Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](F)[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.C([N:28](CC)CC)C.C([O-])(=O)C.[NH4+]>O1CCOCC1>[NH2:28][C:6]1[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCN(CC)CC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2N)c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To stirred solution of 200 grams (0.519 mole) of 3-(4-chloro-2,6-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 1000 mL of dioxane was added 150 mL (1.091 moles) of triethylamine in one portion. Upon completion of addition, the mixture was vigorously stirred and 400 grams (5.189 moles) of ammonium acetate was added in one portion. The reaction mixture was heated to 90° C. where it stirred for two hours. The reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The resulting suspension was collected by filtration and washed with dioxane. The filtrate was concentrated under reduced pressure to yield a viscous dark oil. The oil was poured into ice-water. The resulting solid was collected by filtration and washed with water. The solid was dried under reduced pressure and then at ambient temperature for about 18 hours, yielding 195.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=2)=[CH:20][C:19]=1[Cl:34].BrCC1C=CC(Cl)=C(Cl)C=1.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:34][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[Cl:17])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: Clc1ccc(CBr)cc1Cl
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1,2-Dichloro-4-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1-bromomethyl-3,4-dichloro-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 503 (M+1).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([OH:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.O>CN(C=O)C>[Cl:8][C:23]1[CH:22]=[N:21][C:20]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=3)[N:17]=[CH:18][C:19]=2[C:24]=1[OH:25]
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c(O)c(Cl)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
NCS (1.57 g, 11.8 mmol) was added in one portion to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.00 g, 11.8 mmol) in DMF (30 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. After 18 hours, an additional lot of NCS (0.5 eq.) was added to the reaction mixture and stirred at room temperature for an additional 48 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed once with water (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 2% MeOH/CH2Cl2 to provide 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (466 mg, 1.61 mmol, 13.7% yield). LCMS (APCI+) m/z 290 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][S:25][CH3:26])[NH2:22]>>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][S:25][CH3:26])[NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(CO)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1

Procedure:
The resultant product from Example 16C is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Cc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][O:7][CH2:8][C:9]([NH2:28])([CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2].[C:30]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10][C:9]([NH:28][C:43](=[O:44])[CH2:42][CH2:41][NH:40][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])([CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][O:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH3:18]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCOCC(N)(COCCC(=O)OCC)COCCC(=O)OCC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)CCOCC(COCCC(=O)OCC)(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Yield: 90.1 %

Procedure:
The compound 23 was prepared using General Procedure B with amine 1 (4.0 g, 9.49 mmol), N-Cbz-β-alanine (2.54 g, 11.39 mmol), 1-hydrobenzotriazole (HOBt) (1.53 g, 11.39 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (2.18 g, 11.39 mmol) in CH2Cl2 (50 mL). Purification by flash column chromatography (on silica gel, EtOAc:n-hexane=1:3) afforded 5.36 g (90%) of the desired product 23 as a colorless syrup. 1H NMR (CDCl3): δ 7.31 (m, 5H, ArH), 6.16 (s, 1H, NH), 5.66 (s, 1H, NH), 5.08 (s, 2H, OCH2Ar), 4.12 (q, J=6.4 Hz, 6H, OCH2), 3.67 (m, 12H, CH2O), 3.45 (dt, J=7.4, 15.0 Hz, 2H, CH2NHCO), 2.51 (t, J=8.4 Hz, 6H, CH2CO), 2.37 (dt, J=7.4, 8.6 Hz, 2H CH2CO), 1.24 (t, J=6.4 Hz, 9H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH:10]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=3[CH:23]=2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (190 μL, 1.43 mmol) and 4-nitrobenzoyl chloride (264 mg, 1.43 mmol). The solution was stirred at room temperature for 72 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.42 min, MH+ 459].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][NH:56][CH3:57]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:36])[CH3:37])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:56]([CH3:57])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12)C(C)C
Solvent: C1CCOC1
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12)C(C)C
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a solution of Intermediate 103f (130 mg, 0.13 mmol) in THF (1.5 mL) was added dimethylamine (2M in MeOH, 520 μL, 1.04 mmol). The reaction mixture was heated at 50° C. for 18 h, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (37 mg, 40%). LCMS (Method 5): Rt 3.70 min, m/z 708 [MH+]. 1H NMR (400 MHz, CD3OD): 1.05 (12H, dd, J=6.4, 1.8 Hz), 1.33 (9H, s), 21.89-2.30 (4H, m), 2.43 (6H, s), 2.91 (2H, t, J=5.2 Hz), 3.62-3.74 (2H, m), 4.19 (2H, t, J=5.3 Hz), 4.88-4.97 (1H, m), 5.42 (1H, t, J=4.1 Hz), 6.37 (1H, s), 7.04-7.13 (3H, m), 7.19-7.34 (5H, m), 7.44 (1H, t, J=8.3 Hz), 7.60 (1H, d, J=9.8 Hz), 7.87 (1H, d, J=2.1 Hz).
Reaction SMILES: Cl.[S:2]([Cl:8])([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].[N-:9]=[N+:10]=[N-:11].[Na+].[Cl-].[Na+]>O>[ClH:8].[S:2]([N:9]=[N+:10]=[N-:11])([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: NCCS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)CCN
Temperature: 5 °C

Procedure:
Tauryl chloride hydrochloride and sodium azide were reacted with one another in a ratio of 1:1 in water. For this purpose, the calculated stoichiometric amount of sodium azide was dissolved in water and the solution was cooled to 5° C. Tauryl chloride hydrochloride was added while stirring and the reaction mixture was stirred for 15 min. By stripping off the water, a solid mixture of crystalline sodium chloride and taurylazide hydrochloride was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[CH3:23][CH2:24][C:25]([C:27]1[CH:32]=[C:31]([F:33])[C:30](O)=[C:29]([F:35])[CH:28]=1)=[O:26]>>[F:33][C:31]1[CH:32]=[C:27]([C:25](=[O:26])[CH2:24][CH3:23])[CH:28]=[C:29]([F:35])[C:30]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:8])[C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:3]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: CCC(=O)c1cc(F)c(O)c(F)c1
Product: CCC(=O)c1cc(F)c(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)C2)c(F)c1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone and 3,5-difluoro-4-hydroxypropiophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 496.5 (M+H+, 100%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:13].Cl.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25]>C(O)C>[ClH:13].[NH2:25][C:24]1[N:23]([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:28]=[C:27]([NH2:29])[N:26]=1
Reactant: N=C(N)NC(=N)Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)cc1F

Procedure:
100 ml of ethanol, 5.1 g (29.9 mmol) of 1-undecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (20.0 mmol) of N1- (2,4-difluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol mixed solution (9:1.5)), and recrystallized from 80% aqueous ethanol to obtain 1.7 g of colorless crystals having a melting point of 207 to 209° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].O>C1COCC1.CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:2]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccnc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-yl-acetonitrile (14.65 g) and 1,5-dibromo-pentane (28.52 g) in THF (450 mL) and DMSO (450 mL) is added NaH (60% in mineral oil, 10.42 g) portionwise at 0° C. over 1 h. The mixture is allowed to warm to RT and stirred overnight. The reaction mixture is poured into water and extracted twice with EtOAc. The extract is concentrated and the residue is purified by silica gel chromatography to give 1-pyridin-3-yl-cyclohexanecarbonitrile.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:12]([CH3:31])[CH:11]=1)=[O:8]>C1COCC1>[CH3:31][C:12]1[CH:11]=[C:10]([N:9]2[CH2:4][CH2:5][NH:6][C:7]2=[O:8])[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)NCCCl)cc2C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(N3CCNC3=O)cc2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of NaH (60% in mineral oil, 0.109 g, 2.73 mmol) in THF (13 mL) in a sealable tube under nitrogen was added 1-(2-chloroethyl)-3-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea (0.537 g, 1.30 mmol) in portions. The reaction was sealed and heated to 80 deg. C. for 3 h. The reaction was cooled to ambient temperature and was concentrated under a stream of nitrogen. The resulting solid was suspended in 50 mL water, acidified to pH 1 with 6 N HCl, and filtered. The solid was rinsed with water, diethyl ether, and dried in vacuo to give 1-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)imidazolidin-2-one as a tan solid. MS m/z=377 [M+1]+. Calc'd for C20H20N6O2: 376.16.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:21](/B(O)O)=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:21](/[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1)=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (75 g, 213 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.69 g, 10.6 mmol) and (E)-styrylboronic acid (39.4 g, 266 mmol) in THF (600 mL) was added Na2CO3 (27.1 g, 256 mmol) and water (300 mL). The reaction mixture was degassed with nitrogen for about 45 min. The reaction mixture was heated to about 65° C. for about 16 h then PdCl2 (dppf)-CH2Cl2 adduct (3.50 g, 4.29 mmol) was added. After about 18 h, the reaction was cooled to ambient temperature. The layers were separated and the organic layer was concentrated under reduced pressure. The residue was triturated in EtOH (300 mL)/DCM (100 mL) and filtered. The precipitate was triturated in hot EtOH (400 mL) and filtered, then washed with EtOH (200 mL) and Et2O (400 mL). The filtrates were recombined, concentrated under reduced pressure, and the resulting residue was triturated in EtOH (300 mL)/DCM (100 mL) and stirred overnight while allowing the DCM to slowly evaporate. The mixture was filtered and washed with EtOH (100 mL) and Et2O (100 mL) to give a second crop. The combined filter cakes were dried under vacuum to provide (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.7 g, 91%) as a tan solid: LC/MS (Table 2, Method a) Rt=2.66 min; MS m/z: 376 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([O:34]C1C=CC=CC=1)=O)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[NH:41]([C:32]([NH:31][C:30]1[CH:29]=[CH:28][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]3)=[O:14])[CH:7]=2)=[CH:3][C:2]=1[Cl:1])=[O:34])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Yield: 48.1 %

Procedure:
t-Butyl 4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate (250 mg), aniline (84 mg) and dimethylformamide (3 ml) were stirred at 130° C. for 70 minutes. The mixture was returned to room temperature, water was added and extraction was performed with ethyl acetate. Silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate). The solvent was distilled off under reduced pressure to obtain 120 mg of a colorless oil.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[C:18]=[O:19].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:18]([NH:17][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]4)=[O:19])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azepanyl)-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.50 (s, 1H), 8.67 (s, 1H), 8.60 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 7.83 (t, 1H, J=8.1 Hz), 7.56 (t, 1H), 7.04 (m, 2H), 6.90 (m, 1H), 4.26 (d, 2H, J=6 Hz), 3.32 (m, 4H), 2.79 (s, 3H), 1.75 (m, 4H), 1.55 (m, 4H); MS (ESI) 407 (M+H)+; Anal. Calcd for C24H27FN4O.2HCl: C, 60.13; H, 6.10; N, 11.69. Found: C, 60.09; H, 6.35; N, 11.47.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:12])=[O:11])=[C:6]([O:22][CH3:23])[CH:5]=1)([O-])=O.C>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)NCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1S(=O)(=O)NCCCCCC(=O)O
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution of ε(4-nitro 2-methoxy-benzenesulfonamido)caproic acid (1.4 g) in solution in ethyl acetate (150 cm3) is stirred magnetically under a hydrogen atmosphere in the presence of 5% palladized charcoal (120 mg). After four hours, the hydrogen absorption being terminated, the catalyst is filtered and the filtrate concentrated under reduced pressure. Pure ε(4-amino 2-methoxy-benzenesulfonamido)caproic acid is obtained, with a yield of 98%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CO[C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:9]>>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:32][CH2:33]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:9]
Reactant: CNCCO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CCO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 13 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-methylamino-ethanol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (13%) as amorphous yellow solid.