Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccccc1
Reactant: BrCCCOc1ccc(I)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-bromopropoxy)-4-iodobenzene (277 mg) in dimethylformamide (3 ml), 115 mg of phenol and 49 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2F)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccc(F)cc4F)C3)CC2)cc1
Yield: 44.6 %

Procedure:
The title compound (D154) (55 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(2,4-difluorophenoxy)azetidin-1-yl)nicotinic acid (D108) (82 mg, 0.240 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (54.79 mg, 0.240 mmol).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH2:42](O)[CH2:43][CH2:44]C>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH2:35][CH2:42][CH2:43][CH3:44])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCO
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Agent: C[O-]
Agent: [Na+]
Product: CCCCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1

Procedure:
Prepared analogously to Example 7 by reacting methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate with sodium methoxide in n-butanol.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[O:11].[OH-:20].[Na+]>C1COCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH2:4][CH:5]([CH2:10][CH2:9][CH2:8][SH:7])[C:6]([OH:11])=[O:20])[CH:12]=1)([OH:18])=[O:17]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(Cl)c(CC2CCCSC2=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(CC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A solution of 3-(2-Chloro-5-methoxycarbonylbenzyl)-tetrahydrothiopyrane-2-one IV (9.26 g, 31.0 mmol) in THF (70 mL) was purged for 15 minutes with nitrogen. A degassed aqueous sodium hydroxide solution (2.2 M, 70 mL, 154 mmol) was added to the solution and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with ether, acidified by 3N HCl at 0° C., and extracted with ether. The extract was dried over MgSO4 and concentrated to afford 5-carboxy-2-chloro-alpha-(3-mercaptopropyl) benzenepropanoic acid 10 (8.42 g, 27.8 mmol, 90%) as a white solid: 1H NMR (CD3OD) δ 1.50-1.80 (m, 4H), 2.35-2.50 (m, 2H), 2.65-2.75 (m, 1H), 2.91 (dd, J=6.2, 13.8 Hz, 1H), 2.96 (dd, J=8.8, 13.8 Hz, 1 H), 7.39 (d, J=8.3 Hz, 1H), 7.76 (dd, J=2.0, 8.3 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H); 13C NMR (CD3OD) δ 25.1, 32.5, 33.2, 37.4, 46.8, 130.8, 131.2, 134.0, 139.1, 140.5, 169.2, 178.9. Anal. Calcd for C13H15ClO4S: C, 51.57; H, 4.99; S, 10.59; Cl, 11.71. Found: C, 51.59; H, 4.94; S, 10.43; Cl, 11.80.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[NH2:18])[C:9]1=[O:21])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (5.34 g, 0.0184 mol) in ethanol (100 mL, 2 mol) was added ammonium chloride (9.840 g, 0.1840 mol) in water (100 mL, 6 mol). The reaction heated at 85° C. and iron (4.11 g, 0.0736 mol) was added in four portions 3 minutes apart. The reaction started turning dark and became completely brown. After 2 hours, the flask was removed from the oil bath and 150 ml of ethyl acetate was added in the flask. The organic layer was decanted and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a bright yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)nc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of 2-bromo-7-nitro-5H-pyrrolo[2,3-b]pyrazine (21.76 g, 89.54 mmol) in acetic acid (108.8 mL) and concentrated hydrogen chloride (108.8 mL) was added dichlorotin dihydrate (101.0 g, 447.7 mmol). The reaction mixture was left to stir for 1 hour at ambient temperature. Reaction mixture was quenched by addition of 2M NaOH solution and the aqueous extracted with EtOAc (×3). Organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was washed with saturated NaHCO3 solution and the solid collected, washed with water and dried to give 2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-amine (10.4 g, 54.6%). 1H NMR (400.0 MHz, DMSO) δ 11.50 (br s, 1H), 8.22 (s, 1H), 7.16 (s, 1H) and 4.35 (br s, 2H) ppm; MS (ES+) 214.79
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9](=O)[CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=c1cccc(-c2ccccn2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccccn2)n1

Procedure:
A mixture of 5.3 g of 2-(2-pyridinyl)-6-(1H)-pyridinone and 100 ml of phosphorus oxychloride was heated on a steam bath for 18 hours and then concentrated to dryness under vacuum. Crushed ice was added to the oil residue and the mixture made basic with solid potassium carbonate. The mixture was then extracted with dichloromethane, the extracts treated with activated carbon, filtered and concentrated, giving a solid which was purified by chromatography on silica gel with ethyl acetate as solvent, giving 4.1 g of 6'-chloro-2,2'-bipyridine as white crystals, mp 60°-62° C.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([CH2:27][C:28](=[O:68])[NH:29][C@H:30]([C:57](=[O:67])[NH:58][C:59]3[CH:64]=[CH:63][C:62]([CH2:65][OH:66])=[CH:61][CH:60]=3)[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[OH:66][CH2:65][C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:57](=[O:67])[C@@H:30]([NH:29][C:28](=[O:68])[CH2:27][C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:60][CH:61]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)C[C@H](Cc2ccc(F)cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: COc1ccc(C(NCCCC[C@H](NC(=O)C[C@@H](N)Cc2ccc(F)cc2)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 0 %

Procedure:
In a 50 mL round-bottomed flask, the above prepared {(S)-2-(4-fluoro-phenyl)-1-[((S)-1-(4-hydroxymethyl-phenylcarbamoyl)-5-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-pentylcarbamoyl)-methyl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (793 mg, 857 mol, Eq: 1.001) was combined with THF (12 ml) to give a brownish solution. At 0°, diethylamine (1.13 g, 1.59 ml, 15.4 mmol, Eq: 18) was added. The reaction was stirred at ambient temperature over night. The mixture was poured onto crashed ice/NH4Cl (pH ˜7), extracted 2× with AcOEt, washed with H2O and brine, dried over Na2SO4, and evaporated to dryness. Flash chromatography SiO2/10% MeOH/0.1% NEt3 in CH2Cl2 yielded 500 mg of the title compound as off-white solid. MS: expected mass: 702.3581, found mass: 702.3578.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:23]=[CH:24][O:25][C:26]3[C:30]=2[CH:29]=[CH:28][CH:27]=3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32]>ClCCl>[ClH:32].[ClH:32].[O:25]1[C:26]2=[CH:27][CH:28]=[CH:29][C:30]2=[C:22]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[CH2:15][CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH:23]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reaction time: 2 h

Procedure:
To a mixture of trans-{4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (0.62 g, 1.24 mmol) in dichloromethane (9 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 4.63 ml, 18.5 mmol) and the mixture was allowed to stir for 2 h, the solvent was evaporated, MeOH (20 ml) and diethyl ether (40 ml) were added and the mixture was allowed to stir for 30 min at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried to yield the title compound as a white solid (0.49 g, 99%), MS (ISP) m/z=327.4 [(M+H)+], mp 239° C.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5]>CCOCC>[CH3:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4]([NH2:1])=[O:5]
Reactant: CN(C(=O)Cl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: N
Solvent: CCOCC
Product: CN(C(N)=O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
Saturate with NH3 a solution of 6.7 g (20 mmole) N-methyl-N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]carbamyl chloride in 200 ml Et2O. After 24 hours, wash the Et2O with water, then 1N HCl. Dry, concentrate and recrystallize the solid from ether-hexane to give 5.0 g white solid; m.p. 181°-184°.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[F:36])=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[F:36][C:18]1[CH:19]=[CH:20][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:22][C:17]=1[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-fluoro-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.45 g, 0.91 mmol) in DCM (1.0 mL) 2M HCl in Et2O (8.0 mL) was added and the resulting suspension was stirred at room temperature overnight. 2M HCl in Et2O (5.0 mL) more were added and reaction was left stirring for 24 h. The precipitate was filtered off and tritured with Et2O (3×15 mL) to afford 0.21 g of the title compound (55%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:53][CH2:52][C:35]4([CH2:39][N:38](C(OC(C)(C)C)=O)[C@H:37]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:53][CH2:52][C:35]4([CH2:39][NH:38][C@H:37]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:22])([F:23])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, and concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([N+:17]([O-])=O)=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]>C(O)C.O.[Fe]>[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([NH2:17])=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)/C=C/c1cnc([N+](=O)[O-])c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N)c(OC)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
Iron (1.6 g) and ammonium chloride (3 g) were added to the suspension of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester (787 mg) in ethanol (40 mL) and water (8 mL) obtained above, and the reaction solution was heated to reflux for 1 hour. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by celite. Ethyl acetate and saturated sodium bicarbonate water were added to the filtrate, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 2:1), and 506 mg (66%) (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH2:33][CH3:34]>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([CH2:33][CH3:34])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cn1
Reactant: CCC(=N)NO
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(CC)no4)CC3)cn2)cn1

Procedure:
The title compound is prepared from 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=1.96 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:46](OCC)=[O:47]>C(Cl)Cl>[C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]5[NH:33][O:34][C:46](=[O:47])[N:35]=5)[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=N)NO)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(c5nc(=O)o[nH]5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-{4′-[1-(N-hydroxycarbamimidoyl)-cyclopropyl]-biphenyl-4-yl}-3-methyl-isoxazol-4-yl)-carbamic acid (R)-1-phenyl-ethyl ester (0.66 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.19 mL, 1.32 mmol) and ethyl chloroformate (0.127 mL, 1.32 mmol), and the reaction was stirred overnight at room temperature. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred for 6 hours. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred until complete. The mixture was diluted with CH2Cl2 (20 mL) and washed with 10% aqueous citric acid, and then dried over MgSO4, filtered, and concentrated. The residue was dissolved in toluene (10 mL), and the solution was refluxed for 3 days. After concentrating, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.Cl>P(Cl)(Cl)(Cl)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:12]=3[O:11][CH3:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(O)cc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 1.6 gm (10 mmol) of 4-hydroxy-1,2-phenylenediamine and 4.9 gm (20 mmol) of 2-methoxy-4-methansulfonylamino-benzoic acid were refluxed for 1.5 hours, under stirring, in 80 ml of phosphorus oxychloride. The resulting dark solution was then decanted off to eliminate any undissolved components, the phosphorus oxychloride was distilled off in vacuo, and the residue was carefully mixed with 10 gm of crushed ice. Ten milliliters of 4N sodium hydroxide were added to the suspension thus obtained, and the resulting mixture was stirred for one hour at ambient temperature. It was then neutralized with concentrated hydrochloride acid, while being cooled, the solution was evaporated in vacuo to about 3 to 4 ml, the crude product precipitate was subjected to suction filtration, and the resultant crude product was purified by chromatography (250 gm of silica gel, eluant: methylene chloride with 5% ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.100 g, 0.390 mmol) in DMF (3 mL), was added K2CO3 (0.080 g, 0.58 mmol) and stirred at 25° C. for 10 minutes. To the reaction mixture methyl iodide (0.083 g, 0.58 mmol) was added slowly and stirred at 25° C. for 1 hour. DMF was removed under vacuum and reaction mass quenched with water, extracted with ethyl acetate (3×10 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[N:9]=2)[NH:4][C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[H-].[Na+].[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[N:9]=2)[N:4]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:3]=1[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(Br)c3n2)cc(OC)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(n2)c(Br)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a stirred solution of 7-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 46, 110 mg, 0.205 mmol) in tetrahydrofuran (2 mL), sodium hydride (12.0 mg, 0.300 mmol) was added at 0° C. After 10 min, [β-(trimethylsilyl)ethoxy]methyl chloride (55.7 μL, 0.315 mmol) was added dropwise. After another 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 8% MeOH in DCM) to give the desired product (55 mg, 31%). LCMS calculated for C33H45BrN5O3Si (M+H)+: m/z=666.2. Found: 666.3.