98 (s, 3H), 3.06 (s, 1H), 2.67 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)[CH3:2].C[O:11][CH:12](OC)[N:13](C)C.[C:18]([CH2:20][C:21](N)=O)#[N:19].[H-].[Na+]>C1COCC1.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:21]=[C:20]([C:18]#[N:19])[C:12](=[O:11])[NH:13][C:6]=1[CH3:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Reactant: COC(OC)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C#N)c(=O)[nH]c1C
Yield: 45.6 %

Procedure:
Ethylacetoacetate (6.5 g, 0.050 mole) and dimethylformamide dimethyl acetal (7.14 g, 0.060 mole) were stirred together under argon overnight. The resulting reddish oil was concentrated on the rotary evaporator and the concentrate then dissolved in THF (10 ml) and quickly added to a suspension of cyanoacetamide (4.20 g, 0.050 mole) and sodium hydride in THF (175 ml). The reaction mixture was neutralized to pH 6 with acetic acid and concentrated on the rotary evaporator. The residue was triturated with a 50:50 CH2Cl2 -H2O mixture collected and recrystallized (EtOAC) giving 4.7 g of 3-cyano-1,2-dihydro-6-methyl-2-oxo-5-pyridinecarboxylic acid ethyl ester m.pt. 208°-210° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:26])[C:6]=2[N:7]=1.[NH:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:40]=2)[CH:35]=[CH:34]1>>[OH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:9]3[S:10][C:5]4[C:4]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:3][C:2]([C:38]5[CH:37]=[C:36]6[CH:35]=[CH:34][NH:33][C:41]6=[N:40][CH:39]=5)=[N:7][C:6]=4[C:8]=3[CH3:26])[CH:12]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH2:29])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[CH3:30][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH:29][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(N)c1
Reactant: CC(C)C(=O)Cl
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(NC(=O)C(C)C)c1

Procedure:
5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with isobutyryl chloride by method Q. This resulted in the product with the molecular weight of 474.26 (C28H34N4O3); MS (ESI): 475 (M+H+).