Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30]Br)=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br.[CH3:33][O-:34].[Na+]>C(O)(=O)C.CO>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30][O:34][CH3:33])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[O-]
Reactant: CCCCc1ncc(CBr)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1ncc(COC)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
2-n-Butyl-5-hydroxymethyl-4-{N-[(2-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine hydrochloride, the product of Example 2B, is converted to 2-butyl-5-bromomethyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine by treatment with hydrogen bromide in acetic acid according to the method of A. Schellenberger and K. Winter in Z. Physiol. Chem., 322, 164 (1960). The bromomethyl intermediate is then converted to the title compound by treatment with sodium methoxide in methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C1COCC1.[H][H]>[OH-].[OH-].[Pd+2].CO>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
32.6 grams (0.118 mol) of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid was added to a one liter round bottom flask along with 250 mL of a 1:1 (v/v) mixture of THF and methanol. 3.3 grams of 20% palladium hydroxide on carbon was then added and the flask was fitted with a septa and balloon of hydrogen. The mixture was stirred overnight at room temperature. In the morning, the crude product was filtered through a pad of celite and the pad was washed with THF. The product was evaporated to dryness and triturated with cold diethyl ether to give 32.1 grams of a tan solid (98% yield, 85% purity, UV detection λ=220 nm) that was used without further purification. MS m/z 278.00 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22]>CN(C)C=O>[CH2:1]([CH:8]1[N:12]([CH3:22])[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN1C(=O)NC(Cc2ccccc2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Cc2ccccc2)N(C)C1=O
Temperature: 50 °C
Yield: 85 %

Procedure:
5-Benzyl-3-n-butyl hydantoin (7.38 g, 0.03 mole) was dissolved in dimethylformamide (50 ml.) and added dropwise with stirring to a suspension of sodium hydride (1.44 g. 50% oil dispersion) in dimethylformamide (20 ml). When gassing ceased, iodomethane (2 ml) was added and the mixture warmed to 50° C. and maintained at 50° C. for 5 hours. The mixture was poured into ice/water (500 ml) and extracted with ether. The ether extract was evaporated in vacuo to give a colourless oil which faild to crystallise and was distilled in a Kugelrohr apparatus to give the title compound (6.6 g; 85%) b.p. 145° C./0.02 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].OS(O)(=O)=O.O.[CH3:21]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:21])=[O:13]
Reactant: CO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1.0 g, 5.0 mmol) in CH3OH (20 mL) was added con. H2SO4 (0.50 mL), the reaction was warmed to 80° C. and stirred for about 3 hr. After cooling down to RT, the reaction was poured into water (20 mL) and concentrated to remove CH3OH. The aqueous was extracted with ethyl acetate (2×20 mL), the combined organic phases were washed brine (10 mL), dried over Na2SO4, filtered and concentrated to afford the product about 1.0 g (93.4%) as a colorless oil. MS (ESI) m/e [M+1]+ 214.0.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].C1(C)C=CC=CC=1>[N+:10]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
4-chloro-3-nitrobenzonitrile (10 g, 54.8 mmol), phenylboronic acid (8.68 g, 71.2 mmol), Pd2dba3 (1.002 g, 1.096 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (1.797 g, 4.38 mmol) were charged into a 500 mL 3-neck flask. Toluene (250 mL) was then charged into the reaction mixture followed by potassium phosphate tribasic monohydrate (35.3 g, 153 mmol) dissolved in 60 mL of water. This mixture was degassed with nitrogen then heated at reflux overnight. The reaction mixture was cooled to room temperature then partitioned with water. The toluene layer was dried over magnesium sulfate, filtered, and dried under vacuum. This crude residue was passed through a silica gel column using 15-35% ethyl acetate/hexanes as the eluent. The product fractions were combined and solvents were removed under vacuum. This crude product was triturated with ethyl acetate/hexanes. The product, 2-nitro-[1,1′-biphenyl]-4-carbonitrile, (8.87 g, 39.6 mmol, 72.2% yield) was isolated via filtration as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15](O)[C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=[C:10]([O:27][CH3:28])[CH:9]=3)=[CH:2]1.C(O)(=O)C>CO.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH2:15][C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=[C:10]([O:27][CH3:28])[CH:9]=3)=[CH:2]1
Reactant: COC(=O)c1cccc(C(O)c2c(-c3ccoc3)[nH]c3cc(OC)ccc23)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(Cc2c(-c3ccoc3)[nH]c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of methyl 6-[(2-furan-3-yl-6-methoxy-1H-indol-3-yl)hydroxymethyl]pyridine-2-carboxylate (590 mg) and a boran-2-picoline complex (175 mg) in methanol (3 mL) was added acetic acid (3 mL), and this mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (386 mg). 1H-NMR (CDCl3) δ ppm: 3.85 (3H, s), 4.05 (3H, s), 4.48 (2H, s), 6.62-6.67 (1H, m), 6.76 (1H, dd, J=2.3, 8.5 Hz), 6.87-6.91 (1H, m), 7.17-7.23 (1H, m), 7.34 (1H, d, J=8.5 Hz), 7.47-7.52 (1H, m), 7.62 (1H, t, J=7.8 Hz), 7.78-7.84 (1H, m), 7.90-8.06 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:27])[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F-].[CH2:29]([N+](CCCC)(CCCC)CCCC)[CH2:30]CC.C(B1OC(C)(C)C(C)(C)O1)=C>C1COCC1>[F:27][C:4]1[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:29]=[CH2:30])[CH:3]=1
Reactant: O=C(Nc1nc2ccc(F)cc2s1)C1=CCN(c2ncc(Br)cc2F)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1cnc(N2CC=C(C(=O)Nc3nc4ccc(F)cc4s3)CC2)c(F)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
687 mg of 1-(5-bromo-3-fluoropyridin-2-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide 29 (1.52 mmol) and 0.05 eq. PdCl2dppf catalyst ([1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), 0.08 mMol, Sigma-Aldrich) were placed in a 50 mL vial with a screw-top septum and suspended in 2 mL dry THF. 2 Eq. 1M tetrabutylammonium fluoride in THF (3.04 mL, Sigma-Aldrich) were then added and the vial heated to 65° C. 1.1 Eq. vinylboronic acid pinacol ester (1.6 mMol, Sigma-Aldrich) were added to the vial via a syringe and the reaction progressed over 18 hours. The reaction mixture was transferred to a 500 mL extraction funnel and diluted with 250 mL water. The compound was extracted with 2×100 mL EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed with a gradient of EtOAc in hexane. The fractions containing desired product (visualized by LC/MS) were concentrated and used without further purification or characterization.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48]CCN(C)C)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH2:44][O:47][CH3:48])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H) 8.19 (s, 1H) 8.14 (m, 1H) 8.06 (m, 1H) 7.91 (m, 1H) 7.81 (m, 1H) 7.28 (d, J=8.32 Hz, 1H) 7.22 (d, J=8.32 Hz, 1H) 4.44 (m, 2H) 3.95 (m, 2H) 3.58 (s, 3H) 3.23 (q, J=7.32 Hz, 2H) 2.49 (s, 3H) 1.37 (t, J=7.32 Hz, 3H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([C:34]([F:37])([F:36])[F:35])[CH2:31][C@H:30]([NH:38]C(=O)OC(C)(C)C)[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2.Cl>O1CCOCC1.CO>[NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([C:34]([F:37])([F:36])[F:35])[CH2:31][C@H:30]([NH2:38])[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2
Reactant: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then evaporated under vacuum. The resulting residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C27H33F3N7O [M+H]+: m/z=528.3. found: 528.3.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:9]1[CH:10]=[C:11]2[C@@:22]3([N:27]=[C:26]([NH2:28])[CH2:25][O:24][CH2:23]3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:29]4[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:20]=3)[O:15][C:12]2=[N:13][CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1>[F:35][C:30]1[C:29]([C:19]2[CH:20]=[C:21]3[C@:22]4([N:27]=[C:26]([NH2:28])[CH2:25][O:24][CH2:23]4)[C:11]4[C:12](=[N:13][CH:14]=[C:9]([N:5]5[CH2:6][CH2:7][C@@H:3]([F:2])[CH2:4]5)[CH:10]=4)[O:15][C:16]3=[CH:17][CH:18]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: F[C@@H]1CCNC1
Agent: Cl[Pd+]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(N3CC[C@@H](F)C3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A vial was charged with 2-fluoropyridin-3-ylboronic acid (0.094 g, 0.667 mmol), PdCl2(dppf)-CH2Cl2-adduct (0.026 g, 0.032 mmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.635 mmol), and potassium carbonate (0.351 g, 2.54 mmol). Dioxane (3.5 mL) and water (1.5 mL) were added. The vial was flushed with argon, sealed and heated to 80° C. for 1 hour. The reaction mixture was then diluted with EtOAc, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.202 g, 0.458 mmol) Step 2: A vial was charged with (R)-3-fluoropyrrolidine HCl (0.021 g, 0.170 mmol), (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.050 g, 0.113 mmol) and RuPhos palladacycle (9.05 mg, 0.011 mmol). THF (1 mL) and LiHMDS (1N in THF; 0.567 mL, 0.567 mmol) were added, and the reaction mixture was allowed to stir at RT overnight. Additional RuPhos palladacycle (9.05 mg, 0.011 mmol) and LiHMDS solution (0.567 mL, 0.567 mmol) were added, and the reaction mixture was heated to 45° C. for 2 hours. The reaction mixture was then quenched with MeOH and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.018 g, 0.040 mmol, 35.3% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=O)=O)=CC=1.[C:26]1([C@H:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:16]([O:15][CH2:14][CH:13]([C:19]1[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=1)[CH2:12][NH:34][C@@H:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)c1ccc(Br)cc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(CN[C@H](C)c1ccccc1)c1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 40.5 %

Procedure:
To a solution of (+)-3-acetoxy-2-(4-bromophenyl)propyl 4-methylbenzene-sulfonate (8.00 g, 18.7 mmol) in N,N-dimethylformamide (94.0 ml) was added (R)-(+)-1-phenylethylamine(11.3 g, 93.2 mmol) at room temperature. The mixture was stirred at 120° C. for 7 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propyl acetate as pale yellow oil (2.85 g, 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([Br:20])=[CH:14][CH:19]=2)[CH:3]=1
Reactant: Brc1ccccc1I
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2cccnc2)cc1
Yield: 47 %

Procedure:
3-Bromopyridine (6 g, 38 mmol) is treated as described in EXAMPLE 53, Part A with n-butyl lithium (28.5 mL of a 1.6 M solution in THF, 45.6 mmol) and iodobromobenzene (8.96 g, 31.7 mmol). The crude product is purified by chromatography (30% EtOAc/hexanes) to obtain the title compound (3.5 g, 14.9 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31]>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:7]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])=[CH:11][CH:12]=1
Reactant: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Reactant: CN(C)CCCN
Product: CNc1nccc(-c2cc(NCCCNCCCN(C)C)c3cc(OC)ccc3c2)n1

Procedure:
N′-[3-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)propyl]-N,N-dimethylpropane-1,3-diamine 189 was synthesized according to General Procedure H except in Step 2 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine and N1,N1-dimethylpropane-1,3-diamine were used. N′-[3-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)propyl]-N,N-dimethylpropane-1,3-diamine 191 was isolated as a red-orange solid. M.p.=142-144° C. LCMS (m/z): 423 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:26](=[O:28])[NH2:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10][C:11](OCC1C=CC=CC=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10][C:11](=[O:12])[NH:27][C:26]1=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Reaction time: 5 h
Yield: 89.7 %

Procedure:
(R)-1-Benzyl ethyl 3-t-butyloxycarbonylamino-3-carbamoylsuccinate (550 mg) obtained in Example 20 was dissolved in acetone (11 mL) and water (6 mL), the solution was added with potassium carbonate (231 mg), the mixture was stirred for 5 hours, and poured with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (358 mg, yield: 90%) as colorless crystals. Optical rotation [α]D25 was −29.5° (c 0.50, ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]1=[O:23].[CH3:24]I.Cl>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:24])[C:13]1=[O:23]
Reactant: CI
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Yield: 72.1 %

Procedure:
A mixture of 0.7 gram (0.017 mole) of sodium hydride (60% in mineral oil) in 30 mL of N,N-dimethylformamide was stirred, and a solution of 5.1 grams (0.017 mole) of 3-(2-fluoro-4-methoxyphenyl)-6-trifluoromethyluracil in 35 mL of N,N-dimethylformamide was added dropwise. The reaction mixture was then stirred for about 30 minutes, and a solution of 3.8 grams (0.017 mole) of methyl iodide in 35 mL of N,N-dimethylformamide was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into an aqueous solution of 0.25N hydrochloric acid, and the mixture was extracted with diethyl ether. The ether extract was washed with an aqueous solution of 0.25N hydrochloric acid, water, and then with an aqueous solution saturated with sodium chloride. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate in heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.9 grams of 3-(2-fluoro-4-methoxyphenyl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC>CN(C)C=O>[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29][NH:15][C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:4][CH:3]3[CH2:8][CH:6]2[CH2:7][N:2]3[CH3:1])=[CH:10][CH:11]=1
Reactant: CN1CC2CC1CN2c1ccc(N)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CN1CC2CC1CN2c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1
Yield: 39.6 %

Procedure:
A solution of 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamine (0.1 g, 0.49 mmol), 6-Iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (0.2 g, 0.6 mmol), and N,N-dimethylformamide (0.2 mL) is heated at 90° C. overnight. After the solvent is removed, the residue is treated with ethyl ether and filtered to give crude product as light brown solid. It is purified by HPLC to yield 97 mg (39% yield) of 6-iodo-4-{[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione as bright orange solid. mp 210-211° C.