Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.O1CCOCC1>[OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The N-hydroxy-5-norbornene-2,3-dicarboximide active ester of N-benzyloxycarbonyl DL-2-hydroxy-4-aminoburyric acid was prepared according to the procedure of M. Fujino, et al [Chem. Pharm. Bull. Japan, 22, 1857 (1974)]. To an ice cold solution of 0.40 g. of N-benzyloxycarbonyl-DL-2-hydroxy-4-aminoburyric acid and 0.32 g. of N-hydroxy-5-norbornene-2,3-dicarboximide in 3 ml. of tetrahydrofuran-dioxane (1:1 v/v), there was added, with stirring, 0.36 g. of N,N'-dicyclohexylcarbodiimide and 1 ml. of the above solvent mixture. The solution was stirred in the cold for 30 minutes and then at room temperature for 2 hours. The N,N'-dicyclohexylurea which formed in the above reaction was collected on a filter and washed with three 1-ml. portions of tetrahydrofuran-dioxane (1:1 v/v).
Reaction SMILES: S([O-])(=O)(=O)C.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[CH3:7][NH:6][CH2:10][CH2:9][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CNCCn1ccnc1

Procedure:
1-[2-(N-methylamino)ethyl]imidazole was synthesized from the mesylate of 2-(N-Boc-N-methylamono)ethanol, which was allowed to react with imidazole in the presence of LiHMDS. The starting material was prepared by selective protection of amino group with Boc-anhydride in the presence of Al2O3 according to the procedure described in literature (Yadar, V. K.; Ganesh Babu, K. J. Org. Chem. 2004, 69, 577-580).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH2:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 155.0-156.0° C.; 1H NMR (250 MHz) δ9.17 (s, 2H), 3.50 (s, 1H), 3.25 (s, 1H), 1.94-1.15 (m, 16H), 0.82 (d, 6H); 13C NMR (62.7 MHz) δ51.7 (s), 47.9 (s), 38.4 (s), 30.9 (s), 28.8 (s), 27.8 (s), 26.1 (s), 23.5 (s), 22.5 (s), 22.3 (s), 17.3 (s), 16.8 (s) ppm. FT-IR (neat): 3430, 2948, 1615, 1589, 1557, 1472, 1436, 1418, 1362, 1102, 895. Elemental Analysis for C12H26NCl: C, 65.56%; H, 11.95%; N, 6.37%. Found: C, 64.90%; H, 11.89%; N, 6.26%.
Reaction SMILES: [F:1][C:2]1[C:44]([C:45]([F:48])([F:47])[F:46])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:44]([C:45]([F:48])([F:46])[F:47])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH2:13][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][NH:27][C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:15]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccnc(C(F)(F)F)c6F)CC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H).
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([SH:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([Cl:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl-:23].[C:2]1([N+:8]2[C:13]([S:14][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: Nc1cn[n+](-c2ccccc2)c(S)c1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Nc1cn[n+](-c2ccccc2)c(SCc2ccccc2)c1
Yield: 90.2 %

Procedure:
5parts of 1-phenyl-4-amino-6-mercaptopyridazinium chloride in 100 parts of toluene is stirred with 2.5 parts of benzyl chloride for 1 hour at 110°C. 6.2 parts (90.2% of theory) of 1-phenyl-4-amino-6-benzylmercaptopyridazinium chloride is obtained; C17H16N3SCl, melting point 226° to 228°C after having been recrystallized from alcohol. The perchlorate melts at 170° to 171°C.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])#[N:3].[Cl-].[K+].[OH-].[K+].Cl[C:16]1[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2/[C:29](=[CH:34]\[O:35][CH3:36])/[C:30]([O:32][CH3:33])=[O:31])[CH:17]=1>O.C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:16]1[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2/[C:29](=[CH:34]\[O:35][CH3:36])/[C:30]([O:32][CH3:33])=[O:31])[CH:17]=1)#[N:3]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: N#Cc1ccccc1O
Agent: [Cl-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 97.5 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A slurry of the potassium salt of 2-cyanophenol containing potassium chloride was prepared by mixing 2-cyanophenol (13.2 g), potassium hydroxide (6.8 g) and potassium chloride (20 g) in water (10 g). This solution was added to (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (32.8 g) over 5 minutes while maintaining the temperature at 95-100° C. The resulting mixture was stirred at 110° C. for 3 hours. The reaction mixture was mixed with water and toluene and the organic layer separated. The toluene solution contained (E)-methyl 2-[2-(6- (2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (77.7% yield).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2([C:48](O)=[O:49])[CH2:47][CH2:46]2)=[O:44])=[CH:38][CH:37]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:39]5[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=5)[CH2:46][CH2:47]4)=[O:49])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 43 %

Procedure:
A crude product of [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (1.617 g) was dissolved in N,N-dimethylformamide (25 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.26 g), triethylamine (0.786 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.49 g) were added thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order and dried over anhydrous sodium sulfate. The solvent was removed to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1) to provide the titled compound as white powder (1.007 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([OH:23])[CH3:22].Cl>CN(C=O)C.O>[CH2:21]([O:23][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: CCO
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
2,5-difluoro-4-nitrobenzoic acid (Fluorochem; 1 g, 4.92 mmol) was stirred and dissolved in DMF (10 mL) and caesium carbonate (4.8 g, 14.7 mmol) was added followed by ethanol (2.3 g, 49.9 mmol). The resulting white mixture was stirred at ambient temperature for 3 hours, diluted with water, acidified to pH1 with 2N HCl (aq), extracted with EtOAc (×3). Combined extracts were washed with water, dried (MgSO4), filtered and evaporated to yield the title compound as a yellow solid (1.24 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[P:13](OCC)([CH3:15])=[O:14])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:15][P:13]1(=[O:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)NCc1ccccc1P(C)(=O)OCC
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)N1Cc2ccccc2P1(C)=O

Procedure:
Under anhydrous conditions, a mixture of 2-[P-ethoxy-P-methylphosphinyl]benzyl carbamic acid ethyl ester (1.2 g, 0.0025 mol) and phosphorus pentachloride (0.52 g, 0.0025 mol) in 10 ml. of carbon tetrachloride was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in methylene chloride. The methylene chloride solution was washed with ice water, dried over magnesium sulfate and concentrated to produce a yellow oil. Distillation of this yellow oil at 150° C. and 0.5 torr produced an oil which solidified to yield 1-methyl-2-ethoxycarbonyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a white powder having a melting point of 102°-104° C. and the following analysis:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[N:34][CH:33]=1)[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:11]1([F:15])[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:3]=[C:2]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[N:34][CH:33]=4)=[C:25]([O:24][CH3:23])[CH:26]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Reactant: FC(F)(F)COCc1cc(N2CCC(F)(F)CC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(N3CCC(F)(F)CC3)n2)ccc1-c1cnnc(C)c1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (40 mg, 0.12 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (25 mg, 0.12 mmol), cesium carbonate (75 mg, 0.23 mmol), palladium(II) acetate (4 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)biphenyl (6 mg, 0.02 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate (75 mL) and the eluate was concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a solid, 35 mg (58%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.NC1C=CC=CC=1.[CH3:35][N:36]([CH3:50])[CH2:37][CH2:38][CH2:39][N:40]([CH2:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH3:41]>>[CH3:50][N:36]([CH3:35])[CH2:37][CH2:38][CH2:39][N:40]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:48][CH:49]=1)[CH3:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCCN(C)Cc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-aniline aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O3
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[CH3:8]
Reactant: CCc1ccc(C(=O)OC)c(CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CO)c(CC)c1
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
To a suspension of lithium aluminum hydride (0.47 g, 11.8 mmol) in anhydrous THF (20 mL) at room temperature under nitrogen was added a solution of methyl 2,4-diethylbenzoate (1.5 g, 7.8 mmol) in THF (15 mL) with stirring over a period of ˜5 min. The resulting mixture was stirred at room temperature for 60 min and was then quenched by slow addition of ethyl acetate (until bubbling stopped). The mixture was partitioned between ethyl acetate and 1N HCl (aq). The aqueous layer was separated and extracted with ethyl acetate. Organic layers were combined, dried (MgSO4), and evaporated to dryness to give 1.3 g of the desired alcohol as a clear oil (yield of 100%). 1H NMR (300 MHz, CDCl3) δ 1.13 (t, 3H), 1.17 (t, 3H), 2.58 (q, 2H), 2.61 (q, 2H), 4.43 (d, 2H), 5.02 (t, 1H), 7.05-7.11 (m, 3H).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.FC1C=CC(CC(N=C=O)=[O:54])=CC=1>C1COCC1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[O:54])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) in 1 mL of THF at room temperature was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.36 M, 0.18 mL, Compound C of Example 4) and the solution was allowed to stir overnight. HPLC analysis and LC-MS analysis indicated the completion of the reaction and the organic solvent was thus removed under reduced pressure. The residue was purified on preparative HPLC. The title compound (15 mg, 46%) was finally obtained as a 2.HCl salt after a work-up similar to that described for Compound D of Example 36. 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.58 (s, 1 if), 8.04 (s, 11H), 7.99 (s, 1H), 7.70(d, 1H), 7.35 (m, 4H), 7.16 (m, 2H), 4.44 (br.s, 2H), 3.40–3.70 (m, 12H), 2.81 (s, 3H), 2.39 (s, 3H); MS(ESI+) m/z 580.1 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:42])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:41])[NH:29][C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[CH:35][N:36]5[CH2:39][CH3:40])=[CH:32][CH:31]=4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CCO.[H][H]>[Pd].CCOC(C)=O>[CH2:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([N:19]4[CH2:18][CH2:17][N:16]([C:13]5[CH:12]=[CH:11][C:10]([C:9]([OH:42])=[O:8])=[CH:15][CH:14]=5)[CH2:21][CH2:20]4)=[N:23][CH:24]=3)=[O:41])[CH:38]=2)[CH:34]=[CH:35]1)[CH3:40]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)OCc6ccccc6)cc5)CC4)nc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5)CC4)nc3)cc21
Yield: 96 %

Procedure:
A mixture of 4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid benzyl ester (100 mg, 0.18 mmol), 10% Pd/C (50 mg) in a 1:1 mixture of EtOH and EtOAc (50 mL) was hydrogenated under 1 atm of hydrogen for 2 h. The mixture was then filtered. The solids were washed with a 1:1 mixture of THF and DMF and the combined organic layer was concentrated. The residue was passed through a silica gel plug with DMF to afford the product (85 mg; Yield: 96%). HRMS m/z calcd for C27H27N5O3I [M+H]+: 470.2187. Found: 470.2184.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:21][CH2:22][F:23])(=O)=O>CN(C)C=O>[F:23][CH2:22][CH2:21][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CS(=O)(=O)OCCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCOc1ccccc1-c1ccccc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60 % oil dispersion; 4.0 g) in N,N-dimethylformamide (100 ml), 2-phenylphenol (17.0 g) was added at a temperature of 0 to 5° C., and the resultant mixture was stirred at room temperature for 1 hour. 2-Fluoroethyl methanesulfonate (14.2 g) was added thereto. The resulting mixture was heated to 90° C., followed by stirring for 5 minutes. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent, toluene) to give 1-(2-fluoroethoxy)-2-phenylbenzene (Compound No. 20) (16.4 g). nD24.8 1.5796.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35][NH:5][CH2:6][C:7]3[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)COc1ccc(CN)cc1
Solvent: CC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using methyl [4-(aminomethyl)phenoxy]acetate acetate and 4-[(4-butylphenyl)ethynyl]benzaldehyde as a pale yellow oil (36%). 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.60 (s, 2H), 3.79 (s, 3H), 3.78 (s, 2H), 3.72 (s, 2H), 2.59 (t, J=7.7 Hz, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). M+ (ESI): 442.3. HPLC, Rt: 4.17 min (Purity: 94.9%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13]3[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:12]=3[S:11]2(=[O:26])=[O:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:22]([C:20]1[CH:19]=[CH:18][C:13]2[N:14]([CH3:17])[C:15](=[O:16])[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:28][CH:27]=3)[S:11](=[O:25])(=[O:26])[C:12]=2[CH:21]=1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CN1C(=O)N(Cc2ccc(S(C)(=O)=O)cc2)S(=O)(=O)c2cc(C(=O)O)ccc21
Product: CN1C(=O)N(Cc2ccc(S(C)(=O)=O)cc2)S(=O)(=O)c2cc(C(=O)NCc3ccccc3)ccc21

Procedure:
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazine-7-carboxylic acid was coupled with benzyl amine according to the procedure of Example 2 to give the title compound. 1H-NMR (CDCl3); δ 8.19 (s, 1H), 8.01 (d, 1H), 7.74 (d, 2H), 7.45 (d, 2H), 7.34 (m, 6H), 6.67 (bs, 1H), 4.62 (t, 2H), 3.76 (bs, 2H), 3.22 (s, 3H) and 2.98 (s, 3H) ppm. Anal. (C24H23N3O6S2.0.5C4H10O.0.66H2O) C,H,N. MS: M++1=514.1 Da