Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH2:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CN=CC1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCN(c2cccc(Br)n2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5 g (21.11 mmol) of 2,6-dibromopyridine, 2.09 g (21.11 mmol) of piridin-4-one and 7.29 g of potassium carbonate (52.77 mmol) are suspended in 30 ml of DMSO and stirred at 120° C. overnight. Water is then added to the mixture, which is then extracted with EA. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue formed is purified by means of flash chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36]>COCCO>[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:33][CH2:32][CH2:31][O:30][C:24]2[CH:23]=[C:22]3[C:27]([C:18]([NH:17][C:3]4[C:4]5[O:8][CH2:7][O:6][C:5]=5[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:2]=4[Cl:1])=[N:19][CH:20]=[N:21]3)=[CH:26][C:25]=2[O:28][CH3:29])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CC(=O)N1CCNCC1
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 82.6 %

Procedure:
N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (192 mg, 0.38 mmol) and 1-acetylpiperazine (244 mg, 1.9 mmol) in 2-methoxyethanol (4 ml) were stirred and heated at 100° for 12 hr. then quenched in water and extracted with dichloromethane. The combined extracts were washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. This was then purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (187 mg, 82%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.98 (quintet, 2H), 1.99 (s, 3H), 2.33 (m, 2H), 2.40 (m, 2H), 2.48 (t, 2H), 2.72 (t, 2H), 3.31 (s, 3H), 3.43 (m, 4H), 3.53 (t, 2H), 3.93 (s, 3H), 4.21 (t, 2H), 6.13 (s, 2H), 7.07 (s, 1H), 7.18 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].[C:20](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:20])=[O:14])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a suspension of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) in dry acetone (2 ml) were added potassium carbonate (194 mg, 1.4 mmol) and dry dimethylformamide (1 ml). The mixture was treated with methyl iodide (199 mg, 1.4 mmol) and dry dimethylformamide (2 ml) and stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, the precipitated solid was collected on a filter by suction, dried, and recrystallized from the mixed solvent of methanol and water to give pale yellow crystals of the desired compound (213 mg, yield, 74%). m.p., 126°-127° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24].CC([O-])(C)C.[K+]>>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[C:14]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:2][C:3]2[C:4]([CH:9]=1)=[CH:5][N:6]=[CH:7][CH:8]=2
Reactant: COc1cccc(OC)c1CCC#N
Reactant: Nc1ccncc1C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1cccc(OC)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-amino-3-pyridine carboxaldehyde hydrochloride and 3-(2,6-dimethoxyphenyl)propionitrile. One equivalent of potassium tert-butylate was additionally used.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:29]=4[C:28]4[CH:44]=[CH:45][CH:46]=[CH:47][C:27]3=4)=[O:25])=[CH:20][C:19]=2[CH3:48])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:49]>CO.O1CCOCC1>[ClH:49].[ClH:49].[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:19]([CH3:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E70.1 (230 mg, 0.35 mmol) was dissolved in methanol (5 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 2 h at room temperature then concentrated in vacuo and triturated with diethyl ether to yield the title compound (215 mg, 98%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:29][O:28][C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:10]2[NH:9]1)[N:16]=[C:15]([O:20][CH:21]([CH3:23])[CH3:22])[CH:14]=[C:13]3[C:24]([F:27])([F:26])[F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([C@@H:8]1[CH2:29][O:28][C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:10]2[N:9]1[CH2:13][C:24]([F:27])([F:26])[F:25])[N:16]=[C:15]([O:20][CH:21]([CH3:23])[CH3:22])[CH:14]=[C:13]3[C:24]([F:25])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](Cc1ccccc1)CO3
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)F)[C@H](Cc1ccccc1)CO3
Yield: 190.9 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3-benzyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (25.8 mg, 0.064 mmol) and NaBH4 (300 mg, 7.9 mmol) in 3 mL TFA, to afford 29.6 mg (95%) of (3R)-3-benzyl-3,4-dihydro-8-isopropoxy-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow solid, after column chromatography (1:9 EtOAc:hexane). 1H NMR (400 MHz, CDCl3) δ 7.51–7.10 (m, 8H), 5.51 (septet, 1H, J=6.2), 4,29 (d, 1H, J=10.5), 3.91 (m, 2H), 3.70–3.50 (m, 2H), 2.90 (dd, 1H, J=6.3, 13.3), 2.80 (dd, 1H, J=9.2, 13.3), 1.39 (d, 6H, J=6.2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)O1.C([O:36][C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=1[F:44])(=O)C>>[F:44][C:38]1[CH:39]=[C:40]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)[CH:41]=[CH:42][C:37]=1[OH:36]
Reactant: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Reactant: CC(=O)Oc1ccc(Br)cc1F
Product: O=c1nc(N2CC=C(c3ccc(O)c(F)c3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 41 %

Procedure:
The synthesis was performed using a crude product obtained by synthesis using 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(t rifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 346 and 4-bromo-2-fluorophenyl acetate in a similar manner to Reference Synthesis Example 139, in a similar manner to Reference Synthesis Example 2 (two step yield 41%).
Reaction SMILES: C[O:2][C:3]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26]C)=[C:18]([CH3:28])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1.C(#N)C.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:25][O:24][C:20]1[C:19](=[O:26])[C:18]([CH3:28])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:21]=1[O:22][CH3:23]
Reactant: COc1c(C)c(Cc2ccc(CCCC(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Yield: 64.2 %

Procedure:
The compound (260 mg, 0.67 mmol) obtained in Step 2, acetonitrile (5 ml), water (1.6 ml), and CAN (920 mg, 1.70 mmol) were used, and a method similar to that described in Step 3 of Example 21 was employed and then the reaction mixture was purified by a silica gel column chromatography (methylene chloride:methanol=9:1) to yield the title compound (154 mg, 0.43 mmol, yield 74%).
Reaction SMILES: [S:1]([C:5]1[CH:25]=[CH:24][C:8]([NH:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[C:11]#N)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].O=[CH:27][C:28](=C)[CH3:29].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]([C:8]3[CH:24]=[CH:25][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=3)[CH:27]=[C:28]([CH3:29])[CH:11]=2)=[CH:14][CH:15]=1
Reactant: C=C(C)C=O
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(-c2ccco2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1
Reaction time: 1 h
Yield: 4 %

Procedure:
To a suspension of α-4-sulfamoylanilino-α-[4-(2-furyl)phenyl]acetnitrile (0.28 g, 0.79 mmol) in anhydrous THF (3 mL) at −70° C. was added methacrolein (0.061 g, 0.87 mmol), and then dropwise lithium bis(trimethylsilyl)amide (0.83 mL, 1.0 M solution in hexane, 0.83 mmol). The reaction mixture was stirred at −60° C. to −65° C. for 1 hour, and then the temperature of the reaction mixture was allowed to return to room temperature, and the mixture was stirred for a further 2 hours. The reaction mixture was added a saturated aqueous solution of NH4Cl (10 mL) and the whole was extracted with ethyl acetate (10 mL×2). The organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was redissolved in toluene (5 mL) and heated at reflux temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by thin-layer chromatography eluting with hexane/ethyl acetate (2/1). The resulting solid was recrystallized from CH2Cl2-hexane to give the title compound (0.012 g, 5.6% yield).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([OH:39])[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:51]I>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:42]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([O:39][CH3:51])[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of tert-butyl 4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(hydroxy)methyl)piperidine-1-carboxylate (62.2 mg, 0.089 mmol) in THF at 0° C. was added sodium hydride (10.7 mg, 0.27 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (30 μL, 0.5 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with methanol. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound (45.9 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.16 (m, 1H) 1.17-1.29 (m, 2H) 1.43 (s, 9H) 1.58-1.69 (m, 1H) 1.84 (d, J=13.28 Hz, 1H) 2.44-2.58 (m, 2H) 3.04 (s, 3H) 4.04 (d, J=12.45 Hz, 1H) 4.11 (d, J=7.47 Hz, 1H) 4.15 (d, J=7.05 Hz, 1H) 4.20 (s, 3H) 4.68 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.57 (d, J=7.88 Hz, 1H) 7.65 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 710.3, Found: 711.6 (M+1)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:19]([O:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2CO3 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4 and concentrated to give crude methyl 3-(benzyloxy)-6-bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H)+: 322/324.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCN(c3cccc(Cl)c3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 13.5 g (0.050 mol) of 1-(3-chloro-phenyl)-piperazine in 500 ml of tetrahydrofuran was treated with 35 ml (0.25 mol) of triethylamine and 18.2 g (0.050 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 10 g (63%) of 5-[4-(3-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as beige crystals; m.p. 222°-226°.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([O:22]CC)=[O:21])[S:15][C:10]3=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([C:25]([O:27]CC)=[O:26])=[CH:3]1>C(O)(=O)C.Br>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([OH:22])=[O:21])[S:15][C:10]3=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([C:25]([OH:27])=[O:26])=[CH:3]1
Reactant: CCCc1c2oc(C(=O)OCC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)sc12
Agent: Br
Solvent: CC(=O)O
Product: CCCc1c2oc(C(=O)O)cc(=O)c2cc2c(=O)cc(C(=O)O)sc12
Yield: 85.6 %

Procedure:
The product of step (g) (2.7 g) in glacial acetic acid (100 mls) and 48% aqueous hydrobromic acid (6 mls) was heated under reflux for 4 hours. More aqueous hydrobromic acid (3 mls) was added and refluxing continued overnight. The reaction was allowed to cool and the precipitated solid was collected by filtration, washed with ether and dried in vacuo at 80° C. for 3 hours to give 2.0 g of the desired product, mp 308°-310° dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) ανδ PdCl2 (dppf) (140 mg, 0.18 mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) afforded the title compound title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[O:26]1[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Yield: 32.6 %

Procedure:
To a solution of 4.115 g of 4-allyl-1-(tert-butoxycarbonyl)piperidin-4-ol in dichloromethane (100 ml) were added 7.07 g of 3-chloroperbenzoic acid and 2.87 g of sodium hydrogencarbonate and the resulting mixture was heated under reflux for 24 hours. To the reaction mixture were added ethyl acetate and an aqueous solution of sodium metabisulfite and the resulting mixture was stirred for 1 hour. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 1.43 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:34]([N:41]1[CH2:46][CH2:45][C:44](=[O:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH3:11])[C:8](=[O:10])[CH2:9][C:44]2([OH:47])[CH2:45][CH2:46][N:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C)C(C)=O)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1ccc(N(C)C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A solution of 4′-methoxy-N-methylacetanilide (12 g) in an anhydrous tetrahydrofuran (30 mL) was added to a solution in an anhydrous tetrahydrofuran (100 mL) of lithium diisopropylamide prepared from diisopropylamine (10.5 mL) and n-butyl lithium (1.53M hexane solution; 48 mL) at below −65° C., and the mixture was stirred at −78° C. for 15 minutes. An anhydrous tetrahydrofuran solution (20 mL) of 1-benzylpiperidin-4-one (12.7 g) was then added to this reaction mixture at below −65° C., and the resulting mixture was stirred at −78° C. for 10 minutes. After increasing the temperature to room temperature, water was added to the mixture, and the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue obtained was recrystallized from ether-hexane to obtain the titled compound (17.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=[O:14].C(Cl)(=O)C(Cl)=O.[CH:22](O)([CH3:24])[CH3:23].N1C=CC=CC=1>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH:22]([CH3:24])[CH3:23])=[O:14]
Reactant: CC(C)O
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc2ccccc2c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxynaphthoic acid (458 mg, 2.3 mmol) in dry dichloromethane (9 mL) at 0° C. under a N2 atmosphere was added oxalyl chloride (1.4 mL of a 2M solution in dichloromethane, 2.8 mmol) and 4 drops of N,N-dimethyl formamide. The mixture was stirred at 0° C. for 20 minutes then allowed to warm to room temperature and stirred for one hour. The mixture was concentrated in vacuo. To this dry powder was added isopropanol (9 mL) and pyridine (367 μL, 4.5 mmol), with stirring. After stirring for 2 hours at room temperature, the mixture was concentrated and partitioned between H2O (10 mL) and ethyl acetate (3×10 mL) and the combined organic layers was washed with saturated NaCl (10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using 10% ethyl acetate in hexane. The title compound was obtained as a colorless solid (260 mg, 47%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=O)=[C:5]2[O:15][CH3:16].Cl.[NH2:18][CH2:19][C:20](=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[O:22]=[C:20]([CH3:21])[CH2:19][NH:18][C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[O:15][CH3:16])=[CH:3][C:2]([I:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COc1c(C(=O)O)cnc2ccc(I)cc12
Reactant: CC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C(=O)NCC(C)=O)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
To the mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid (example 1b) (4 g, 12.2 mmol), 1-amino-propan-2-one hydrochloride (3.94 g, 36.5 mmol), HOBt (1.97 g, 14.6 mmol) and DIEA (diisopropylethylamine) (8.5 mL, 48.8 mmol) in DMF (N,N-dimethylformamide) (100 mL) was slowly added the solution of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (5.5 g, 14.6 mmol) in DMF (10 mL). After stirring at room temperature for 12 hours, the product was extracted with methylene chloride (2×300 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×150 mL) and water (3×150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0-10% MeOH in methylene chloride) afforded 6-iodo-4-methoxy-quinoline-3-carboxylic acid (2-oxo-propyl)-amide (1.63 g, 33%) as a yellow solid. LC-MS m/e 385 (MH+).