Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18](=[O:30])[C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=O)[CH3:16].CCOC(C)=O.C(Cl)(Cl)Cl>CC#N.[Cl-].[Na+].O>[CH2:26]([O:25][C:23]1[O:24][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:30])=[N:21][CH:22]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCOc1cnc(C(=O)OCC)o1
Temperature: 50 °C

Procedure:
A suspension of P2O5 (22 g, 155.6 mmol) in CH3CN (50 mL) under nitrogen was warmed to 50° C. and treated with butyl N-[ethoxy(oxo)acetyl]glycinate (6 g, 25.9 mmol) dissolved in 10 mL CH3CN. The mixture was heated to 65° C. for 1.5 hours, then cooled in an ice bath. Ice and brine were added to the reaction mixture, then EtOAc was added and the mixture transferred to a separatory funnel. CHCl3 was added to dissolve solids and the organic layer was isolated. The aqueous layer was washed repeatedly with CHCl3 and EtOAc, the organic layers were combined and dried with Na2SO4, then concentrated. The residue was chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes to give the product as a clear, colorless oil.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[F:41][C:42]([F:54])([F:53])[O:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1C(Cl)=O>CCOC(C)=O.C(Cl)Cl>[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([CH2:8][NH:7][C:6](=[O:30])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[O:43][C:42]([F:41])([F:54])[F:53])[CH2:14][CH2:13]2)[N:26]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)c3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester obtained in step G of example 1 (800 mg, 1.93 mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 60 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (10 mL) was added diisopropylethylamine (706 μL, 4.05 mmol). The mixture was cooled at 4° C. and a solution of 2-(trifluoromethoxy)benzoyl chloride (455 mg, 2.03 mmol) in CH2Cl2 (4 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 90 min. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide (772 mg, 80%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:15])[CH2:18][CH2:17][CH2:16]2)=[CH:3][C:4]=1[F:9]
Reactant: C1CCOC1
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Product: OC1(c2ccc(Cl)c(F)c2)CCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 4-bromo-1-chloro-2-fluorobenzene (2.99 g, 14.27 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (5.71 mL, 14.27 mmol, 2.5 m in hexane) over 5 minutes. The reaction was stirred at −78° C. for 15 min, and cybutanone (1.0 g, 14.27 mmol) was added dropwise. After 15 minutes, the reaction mixture was quenched by the addition of saturated aqueous of NH4Cl (50 mL) and diethyl ether (50 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×50 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid Chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a solid. MS (ESI) m/z 201[M+H]+.
Reaction SMILES: B(Cl)(Cl)Cl.CO[C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23]C>ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:7](=[O:25])[O:23][C:16]=2[CH:17]=1
Reactant: COC(=O)c1ccccc1Oc1ccc(OC)cc1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(=O)c1ccccc1O2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of boron trichloride (1 ml of 1 mol/L solution in dichloromethane) in dichloromethane (2 ml) was added to a stirred solution of 2-(2,4-dimethoxy-phenoxy)-benzoic acid methyl ester (0.364 g) in dichloromethane (15 ml) under ice bath. The solution was stirred for 20 min and then stirred at room temperature for 2 h. The solution was carefully poured into ice water and the crude product was extracted with dichloromethane, washed with saturated brine, dried over anhydrous MgSO4, filtered and evaporated by a rotary evaporator to obtain the product, which was purified by column chromatography.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19]Br>O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]=1[Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrBr
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Br

Procedure:
A 25 g (0.1 mole) amount of p-octyloxybenzoic acid was suspended in 120 ml of water. The temperature was increased to between 50° C. and 55° C. and 17.6 g (0.11 mole) of bromine were added over a period of 7 hours at that temperature. The suspended solids were then filtered and recrystallized from ethanol and pure 4-octyloxy-3-bromobenzoic acid was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:24]=1
Reactant: Nc1cccc(CCN2CCCC2)c1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 58.2 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (240 mg, 1.3 mmol) to afford the desired product (230 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.79 (br s, 1H), 8.99 (s, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29-7.20 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.03-6.96 (m, 2H), 2.85-2.77 (m, 2H), 2.72-2.66 (m, 2H), 2.59-2.49 (m, 4H), 2.53 (s, 3H), 1.84-1.74 (m, 4H); ESI MS m/z 395 [M+H]+
Reaction SMILES: C(=[N:14][N:15]=[CH:16][C:17]1[S:18][C:19]([C:23](C)(C)[O:24][SiH2]C(C)(C)C)=[CH:20][C:21]=1Br)(C1C=CC=CC=1)C1C=CC=CC=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P[C-]2C=CC=C2)C=CC=CC=1.[C-]1(PC2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:14]1[C:21]2[CH:20]=[C:19]([CH2:23][OH:24])[S:18][C:17]=2[CH:16]=[N:15]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Br)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: OCc1cc2[nH]ncc2s1
Temperature: 90 °C
Reaction time: 20 h
Yield: 26.7 %

Procedure:
To a solution of N-benzhydrylidene-N′-[1-[3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-methylidene]-hydrazine [41.2 g, 80.2 mmol, Intermediate (69)] in toluene (500 mL) were added benzophenone hydrazone (18.9 g, 96.2 mmol), cesium carbonate (44.3 g, 136.3 mmol) then 1,1′-diphenylphosphinoferrocene (6.66 g, 12 mmol), and palladium acetate (1.35 g, 6 mmol). The orange mixture was stirred at 90° C. for 20 hours. The insoluble was filtered off and the filtrate was concentrated. The residue was chromatographed (n-heptane/ethyl acetate, 90/10). The resulting dark orange oil (45.7 g) was dissolved in ethanol (400 mL), then concentrated hydrochloric acid (150 mL) was added. The dark red mixture was stirred at 75° C. overnight. A 2.5 N solution of sodium hydroxide in water was added until pH is neutral. The mixture was then extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 50/50 then 20/80 as eluant) to afford (1H-thieno[3,2-c]pyrazol-5-yl)-methanol [3.3 g, 27%, Intermediate (70)] as an orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:43][C:44]([F:52])([F:51])[CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:48]3[CH2:49][CH2:50][CH:45]([C:44]([F:52])([F:51])[F:43])[CH2:46][CH2:47]3)=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:10]1=[O:19]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Treat a solution of Example 4 (0.079 g, 0.18 mmol) in CH2Cl2 (8 mL) with 1,1′-carbonyldiimidazole (0.047 g, 0.29 mmol) and stir for 1 hour at room temperature under N2. Then, treat the reaction with 4-(trifluoromethyl)piperidine HCl (0.087 g, 0.46 mmol) and diisopropylethylamine (0.12 g, 0.92 mmol) and stir for 16 hours at room temperature under N2. Dilute the reaction with ethyl acetate and wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with a 0 to 10% methanol in CH2Cl2 gradient on silica gel and then isocratically with 50/50 ethyl acetate/hexanes gradient on silica gel to afford 0.067 g (64%) of the titled product. Rf=0.68 (9/1 CH2Cl2/methanol). MS (m/z): 567 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[C:13]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Product: CC(C)c1cc(OCc2ccc(F)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 1.27 (d, J=6.8 Hz, 6H), 2.90-3.10 (m, 1H), 5.54 (s, 2H), 6.88 (s, 1H), 7.24 (t, J=8.9 Hz, 2H), 7.57 (d, J=8.9, 8.5 Hz, 2H), 7.81 (s, 1H), 8.33 (s, 2H); LC retention time 4.45 min; MS: m/z (ESI) 391 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2cc(N3CCOCC3)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
50 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 17 mg of morpholine and 64 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N-(4-Methoxyphenyl)-6-morpholinopyrimidin-4-amine in the form of a colorless solid was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][N:42]([C:53]([NH:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:54])[CH2:41]1)=[O:39]
Reactant: O=C=Nc1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCN(C(=O)Nc2ccccc2)C1
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 46% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.42 (s, 1H), 9.34 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.50 (d, 2H), 7.20 (m, 3H), 7.08 (m, 2H), 6.90 (m, 2H), 6.78 (d, 1H), 3.70 (m, 1H), 3.60 (m, 2H), 3.40 (m, 1H), 3.27 (m, 1H), 2.87 (m, 4H), 2.19 (m, 2H). LCMS for C30H29ClN7O2 (M+H)+: m/z=554.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH:13]=[CH:14][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C(O)Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C=Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Temperature: 5 °C

Procedure:
2-(1,2,3,4-Tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[C:28]([Mg]Br)#[C:29][CH3:30].O1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]1[C:23]2[CH:22]([C:28]#[C:29][CH3:30])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: CC#C[Mg]Br
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a suspension of 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide in tetrahydrofuran (0.5 M, 17 mL, 8.5 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-13-methyl-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (100 mg, 61%). LC/MS m/e calcd for C24H23NO4 (M+H)+: 390.46, observed: 390.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (d, J=1.52 Hz, 3 H) 2.22 (s, 3 H) 2.59-2.69 (m, 1 H) 2.89-2.99 (m, 1 H) 3.16-3.27 (m, 2 H) 3.81 (d, J=7.58 Hz, 6 H) 5.38 (d, J=1.77 Hz, 1 H) 6.04 (d, J=2.78 Hz, 2 H) 6.84 (s, 1 H) 6.96 (m, 2 H) 7.06 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.N12CCCN=C1CCCCC2.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:52]([CH2:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)=[N+:53]=[N-:54]
Reactant: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(CN=[N+]=[N-])cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution (7 mL) of the compound (1.3 g, 3.4 mmol) obtained in Example 95c in tetrahydrofuran were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol) and diphenylphosphoryl azide (1.1 g, 4.1 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=85/15) to give the title compound (1.1 g, 80%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Br)=[CH:5][S:4][CH:3]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:7][C:6]1[C:2]([Br:1])=[CH:3][S:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: BrCc1cscc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1cscc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-methylthiophene (8.85 g), N-bromosuccinimide (8.85 g), 2,2'-azobis(isobutyronitrile) (0.16 g) and carbon tetrachloride (100 ml) was stirred under reflux for 6 hours. The mixture was concentrated under reduced pressure to give a crude product of 3-bromo-4-bromomethylthiophene. A suspension of this crude product of 3-bromo-4-bromomethylthiophene and potassium acetate (30 g) in acetone (100 ml) was stirred at room temperature for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 4-acetoxymethyl-3-bromothiophene. This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-4-hydroxymethylthiophene (5.33 g) as oil. 3-Bromo-4-hydroxymethylthiophene was dissolved in methylene chloride (100 ml), and manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-3-thiophenecarbaldehyde. The crude product of 4-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added. Further, sodium chlorite (3.7 g) in water (40 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromo-3-thiophenecarboxylic acid (3.40 g) as crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]=[C:19]([NH2:29])[N:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>C1COCC1>[NH2:29][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:34])[N:32]([CH2:36][CH3:37])[CH2:30][CH3:31])[CH:8]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
N4-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy} phenyl)-6-phenylpyrimidine-2,4-diamine (50 mg, 0.13 mmol, Example 39) and diethylcarbamyl chloride (20.6 mg, 0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLC and LC-MS indicated that the reaction was complete. The mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H2O (3×). The organic layer was dried and concentrated to give 72 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 40 mg (63%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 8.28 (d, 1H), 7.84 (m, 3H), 7.81 (s, 1H), 7.48 (m, 3H), 7.05 (d, 2H), 6.84 (m, 1H), 6.75 (s, 1H), 6.44 (s, 1H), 4.39 (s, 2H), 3.23 (m, 4H), 1.20 (t, 6H); MS ES 484 (M+H)+, calcd 484, RT=2.37 min; TLC (MeOH/EtOAc=20/80) Rf=0.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Cl>CC(N(C)C)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc(CCCCc2ccccc2O)cc(OC)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCC1CO1
Product: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Yield: 79.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), 1.9 g of 2-[4-(3,5-dimethoxyphenyl)butyl]phenol (prepared as described in Preparation 9), 0.75 g of potassium t-butoxide and 0.91 g of epichlorohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified to give 1.81 g (yield 80%) of the title compound as a colorless oil.