Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Clc1ccc2c(I)n[nH]c2n1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (0.70 g, 2.5 mmol), dihydropyran (690 μL, 7.5 mmol) and methanesulfonic acid (33 μL, 0.50 mmol) in methylene chloride (30 mL) and tetrahydrofuran (10 mL) in reaction flask was stirred at r.t. overnight. It was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.80 g). LCMS (M-84+H)+=279.9.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:13][C:12]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][C:10]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)C.[OH-].[K+]>CO.Cl.O>[CH3:22][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[C:12]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:11]=[C:10]([C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=3)[C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: CCOC(=O)CCCOc1c(-c2cc(C)cc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cc(C)cc(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCCC(=O)O)c1
Yield: 45.1 %

Procedure:
To a suspension of 4-[3,5,3″,5″-Tetramethyl-5′-(7-phenyl-heptylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-butyric acid ethyl ester (170 mg, 0.256 mmol) in 4 mL MeOH/1 mL H2O was added solid KOH (12 mg, 0.213 mmol). The reaction mixture was refluxed for 2 d and then the reaction mixture was diluted with 2N HCl and water. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were dried over Na2SO4. The solvent was removed in vacuo to give an oil that was flash chromatographed (10% EtOAc:90% Hexanes) on silica gel to yield 70 mg, 43% of the acid as an oily white foam. mp 64-66° C.; 1H NMR (DMSO-d6) δ 1.29-1.30 (m, 6H); 1.32-1.39 (m, 2H); 1.46-1.48 (m, 4H); 1.86 (t, J=7.47 Hz, 2H); 2.33 (s, 12H); 2.53 (t, J=7.58 Hz, 2H); 3.19-3.31 (m, 4H); 7.01 (s, 2H); 7.12-7.16 (m, 3H); 7.17-7.19 (m, 4H); 7.21-7.24 (m, 2H) 7.71 (s, 2H); 8.48 (t, J=7.00 Hz, 1H); 11.86 (s, 1H); IR 3325, 2925, 2875, 1710, 1630, 1600, 1535, 1450, 1290, 1225, 1210, 850, and 700 cm−1; mass spectrum [(+)APCI], m/z 606 [M+H]+; Anal Calcd. for C40H47NO4: C, 79.30; H, 7.82; N, 2.31; Found: C, 78.65; H, 7.86; N, 1.87.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2Br)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 110 °C
Yield: 71.4 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (1 g, 2.1 mmol), phenylboronic acid (0.79 g, 6.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.351 g, 0.43 mmol) and K2CO3 (0.890 g, 6.4 mmol) in dioxane (24 mL) and water (4 mL) was heated at 110° C. overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product, which was purified by column chromatography (eluting with 10-40% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.710 g racemate, 1.5 mmol, 71%) as an off-white powder. The racemic material was further separated by chiral SFC (Table 2, Method 1) to give two isomers: 3-(4(R)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 1), Rt=3.374 min., 0.281 g, 0.61 mmol, 29%) and 3-(4(S)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 1), Rt=4.333 min., 0.252 g, 26%). LC/MS (Table 1, Method 2) Rt=1.25 min.; MS m/z: 464 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 4-ethylbenzenesulfonyl chloride (90%, 4.25 g (20.8 mmol)) in pyridine (10 ml), 4-chloroaniline (2.55 g (20.0 mmol)) was added with stirring at room temperature. After 18 hours' stirring at room temperature, water (100.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.26 g (89%) of 4′-chloro-4-ethylbenzenesulfonanilide as white crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:44](=[O:46])[CH3:45])[CH:42]=1>>[C:44]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]1[CH:42]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:52])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:46])[CH3:45]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN(C(C)=O)c1cc(CCl)ccc1C
Product: COCCCN(C(C)=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.147 g of N-(5-chloromethyl-2-methylphenyl)-N-(3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.12 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [C:1]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][C:15](=[O:17])[CH3:16])[CH2:7][CH2:8]C(OCC)=O)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].C([OH:28])(C)C>CN(C)C=O>[C:18]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][C:8](=[O:28])[CH2:16][C:15](=[O:17])[CH2:14]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)O
Reactant: CCOC(=O)CCC(CC(C)=O)(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)CC(=O)C1
Reaction time: 15 h

Procedure:
A solution of 14.3 g (0.047 mol) of ethyl 3,3-biscarbethoxy-5-oxo-hexanecarboxylate in 40 ml of dimethylformamide was added dropwise to a suspension of 3.6 g (0.118 mol) of 80 % strength by weight sodium hydride in 200 ml of dimethylformamide. After stirring at 20°-25° C. for about 15 hours, the reaction was stopped by adding 5 ml of isopropanol. The reaction products were partitioned between ethyl acetate and 1 molar hydrochloric acid. The organic phase was then separated, dried and evaporated down. Yield: 2.2 g of a crude product oil.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)(C)C.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:4]4[C:5]5[C:24](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:23][CH2:22][CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:11]4[C:10]5[C:24](=[CH:17][CH:18]=[CH:13][CH:14]=5)[CH2:23][CH2:22][CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21
Yield: 65.7 %

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquin 3line (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[C:23]([CH2:28][NH:29][C:30]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])=[O:31])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[CH3:41])=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][CH2:67][C:68]1[C:73]([CH2:74][CH3:75])=[N:72][C:71]2[N:76]([CH2:79][CH3:80])[N:77]=[CH:78][C:70]=2[C:69]=1[NH:81][CH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:79]([N:76]1[C:71]2=[N:72][C:73]([CH2:74][CH3:75])=[C:68]([CH2:67][NH:66][C:35]([C:34]3[CH:33]=[C:32]([C:30]([NH:29][CH2:28][C:23]4[CH:24]=[CH:25][C:26]([F:27])=[C:21]([C:17]5[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]6[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[C@@H:9]([CH3:41])[CH2:10]6)[CH:16]=5)[CH:22]=4)=[O:31])[CH:40]=[CH:39][CH:38]=3)=[O:36])[C:69]([NH:81][CH:82]3[CH2:83][CH2:84][O:85][CH2:86][CH2:87]3)=[C:70]2[CH:78]=[N:77]1)[CH3:80]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
205(a) 3-{[({3′-[((3S)-4-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)amino]carbonyl}benzoic acid (1150 mg, 2.0 mmol) was dissolved in dichloromethane (DCM) (100 mL), and then HBTU (830 mg, 2.2 mmol), 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (620 mg, 2.0 mmol), and DIPEA (1.4 mL, 8.0 mmol) were added. The mixture was allowed to stir under argon at room temperature overnight. Solvents were concentrated and then purified on a 40 g Redi-Sep cartridge and eluting with 0.5% MeOH in DCM. Collected clean fractions were combined solvent concentrated to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (1.15 g, 66.5%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][N:30]=[C:31]3[Cl:34])=[CH:26][CH:25]=2)[C:19]1=[O:35]>N1C=CC=CC=1>[Cl:34][C:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][S:12]([C:10]4[S:11][C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:8][CH:9]=4)(=[O:14])=[O:13])[C:19]3=[O:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccncc3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reaction time: 8 h

Procedure:
5-Pyridin-4-yl-thiophene-2-sulfonyl chloride is added to a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.12 g, 0.38 mmol) in pyridine (2 mL). The resulting mixture is stirred overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated to give 105 mg of a crude solid. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to afford the title product (0.026 g, 0.052 mmol) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)([O-])=O>O1CCOCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH:10]=1
Reactant: O=[N+]([O-])c1cnn(-c2cccnc2)c1
Solvent: C1COCCO1
Product: Nc1cnn(-c2cccnc2)c1
Reaction time: 8 h

Procedure:
98.9 g (520 mmol) of 3-(4-nitro-1H-pyrazol-1-yl)pyridine were dissolved in 1.3 l of warm dioxane, and twice evacuated and filled with argon. 500 ml of ammonia in methanol (˜7 mol/l) were added and the mixture was again twice evacuated and filled with argon. 27.5 g of Raney nickel (watermoist slurry) were added and the mixture was twice evacuated and filled with argon, and three times more evacuated and filled with hydrogen. The suspension was stirred under a hydrogen balloon overnight. A further 32 g of Raney nickel were added and the mixture was stirred under a hydrogen atmosphere for a further 24 hours. The hydrogen atmosphere was exchanged for argon, and the reaction mixture was filtered through Hyflo and washed with 500 ml of dioxane. The filtrate was concentrated on a rotary evaporator and dried under HV (high vacuum). The brown oil obtained crystallized in a refrigerator. The crude product was dissolved in 750 ml of ethyl acetate, 20 g of activated carbon were added and the mixture was stirred at 50° C. for 30 minutes. After filtration, activated carbon was added again and the mixture was again stirred at 50° C. for 30 minutes. Filtration through Hyflo was followed by concentration to approx. 250 g. 350 ml of diisopropyl ether were added and the mixture was stirred at room temperature. The solid was filtered off and washed with diisopropyl ether and heptane. Drying on a rotary evaporator gave a beige solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:25][CH2:24][C@:12]34[C:13]5[C:14]6[O:23][C@H:11]3[C:10](=O)[CH2:9][CH2:8][C@@:7]4([OH:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]([NH2:22])=[O:21])[CH2:3][CH2:2]1.Cl>C(O)(=O)C.[Zn]>[CH:1]1([CH2:4][N:5]2[CH2:25][CH2:24][C@@:12]34[C:13]5[C:14]([OH:23])=[C:15]([C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:27])[CH2:8][CH2:9][CH2:10][CH2:11]4)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)c1ccc2c(c1O)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CC1)CC3
Temperature: 125 °C
Yield: 29.4 %

Procedure:
To a mixture of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carboxamide [P3] (3.74 g, 10.2 mmol) and zinc powder (33.0 g, 0.51 mol) in acetic acid (220 mL) was added 12N HCl (30 mL). The reaction was heated at 125° C. for 3 hours then allowed to return to room temperature. The mixture was slowly quenched into an ice/water cooled ammonium hydroxide solution at such a rate to ensure the temperature remained below 20° C. The resultant suspension was extracted with DCM (3×500 mL) and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product that was purified by prep-HPLC [Xbridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile Phase A: 10 mM NH4HCO3 (pH 10), Phase B: MeCN; Flow: 50 ml/min; Column Temperature: 30° C.; Runtime: 25 min.] giving 17-(cyclopropylmethyl)-4,14-dihydroxymorphinan-3-carboxamide 1131 (1.07 g, 29% yield); LC/MS (r.t. 10.2 minutes [5 to 95% B]), 357 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCOCC4)c23)ccc1OCc1ccccn1
Reactant: O=C(O)CO
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCOCC1
Yield: 12 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(tetrahydro-2H-pyran-4-ylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 20, preparation of starting materials) to give the title compound in 12% yield; NMR spectrum (DMSO-d6) 1.53-1.69 (m, 2H), 1.77-2.07 (m, 2H), 3.34-3.42 (m, 2H), 3.73-3.92 (m, 5H), 4.14-4.25 (m, 2H), 4.31-4.54 (m, 3H), 5.31 (s, 2H), 7.21-7.29 (m, 2H), 7.32-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 8.03 (s, 1H), 8.47 (s, 1H), 8.61 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 564.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:12]([CH3:19])[C:11]=1[CH2:20][CH2:21][Cl:22]>C(Cl)(Cl)Cl>[Br:1][C:18]1[CH:17]=[N:16][N:15]2[C:10]([Cl:9])=[C:11]([CH2:20][CH2:21][Cl:22])[C:12]([CH3:19])=[N:13][C:14]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Br)cnn2c(Cl)c1CCCl
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2.35 g (13.2 mmoles) of N-bromosuccinimide was added to a solution of 2.53 g (11 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (prepared as described in Example 3) dissolved in 20 ml of chloroform, and the mixture was heated under reflux, with stirring, for 30 minutes. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through alumina (eluted with chloroform) and recrystallized from diisopropyl ether to afford 3.33 g (yield 98%) of the title compound as colorless needles, melting at 128.5°-129.5° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)c(F)cc1O
Reactant: COc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(F)c(Br)cc2OC)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a stirred solution of 4-bromo-5-fluoro-2-methoxyphenol (2.82 g, 12.25 mmol) in N,N-dimethylformamide (50 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (2.50 g, 12.86 mmol) and potassium carbonate (5.08 g, 36.75 mmol). The reaction mixture was heated to 100° C. After 2 h, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (0-33% ethyl acetate/hexanes elute) afforded 2.76 g (66%) of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)=O.[NH2:21][C:22]([NH2:24])=[O:23]>Cl.O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:24][C:22](=[O:23])[N:21]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)[CH:10]=1
Reactant: NC(N)=O
Reactant: Cc1cc(C(=O)/C=C/c2cccc(Cl)c2Cl)ccc1O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(Cl)c3Cl)[nH]c(=O)n2)ccc1O
Temperature: 120 °C
Yield: 25.2 %

Procedure:
A mixture of (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one (123 mg, 0.4 mmol) and urea (28 mg, 2.0 mmol,) (SIGMA-ALDRICH) in 4N HCl/dioxane (5 mL) was heated to 120° C. in a sealed vessel overnight. The reaction was complete as determined by LCMS, and the solution was cooled to room temperature. The crude reaction mixture was purified by reverse-phase HPLC (acetonitrile/10 mM aqueous ammonium acetate) to yield the desired product (35 mg, 25%) 1H NMR (400 MHz, d6-DMSO): 7.93 (s, 1H), 7.80-7.82 (dd, 1H), 7.49-7.58 (m, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 2.18 (s, 3H). MS (EI) for C17H12Cl2N2O2: 348.5 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([N:2]([CH3:3])[CH3:1])=[O:13]
Reactant: CNC
Reactant: O=C(Cl)c1cc(I)ccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a 2.0 M solution of dimethylamine in tetrahydrofuran (5 mL, 10.1 mmol) to a solution of 2-fluoro-5-iodobenzoylchloride (1.3 g, 4.6 mmol) in dichloromethane (20 mL) and stir at room temperature for 0.5 h. Sequentially wash the reaction mixture with a 1 N hydrochloric acid (50 mL), a 1 N sodium hydroxide (50 mL), and an aqueous saturated solution of sodium chloride (50 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as a white solid (1.3 g, 98%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)(=O)C>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CCc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Reactant: Nc1ccccc1Cl
Solvent: CC(=O)O
Product: CCc1ccc2ncc([N+](=O)[O-])c(Nc3ccccc3Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19d starting from 0.7 g (2.957 mmol) of 4-chloro-6-ethyl-3-nitro-quinoline (Example 49e) and 0.37 g (3.55 mmol) 2-chloroaniline in 3 ml acetic acid. Crystallization from ethyl acetate-hexane. mp: 134-136° C.; MS: 328 (M++1); HPLC: tret=10.61 min (Grad 1).