Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:31]([O:34][CH2:35]Br)(=[O:33])[CH3:32].O>CC#N.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH:22][CH2:32][C:31]([O:34][CH3:35])=[O:33])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNC(C)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)no1
Reaction time: 2 h
Yield: 24.5 %

Procedure:
To a solution of Example 40D (100 mg, 0.22 mmol) in CH3CN (1.0 mL) was added K2CO3 (150 mg, 1.1 mmol) and bromomethyl acetate (20 μL, 0.22 mmol). The reaction solution was heated to reflux with stirring for 2 hours, cooled, diluted with ethyl acetate and poured into water. The organics were separated, dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC (water:acetonitrile; gradient of 5% to 90% acetonitrile) to provide the title compound (23 mg, 0.054 mmol, 24%). MS (ESI APCI) m/z 419.19 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H) 7.37 (d, J=8.82 Hz, 2H) 7.04 (d, J=9.19 Hz, 2H) 4.57-4.72 (m, 2H) 3.83 (bs, 2H) 3.66 (s, 3H) 1.57 (d, J=6.99 Hz, 3H) 1.29 (d, J=6.25 Hz, 6H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].OS(O)(=O)=O.C([O-])(O)=O.[Na+].C(=O)=O.[CH3:25][CH2:26]OCC>O.C(O)C>[CH2:25]([O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:11])[CH2:3][CH2:2][Br:1])[CH3:26]
Reactant: CCOCC
Reactant: CC(CCBr)CCCC(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCC(C)CCBr

Procedure:
14.0 g of 7-Bromo-5-methylheptanoic acid, 26 ml of absolute ethanol and 1 ml of concentrated H2SO4 were heated to the boil for 10 hours with exclusion of humidity. After cooling the reaction mixture was poured, while stirring and strongly cooling, onto a mixture of 50 ml of ether, 20 ml of water and 6 g of NaHCO3. When the development of CO2 was finished, the organic phase was separated and the aqueous phase was extracted twice with ether. The combined organic phases were washed with a saturated NaHCO-hd 3-solution, dried, evaporated and distilled off.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.C(N(C(C)C)C(C)C)C.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)CC>[NH2:8][C:4]1[N:3]=[C:2]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCNc1ccnc(N)n1)C(=O)OC(C)(C)C

Procedure:
A solution of 4-chloropyrimidin-2-amine (CAS#3993-78-0, 0.200 g, 0.0015 mole), N-ethyl-N-isopropylpropan-2-amine (1.88 mL, 0.0108 mole), and tert-butyl 3-aminopropyl(methyl)carbamate (0.300 g, 0.0015 mole) in n-propanol (3 mL) was heated at 200° C. under microwave irradiation for 10 minutes. Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 97:3:trace DCM/MeOH/aq. NH4OH. Two major products were isolated. The first product to elute was the isomeric byproduct, tert-butyl 3-((2-aminopyrimidin-4-yl)(methyl)amino)propylcarbamate. The second product to elute was the desired product, tert-butyl 3-(2-aminopyrimidin-4-ylamino)propyl(methyl)carbamate (0.040 g, 9.2%). 1H NMR (300 MHz, CD3OD) δ ppm 1.43 (s, 9H), 1.79 (pentet, J=7 Hz, 2H), 2.86 (s, 3H), 3.26-3.33 (m, 4H), 5.81 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H). MS (DCl—NH3) m/z=282 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][C:10]=1[CH3:11]
Reactant: COc1c(C)cc(CO)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(C)cc(C=O)cc1C
Yield: 94.7 %

Procedure:
The aldehyde was synthesized according to the procedure of Example 46, Step 1 using the alcohol from Step 2 (7.5 g, 45 mmol), oxalyl chloride (6.35 g, 50 mmol), dimethylsulfoxide (8.8 g, 100 mmol) and triethylamine (10.2 g, 110 mmol) and in methylene chloride (100 ml). There was obtained 7 g (92%) of the desired aldehyde which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 18.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethoxy)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.22 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.33 mmol) to afford the desired product (21 mg, 18%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.25 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 7.94 (m, 2H), 7.82 (s, 1H), 7.56 (dd, J=8.8, 2.7 Hz, 1H), 7.06-6.96 (m, 2H), 6.92 (d, J=8.8 Hz, 1H), 4.53 (t, J=5.5 Hz, 2H), 3.00 (t, J=5.5 Hz, 2H), 2.95-2.86 (m, 1H), 2.51 (s, 6H), 1.23-1.14 (m, 2H), 1.17-1.07 (m, 2H); ESI MS m/z 521 [C28H26ClFN4O3+H]+; HPLC>99% (AUC), tR=11.15 min.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 20 g of 3-bromo-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine in 50 ml of dimethylformamide at 65° is added to a suspension of 114.7 g of potassium carbonate in 200 ml of dimethylformamide at room temperature maintaining the temperature of the reaction mixture below 30°. The reaction mixture is then stirred at room temperature for 90 minutes. A solution of 20.7 g of ethyl bromoacetate in 50 ml of dimethylformamide is added over a period of 30 minutes at room temperature. The reaction mixture is then stirred at 55° for one hour, filtered, the filter cake is washed with 100 ml of dimethylformamide, and the filtrate is evaporated to a small volume (removing about 200 ml of dimethylformamide) at 65° and 40 mm Hg. After cooling to 5°, 250 ml of water is added over a one hour period, maintaining the temperature below 10°, and the suspension is stirred at about 5° for 15 minutes. The solid is filtered off, washed with 200 ml of cyclohexane, and dried at 55° and 40-60 mm for 16 hours to give 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2cccc3ccccc23)CCNCC1
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2cccc3ccccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.167 gm (0.88 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.200 gm (0.88 mmol) 4-hydroxy-4-(naphth-1-yl)piperidine in 10 mL methanol was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted again with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 5% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.309 (84%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:28]([CH3:31])=[N:29][N:30]=2)[N:5]=[C:6]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:14]3[C:13]([CH3:23])=[N:12][N:11]([CH:24]4[CH2:26][CH2:25]4)[C:10]=3[C:9]2=[O:27])[CH:7]=1.[CH3:32][C:33](OC(C)=O)=[O:34]>N1C=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[C:14]3[C:13]([CH3:23])=[N:12][N:11]([CH:24]4[CH2:26][CH2:25]4)[C:10]=3[C:9](=[O:27])[N:8]2[C:6]2[CH:7]=[C:2]([NH:1][C:33](=[O:34])[CH3:32])[C:3]3[N:4]([C:28]([CH3:31])=[N:29][N:30]=3)[N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N)c3nnc(C)n3n1)C2=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Temperature: 115 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A flask was charged with 5-(8-amino-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 126.3) (40 mg, 0.092 mmol) and Ac2O (0.434 mL, 4.60 mmol) in pyridine (2 mL) under Ar and the resulting mixture was heated up and stirred for 20 hr at 115° C. The reaction was quenched with a saturated aq.NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) and triturated in Et2O to afford the title product (27 mg, 0.057 mmol, 62% yield) as white solid. tR: 4.73 min (HPLC 1); tR: 1.07 min (LC-MS 2); ESI-MS: 477 [M+H]+ (LC-MS 2); ESI-MS: 475 [M−H]− (LC-MS 2); Rf=0.50 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.11 (m, 2H) 1.17-1.30 (m, 2H) 1.90 (s, 3H) 2.25 (s, 3H) 2.51 (s, 3H) 3.76-3.88 (m, 1H) 6.43 (s, 1H) 7.29-7.37 (m, 2H) 7.38-7.48 (m, 2H) 9.12 (s, 1H) 11.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)=[O:30])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 2 ml of dimethylformamide at 0° C. is added 0.23 g (1.55 mmol) of 2-thiophencarbonylchloride. The reaction mixture solution is allowed to stir overnight while slowly reaching room temperature. The reaction mixture is then diluted with water producing a tan precipitate which is collected by filtration, washed with water and dried to yield 0.282 (50%) of the title compound as a tan solid: m.p.>250° C.; IR (KBr) 3420, 1640, 1440 cm-1 ; NMR (DMSO-d6) δ14.1 (s, 1H), 9.6 (s, 1H), 8.6 (d, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.2 (d, 1H), 5.0 (s, 2H), 4.0 (t, 2H), 3.1 (m, 2H); m/e 368 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([C:9](OCC)=[O:10])=[N:7][CH:8]=[C:2]12.[BH4-].[Na+].Cl>CO>[OH:10][CH2:9][C:6]1[N:3]2[C:2]([S:1][CH:5]=[CH:4]2)=[CH:8][N:7]=1
Reactant: CCOC(=O)c1ncc2sccn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 0.929 g of the ethyl imidazo[5,1-b]-thiazole-5-carboxylate obtained in Preparation 9 in 20 ml of methanol was added 0.897 g of sodium borohydride, and the mixture was stirred overnight at room temperature. 2 ml of concentrated hydrochloric acid was added dropwise to the reaction solution with ice-cooling. The mixture was stirred for 10 minutes, and then concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of methanol, and concentrated to dryness again. To the residue were added 30 ml of an aqueous potassium carbonate solution (50 wt. %) and 30 ml of dichloromethane with ice-cooling. The mixture was stirred for 10 minutes, and then filtered to remove insoluble matters. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 ml×2). The combined organic layers were dried over anhydrous potassium carbonate, and purified by flash column chromatography using silica gel, eluting first with ethyl acetate and then with a 20:1 mixture of ethyl acetate and methanol to give 0.628 g (yield 86%) of the title compound as light yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[C:17]([CH:24]=O)=[CH:16]1.[ClH:26]>C(O)C>[ClH:26].[NH:15]1[C:23]2=[N:22][CH:21]=[CH:20][CH:19]=[C:18]2[C:17]([CH:24]=[C:6]2[O:5][C:4]([NH:3][CH2:1][CH3:2])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:16]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCNC1=C(C(=O)OCC)C(=O)CO1
Agent: Cl
Solvent: CCO
Product: CCNC1=C(C(=O)OCC)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-(ethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.17 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.024 g, 0.17 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.026 g, y. 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:28]3[CH2:29][CH:30]([CH3:32])[CH2:31][CH:26]([CH3:25])[CH2:27]3)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 43 %

Procedure:
The condensation of with 1-(2′,4′-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3,5-dimethylpiperidine in a similar manner as described in example 1 gave the titled product. Yield 43%, m.p 224–26° C., C23H21F3N2O3, m/z 431. (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][C:18](OC)=[O:19])[C:13](OC)=[O:14])=[CH:4][N:3]=1.[BH4-].[Li+].O>C(O)(C)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][CH2:18][OH:19])[CH2:13][OH:14])=[CH:4][N:3]=1
Reactant: COC(=O)CC(Cn1cnc2cnc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1ncc2ncn(CC(CO)CCO)c2n1
Reaction time: 1 h

Procedure:
To a solution of crude dimethyl (2-aminopurin-9-ylmethyl)succinate (3.2 g, 10.9 mmol), dissolved in tert. butanol (250 ml) at 40° C., was added lithium borohydride (1.3 g, 60 mmol) in portions with stirring. After 1 hour at ambient temperature, water (30 ml) was added slowly and stirring continued over night. Inorganic salts were filtered and the solution evaporated to dryness. Yield of crude product was 1.6 g (50%). Chromatography on silica (chloroform+methanol 7+1) afforded pure product.
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14](Cl)=[O:15])[CH2:2][CH2:3][CH3:4].[Br:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:30][NH:31][CH3:32])=[CH:23]2.C(N(CC)CC)C>C(Cl)Cl>[Br:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:30][N:31]([CH3:32])[C:14]([C:6]1[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:15])=[CH:23]2
Reactant: CNCc1ccc2c(Br)c(OC)ccc2c1
Reactant: CCCCc1c(C(=O)Cl)oc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-butyl-benzofuran-2-carbonyl chloride (9.0 mmol), prepared in the previous step, in 50 mL of methylene chloride was added under nitrogen dropwise over 2 h to a solution of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amine (2.52 g, 9.0 mmol), prepared in step 7 of Example 36, and triethylamine (1.26 mmol, 9.0 mmol) in 250 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature overnight. The reaction was extracted with 1 N HCl, 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to 4.13 g of a residue. Purification of the residue on 500 g of silica gel (230-400 mesh) using 90% hexane-methylene chloride to 5% EtOAc-methylene chloride as the eluents gave 3-butyl-benzofuran-2-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide as a clear oil, MS m/z: 480 [M+H]+.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>ClCCCl>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sccc12
Solvent: ClCCCl
Product: Clc1ncnc2sccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
Thieno[2,3-d]pyrimidin-4(3H)-one (1.2 g, 7.9 mmol) was diluted in 1,2-dichloroethane (10 mL). Phosphorous oxychloride (1.4 mL, 15.7 mmol) was added. The reaction was stirred at 90° C. for 16 hours. An additional equivalent of phosphorous oxychloride (0.7 mL, 7.9 mmol) was added and the solution continued stirring for 4 hours. The solution was cooled, concentrated, and neutralized with saturated NaHCO3 solution. The material was extracted with a chloroform:isopropyl alcohol mixture and the organic layer was separated and concentrated. Flash chromatography gave the title compound (0.39 g, 29%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[CH:38]=1)[C:33](O)=[O:34])=[O:5])C.C1[CH2:48][N:47]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:46]C1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)C.CN(C=O)C>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:33](=[O:34])[N:47]([CH3:48])[CH3:46])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid (130 mg, 0.21 mmol), PyBroP (263 mg, 0.63 mmol) and diisopropylethylamine (0.11 mL, 0.63 mmol) in CH2Cl2 (4 mL)/DMF (1 mL) was added dimethylamine hydrochloride (51 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The total amount of the product obtained from the previous step was dissolved in ethanol (5 mL) and 1 M NaOH solution was added (2 mL) and the reaction mixture stirred for 3 h. Then the reaction mixture was diluted with ethyl acetate, washed with 10% aq. HCl and brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude oil was purified by preparative HPLC using acetonitrile/water gradient to afford the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[N:8]1([C:6]2[N:7]=[C:2]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]4=[N:21][CH:20]=3)[CH:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(N2CCOCC2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(N4CCOCC4)n3)cnc2n1
Yield: 35 %

Procedure:
4-(6-Bromopyridin-2-yl)morpholine (0.46 g, 1.9 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.8 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-10%) and crystallisation from ethyl acetate-isohexane gave 3-[6-(morpholin-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (220 mg) as a yellow solid: δH (400 MHz, CDCl3) 3.57 (4H, t, J 5), 3.90 (4H, t, J 5), 6.65 (1H, d, J 8), 7.20 (1H, d, J 8), 7.33 (1H, d, J 7), 7.65 (1H, dd, J 8 and 8), 8.42 (1H, s), 10.19 (1H, d, J 7); m/z (ES+) 350 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([S:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=3[S:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCSc1ncccc1C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CCCCCSc1ncccc1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(n-pentylthio)pyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(pentylsulfanyl)nicotinamide as a tan powder, m.p. 158.0-161.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.47-8.41 (m, 2H), 8.21 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=7.6, 1.8 Hz, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.08 (dd, J=7.5, 4.8 Hz, 1H), 6.57 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.27 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.96 (m, 2H), 1.62-1.46 (m, 4H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.1 Hz, 3H); MS (EI) m/e 462.2196 (462.2202 calcd for C25H3oN6OS).