Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OCC)C.[F:7][C:8]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:9]=1[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1>>[NH2:27][CH2:26][CH:25]([NH:24][C:22]([C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:8]=3[F:7])[C:13]2=[N:20][C:19]=1[CH3:21])=[O:23])[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CNC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3.1 ml of 2 M hydrochloric acid in diethyl ether (6.2 mmol) were added to 355 mg of rac-tert-butyl {2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-(3,4-difluorophenyl)ethyl}carbamate (Example 77A, 0.62 mmol), and the mixture was stirred at RT for 5.5 h. The resulting precipitate was filtered off, washed with diethyl ether, suspended in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and dried under high vacuum. This gave 279 mg of the title compound (94% of theory).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1)=[O:4].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:34][C:31]2[CH:32]=[CH:33][C:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:29][CH2:28][C:27]=3[CH:30]=2)[N:12]=1)=[O:4]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 120 °C
Yield: 52.9 %

Procedure:
cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide (60 mg, 0.208 mmol), 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (46 mg, 0.208 mmol) and camphorsulfonic acid (72 mg, 0.312 mmol) were combined in 2 mL isopropanol and heated at 120° C. in microwave for a total of 75 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on an ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 52 mg (53%) of a white foam. Compound 2: mp 176° C.; MS (ES+ calculated—472; found—473 M+H). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 7.03 (d, J=8 Hz, 1H), 6.21 (d, J=7, 1H), 5.52 (br s, 1H), 4.58 (t, J=7 Hz, 1H), 3.55 (t, J=5, 2H), 3.34 (s, 3H), 2.91 (br s, 6H), 2.75 (m, 4H), 2.72 (m, 4H), 2.15 (m, 2H), 1.96 (m, 4H), 1.64 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8]O)=[NH:7])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:18])[C:16]#[CH:17])[CH3:13]>CO>[CH2:12]([O:14][C:15]([C:16]1[NH:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][CH:17]=1)=[O:18])[CH3:13]
Reactant: C#CC(=O)OCC
Reactant: N=C(NO)c1ccc(Cl)cc1
Solvent: CO
Product: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)[nH]1
Temperature: 190 °C

Procedure:
1.0 g (5.9 mmol) of 4-chloro-N-hydroxy-benzamidine and 776 mg (7.96 mmol) of propynoic acid ethyl ester were dissolved in methanol and the resulting solution was boiled under reflux for 15 h. The solvent was removed under reduced pressure, and the residue was dissolved in Dowtherm A. This solution was heated to 190° C. for 2.5 h, allowed to cool, then poured into n-heptane. The precipitated product was filtered off and washed with n-heptane.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methoxytetrahydro-4H-pyran-4-one (12.3 mg, 0.0709 mmol) and triethylamine (6.58 μL, 0.0472 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.0708 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (45 mg) was purified by silica gel column (30:70 MeOH/EtOAc) to provide 1.6 mg (14%) of pure product. LC-MS calculated for C26H36F3N3O3:(M+H) 496; found 496.1.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:4]2[N:3]=1.CC1(C)C(C)(C)OB(C2C=C(C)C=CC=2OC(C(C)C=C)C)O1.BrC1C=C(N)NN=1.[CH2:48]([O:51][C:52]1([CH3:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH:49]=[CH2:50].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:48]([O:51][C:52]1([CH3:58])[CH2:53][CH2:54][N:55]([C:9]2[N:4]3[N:3]=[C:2]([Br:1])[CH:17]=[C:5]3[N:6]=[C:7]([CH3:16])[C:8]=2[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:56][CH2:57]1)[CH:49]=[CH2:50]
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Reactant: C=CCOC1(C)CCNCC1
Agent: C=CC(C)C(C)Oc1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Nc1cc(Br)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c(CC(=O)OC)c(C)nc3cc(Br)nn23)CC1
Yield: 97 %

Procedure:
A solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (prepared according to the procedure for intermediate 4 starting from 3-bromo-1H-pyrazol-5-amine; 13.4 g, 41.9 mmol, 1 equiv), 4-(allyloxy)-4-methylpiperidine (7.16 g, 46.1 mmol, 1.1 equiv), and DIEA (17.6 mL, 101 mmol, 2.4 equiv) in DMF (84 mL) was heated at 60° C. for 2 h. The reaction was then added to water and extracted with ether (×2). Combined ether extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-50% EtOAc/hex) to provide methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (17.7 g, 97%). 1H NMR (500 MHz, CDCl3) δ 6.52 (s, 1H), 6.02 (ddt, J=17.2, 10.4, 5.2 Hz, 1H), 5.43 (dd, J=17.2, 1.6 Hz, 1H), 5.22 (dq, J=10.4, 1.5 Hz, 1H), 3.99 (dt, J=5.2, 1.6 Hz, 2H), 3.77 (s, 3H), 3.79-3.76 (m, 2H), 3.70-3.56 (m, J=7.4 Hz, 2H), 3.33 (br. s., 2H), 2.50 (s, 3H), 1.97-1.89 (m, 2H), 1.87-1.78 (m, J=9.3 Hz, 2H), 1.32 (s, 3H). LCMS (M+1)=437.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:24]4[C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:30]5[C:22]([C:18]5[NH:17][CH:21]=[CH:20][N:19]=5)=[N:23]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.23 mmol), 2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridine-1-yl]acetic acid (0.050 g, 0.21 mmol) and Et3N (0.15 mL, 1.07 mmol) in DMF (0.7 mL) was added HATU (0.130 g, 0.33 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 100 mL) and sat. NaHCO3 (40 ml). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.090 g, 96%). 1H NMR (TFA salt) (400 MHz, CD3OD) δ 8.73 (dd, J=4.8, 1.6 Hz, 1H), 8.69 (dd, J=8.0, 1.6 Hz, 1H), 8.14 (s, 1H), 7.72 (s, 2H), 7.55 (m, 3H), 7.28 (dd, J=9.2, 8.4 Hz, 2H), 5.89 (s, 2H), 4.06 (m, 2H), 2.92 (t, J=6.2 Hz, 2H), 2.20 (m, 2H); MS: (ES) m/z calculated for C23H19FN8O [M+H]+ 443.1, found 443.1.
Reaction SMILES: S=C1O[CH:5]2[C:6]3[C:7]([N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH:4]2[O:3]1)=[N:8][C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[N:11]=3.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[OH:3][CH:4]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:7]2=[N:8][C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=[C:6]2[CH2:5]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC2OC(=S)OC32)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(O)C3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of tert-butyl 2-thioxo-7,8-di-p-tolyl-3a,4-dihydro-[1,3]dioxolo[41,51:4,5] pyrido[2,3-b]pyrazine-5(9bH)-carboxylate (step 3)(14 g, 28.6 mmol) in toluene (400 ml) was treated with tributyltin hydride (16.65 g, 57.2 mmol) and heated at reflux for 2 h. A further portion of tributyltin hydride (10 g) was added and refluxing continued for 6 h. The reaction mixture was left stirring over night at room temperature. The reaction mixture was evaporated to dryness and the iso-hexane (250 ml) was added to the residue. The suspension was stirred for 30 minutes at room temperature and then filtered. The solid was washed with iso-hexane (3×50 ml) to afford the titled compound;
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][C:22](=O)[CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CCC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCC
Product: COc1ccc(CCCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 99 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-3-(4-methoxyphenyl)propionamide, the title compound was synthesized according to Example 2b. Yield: 99%. Melting point: 62-65° C. (Pentane).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:38][CH2:37]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (600 mg), 4,4-difluorocyclohexanol (362 mg,), diisopropyl azodicarboxylate (1.9 M in toluene, 1.4 mL), triphenylphosphine (698 mg) and tetrahydrofuran (10 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (635 mg, 86%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH:17]([NH2:19])[CH3:18].CS(C)=O>O>[CH3:14][O:15][CH2:16][CH:17]([N:19]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1)[CH3:18]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Solvent: CS(C)=O
Solvent: O
Product: COCC(C)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 67.5 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296c (1.0 g, 3.7 mmol), 1-methoxypropan-2-amine (1.0 g, 11.2 mmol), and DMSO (6 mL). The mixture was heated at 120° C. under microwave irradiation for 1.0 h. It was the cooled to room temperature and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (60/1 to 1/1) to afford 300a (600 mg, 68%) as a yellow solid. MS-ESI: [M+H]+ 241.0
Reaction SMILES: [Br:1]Br.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Br:1][CH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(CO)s1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)s1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Bromine (0.47 mL, 9.12 mmol) was added to a solution of imidazole (617 mg, 9.06 mmol) and triphenylphosphine (2.40 g, 9.15 mmol) in CH2Cl2 (30 mL) at room temperature. A solution of methyl 5-hydroxymethyl-thiophene-2-carboxylate (prepared according to the procedures described in WO2004/037808; 1.30 g, 7.59 mmol) in CH2Cl2 (10 mL) was then added. After 10 min at room temperature, the reaction mixture was concentrated in vacuo. Purification of the crude residue by flash column chromatography on 80 g of silica gel (hexane→EtOAc, gradient) afforded 1.70 g (95%) of the title compound (B).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O.[C:8]1([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:8]1([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:8]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH3:9]
Reactant: C[C@H](N)C(=O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](C)N
Temperature: 70 °C

Procedure:
L-alanine (1.50 g, 16.84 mmol) and benzenesulfonic acid monohydrate (BsOH H20) (3.56 g, 20.20 mmol) were added to ethanol (10 ml), and the mixture was heated overnight at 70° C. to perform esterification. To complete the esterification reaction, the mixture was heated to 90° C. and ethanol (200 ml) was added over 3.5 hours while distilling away almost the same amount of ethanol. Thereafter, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. Ethanol (0.5 ml) and diethyl ether (30 ml) were added to partially crystallize an oily residue, and the mixture was stirred at room temperature to give a slurry. This slurry was cooled overnight in a refrigerator, and the crystals were separated and dried to give 4.55 g of L-alanine ethyl ester benzenesulfonate (L-Ala-OEt BsOH salt) dry crystals (L-Ala-OEt BsOH salt content 87.6%, (14.47 mmol), yield 86.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:26]5[C:25]([CH3:24])=[CH:30][CH:29]=[CH:28][N:27]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 3-methylpyridine-2-carboxylic acid (66 mg, 0.485 mmol) and 1-hydroxybenzotriazole (71 mg, 0.522 mmol) in N,N-dimethylformamide (4.0 mL) were added triethylamine (0.08 mL, 0.549 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) and recrystallized from ethyl acetate/methanol to give the title compound (98 mg, 71%) as colorless crystals.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:37]([OH:41])[C:38]([OH:40])=[O:39].CI>C1COCC1.CN1C(=O)N(C)CCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:29]([O:28][C:27]1[C:22]([O:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[C:23]([CH:37]([OH:41])[C:38]([OH:40])=[O:39])[CH:24]=[CH:25][CH:26]=1)[CH3:1]
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(Oc1cccc(C(O)C(=O)O)c1OCc1ccccc1Cl)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred solution of diisopropylamine (170 μL, 1.21 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (483 μL, 2.5 M in hexanes, 1.21 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 1 Part B compound (248 mg, 0.537 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and then methyl iodide (42 μL, 0.68 mmol). The reaction mixture was stirred for 2 h and then warmed to −40° C. After 14 h, the reaction was quenched with sodium hydroxide solution (1 M), warmed to room temperature and stirred for 1 h. The reaction mixture was acidified with 5% potassium hydrogen sulfate, extracted with CH2Cl2, dried (MgSO4) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound, a colorless oil, as a 1:1 mixture of diastereomers, 75 mg (31% yield). LC/MS gave the correct molecular ion [(M+H)+=447] for the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(C(=O)O)ccc1OC

Procedure:
The reaction of methyl 3-hydroxyl-4-methoxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-Allyloxy-4-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.63 (s, —CO2H); 7.54 (d-like, 1 arom. H); 7.43 (m, 1 arom. H); 7.04 (m, 1 arom. H); 6.02 (m, —CH═CH2); 5.39, 5.23 (2 d-like, CH═CH2); 4.57 (d-like, CH2—CH═CH2); 3.81 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.04 (—C═O); 152.87; 147.07; 133.59; 123.40; 122.86; 117.60; 113.62; 111.23; 68.88; 55.69.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
Triethylamine (0.59 mL, 4.3 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) in chloroform (100 mL). The solution was stirred in an ice bath for 5 min. Phenyl isocyanate (0.38 mL, 3.5 mmol) was slowly added. The resulting precipitate was isolated by filtration, washed with chloroform (4×30 mL), and then dried in an Abderhalden drying apparatus overnight to provide 1.11 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a white solid, m.p. 179.7-181.4° C. Analysis: Calculated for C23H26N6O.0.6H2O: % C, 66.84; % H, 6.63; % N, 20.33. Found: % C, 67.20; % H, 6.61; % N, 20.46.