Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]1([C:32]2[NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:29]1([C:32]2[N:33]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:14][CH:15]([N:17]6[CH2:22][CH2:21][O:20][CH2:19][CH2:18]6)[CH2:16]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:3]=3)[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: Cn1c(CN2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1c(CN2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 145 °C
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-yl-azetidin-1-ylmethyl)-9H-purine (83 mg, 0.20 mmol), 2-cyclopropylbenzimidazole (39 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), Xphos (19 mg, 0.04 mmol) and Cs2CO3 (133 mg, 0.41 mmol) in dioxane (2 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:DCM, 0-20%) affording 548 as a beige foam (92 mg, 87%). LCMS (Method I): RT 2.52 min, [M+H]+ 530.3. 1H NMR (CDCl3, 400 MHz): δ 7.95-7.91 (m, 1 H); 7.69-7.65 (m, 1 H); 7.27-7.18 (m, 2 H); 4.36 (m, 4 H); 3.93 (s, 2 H); 3.89-3.83 (m, 7 H); 3.75 (m, 4 H); 3.65 (m, 2 H); 3.24 (m, 2 H); 3.13 (m, 1 H); 2.89-2.81 (m, 1 H); 2.39 (m, 4 H); 1.37-1.32 (m, 2 H) and 1.08-1.02 (m, 2 H)
Reaction SMILES: ClC1SC2C=C(OC)C=CC=2N=1.C([Sn](CCCC)(CCCC)C1C=CC(OC)=CC=1[N+]([O-])=O)CCC.[CH3:37][O:38][C:39]1[CH:58]=[CH:57][C:42]2[N:43]=[C:44]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=3[N+:54]([O-])=O)[S:45][C:41]=2[CH:40]=1.O.O.[Sn](Cl)Cl.N>C(O)C.Cl>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:44]2[S:45][C:41]3[CH:40]=[C:39]([O:38][CH3:37])[CH:58]=[CH:57][C:42]=3[N:43]=2)=[C:47]([NH2:54])[CH:48]=1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)c([N+](=O)[O-])c1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Agent: COc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(OC)cc3s2)c(N)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.5 %

Procedure:
Synthesized from 2-chloro-6-methoxybenzothiazole and tributyl(4-methoxy-2-nitrophenyl)tin according to an analogous synthetic method to Preparation Example 77, to a suspension of the resulting 6-methoxy-2-(4-methoxy-2-nitrophenyl)benzothiazole (695 mg) in ethanol (10 ml) and concentrated hydrochloric acid (2 ml) was added tin(II) chloride dihydrate (1.3 g), and the solution was stirred for 7 hours at room temperature. The solution was neutralized with ammonia solution on an ice bath, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (475 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccncc1
Temperature: 60 °C
Yield: 149.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol), (prepared as described for the starting material in Example 24), potassium carbonate (414 mg, 3 mmol), potassium iodide (40 mg) and 4-(chloromethyl)pyridine hydrochloride (250 mg, 1.5 mmol) in DMF (15 ml) was heated at 60° C. for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was suspended in ethanol (20 ml) and concentrated hydrochloric acid (0.5 ml) was added. The volatiles were removed by evaporation and the solid residue was azeotroped with toluene. The solid product was recrystallised from isopropanol to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline hydrochloride (335 mg, 70%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[Cl:1][S:2]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[F:6])[C:11]([OH:13])=[O:12])(=[O:5])=[O:3]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 150 °C

Procedure:
Chlorosulphonic acid (100 ml, 1.5 mol) was gradually added to 4-fluorobenzoic acid (43 g, 0.307 mol) with stirring. The clear dark yellow mixture was heated to 150° C. for 24 hours. The yellow solution was cooled back to room temperature and poured onto ice with vigorous stirring. The white precipitate was filtered and pressed dry. The solid was dried overnight in a desiccator under vacuum and over activated silica (54.65 g, 75%). Mp: 116-117° C.; m/z (LC-MS, ESP), RT=4.03 min, (M−−1)=237-239 (ratio 1:3).
Reaction SMILES: C(N)CCCCCC.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21](Cl)=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH2:24]([NH:31][C:32](=[O:45])[CH2:33]CCC1C=CC([N+]([O-])=O)=CC=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].B#B.C(NCCCCC1C=CC([N+]([O-])=O)=CC=1)CCCCCC.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(=O)C>CC(C)=O.O>[C:32]([N:31]([CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:45])[CH3:33]
Reactant: CCCCCCCNC(=O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCCc1ccc([N+](=O)[O-])cc1
Agent: B#B
Agent: CCCCCCCN
Agent: CCCCCCCNCCCCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCN(CCCCc1ccc([N+](=O)[O-])cc1)C(C)=O

Procedure:
n-Heptylamine was reacted with 4-(4-nitrophenyl)butanoyl chloride to provide 29.3 g. of N-n-heptyl-4-(4-nitrophenyl)butyramide. The amide was reacted with diborane to afford 25.8 g. of N-n-heptyl-4-(4-nitrophenyl)butylamine. The amine was dissolved in 70 ml. of acetone and added in one portion to 70 ml. of water containing 18.5 g. of sodium carbonate. The aqueous reaction mixture was stirred while 14.4 ml. of acetyl chloride in 70 ml. of acetone was added dropwise over one hour. The reaction mixture was stirred at room temperature for sixteen hours following the addition, and then the mixture was concentrated by evaporation of the acetone solvent under reduced pressure. The aqueous layer was extracted with diethyl ether, and the ethereal extract was then washed with water, with 2 N hydrochloric acid, again with water, and finally with saturated sodium chloride solution. The solution was dried and the solvent was removed by evaporation under reduced pressure to give 28.78 g of N-acetyl-N-n-heptyl-4-(4-nitrophenyl)butylamine.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([C@@H:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:20][F:21])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].FC(F)(F)C(O)=O>ClCCl>[F:21][CH2:20][CH2:19][C@@H:18]([N:14]1[C:13]2[CH:28]=[CH:29][C:10]([S:7]([NH:6][C:30]3[S:34][N:33]=[CH:32][N:31]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[O:16][C:15]1=[O:17])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)oc(=O)n3[C@H](CCF)c2ccccc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)ccc2n1[C@H](CCF)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound of Formula 37-3 was prepared by dissolving the compound of Formula 37-2 (crude from previous step) in dichloromethane (1 mL), and treating the resulting solution with trifluoroacetic acid (0.2 mL). After stirring for 30 minutes at RT, the solution was concentrated and purified by reverse phase HPLC (20-100% MeCN in water with 0.1% TFA, C18 column) to yield the compound of Formula 37-3 as the a white solid. 1H NMR δ (ppm)(Methanol-d): 8.20 (s, 1H); 7.74 (m, 1H); 7.51 (m, 2H); 7.42-7.42 (m, 3H); 7.12 (m, 1H); 5.60 (m, 1H); 4.65-4.37 (m, 2H); 3.01-2.65 (m, 2H). HRMS C18H15F2N404S2 [M+H] calc 453.0425, obs 453.0497.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(OCC)OCC)=CC=3)N=2)=C(C(=O)NC)C=1.COCCN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:35][CH:34]=4)[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:17])[CH:18]=2)[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCOC)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Agent: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCOC)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Diethyl (4-{[4-({7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 97) using Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ES+): m/z 662.36 (100) [MH+] HPLC: tR=1.00 min (UPLC, purity).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:28])[CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:28])[CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccc(Cl)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(Cl)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 56.8 %

Procedure:
The title compound was prepared from 2-bromo-8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.6 g, 1.25 mmol), cyclohexene (0.32 mL, 3.13 mmol), and 1.0 M boron tribromide in dichloromethane (7.52 mL, 7.52 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(2-bromo-8-chloro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.33 g, 0.71 mmol, 56%) as a light-yellow solid, m.p. 213-215° C.;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 45 °C
Yield: 65.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL, 391.2 mmol) in tetrahydrofuran (311 mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M in tetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resultant solution was heated to 45° C. for 15 hours. The mixture was cooled to room temperature and quenched by the addition of water. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g, 66%) as a tinted off-white solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 8.11 (m, 2H), 7.66 (t, 1H), 7.30–7.25 (m 2H), 7.17 (t, 2H), 4.48 (s 2H), 19F NMR (CDCl3) δ −104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).
Reaction SMILES: [C:1]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C:23]1[CH:44]=[CH:43][C:26]([C:27]([O:29][CH:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([F:34])([F:33])[F:32])=[O:28])=[CH:25][CH:24]=1>O1CCCC1>[C:1]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([F:32])([F:33])[F:34])=[O:28])=[CH:43][CH:44]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC(CCCCCCCC)C(F)(F)F)cc2)cc1

Procedure:
To a solution of the 4-n-decanoyloxybenzoic acid (0.4 g) obtained in (3) and the 1,1,1-trifluoro-2-decyl 4-hydroxybenzoate (0.4 g) obtained in (2) in tetrahydrofuran (about 30 ml) were added dicyclohexylcarbodiimide (0.32 g) and dimethylaminopyridine (0.01 g). The mixture was stirred at room temperature for about 20 hours and was distilled to remove the solvent. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and was distilled to remove the solvent. The residue was purified by silica-gel column chromatography (a developer : hexane/ethyl acetate=20/1) to obtain the titled compound (0.15 g). Phase transition temperatures (° C.) were observed under a polarization microscope using a hot stage as follows: ##STR53## where
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:27][C:23]1[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Cc1cccc(O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(C)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methyl-phenol to give (6-methoxy-1-m-tolyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3cccs3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3cccs3)noc2c1O
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Ethyl 7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.569 g, 7.59 mmol) and sodium ethoxide (0.387 g, 5.69 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 92 mg of the title compound. MS: (+) m/z 320.37 (M+1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=3)[CH2:38]2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:49][C:46]3[CH:47]=[CH:48][C:43]([N:39]4[CH2:40][CH2:41][CH2:42][CH:37]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:38]4)=[CH:44][CH:45]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C2CCCN(c3ccc(N)cc3)C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(N5CCN(C)CC5)C4)cc3)nn12
Yield: 45 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.0003480 mol), N,N-Diisopropylethylamine (0.0909 mL, 0.000522 mol) and 4-[3-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.191 g, 0.000696 mol) were dissolved in 1-Methoxy-2-propanol (0.99 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 78.00 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{4-[3-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a lyophilized powder. (M+H)=498.3. 1H NMR (400 MHz, DMSO, d6) δ 9.37 (s, 1H), 8.93 (s, 1H), 7.81 (dd, 1H, J=1.62, 5.96 Hz), 7.67 (d, 2H, J=8.56 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.05 Hz), 7.11 (m, 3H), 6.92 (m, 2H), 3.92 (m, 4H), 3.79 (s, 3H), 3.62 (m, 2H), 3.45 (m, 3H), 3.31 (m, 2H), 3.13 (m, 2H), 2.79 (m, 3H), 1.99 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N=C=N.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([Br:50])[C:34]1=[O:51].CN=C=O>CN(C)C=O.O1CCCC1>[Br:50][C:35]1[C:34](=[O:51])[N:33]([CH2:32][C:31]2[CH:30]=[C:29]([CH:54]=[CH:53][CH:52]=2)[CH2:28][NH:27][C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:38]([CH3:39])=[CH:37][C:36]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]
Reactant: COCC(=O)O
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CN)c1
Agent: CN=C=O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC(=O)NCc1cccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added methoxyacetic acid (0.09 g, 1.00 mmol). A stock solution of 1-hydroxybenzotriazole (3 mL, 0.16 M) and N-methylmorpholine (3 mL, 0.43 M) in N,N-dimethylformamide were added to the reaction vessel followed by approximately 0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (3 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. 1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (EXAMPLE 161) (0.30 g, 0.668 mmol) was then added to the reaction vessel followed by additional N,N-dimethylformamide (5.0 mL) and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.06 g of polyamine resin (2.63 mmol/g) and approximately 2.67 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) afforded a tan solid (0.321 g, 89.4%). 1H NMR (400 MHz, DMF-d6) δ 8.33 (br s, 1H), 7.81 (app q, J=7-85 Hz, 1H), 7.40-7.23 (m, 5H), 7.09 (d, J=7.25 Hz, 1H), 6.68 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, J=6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m/z 521.0891 (M+H C24H23BrF2N2O4 requires 521.0882).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[CH3:11][C:2]([O:1][C:23](=[O:24])[CH2:22][CH2:21][Cl:20])([CH3:12])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(OC(=O)CCCl)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 72 h
Yield: 6.5 %

Procedure:
9.9 g (60 mmol) 2-hydroxy-2-methyl-1-phenyl-1-propanone (DAROCUR™ 1173) was dissolved in 60 ml tetrahydrofuran. 6.1 g (60 mmol) triethyl amine was added and the reaction mixture was cooled to −10° C. 7.6 g (60 mmol) 3-chloro-propionyl chloride was added while the temperature was kept below −5° C. The reaction was allowed to continue for 30 minutes at 0° C. and for 72 hours at 40° C. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was purified by preparative column chromatography on a Prochrom LC80 column, using n.-hexane/ethyl acetate 80/20 as eluent at a flow rate of 150 ml/min and Kromasil 60A 10 micron as silica. 1 g of 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was isolated.