Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:38])SC)=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][NH2:40]>ClCCl.CO>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:39][NH2:40])=[NH:38])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)SC)cc1
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)NN)cc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[imino-(methylthio)methyl]benzyl}-L-methioninamide (49 mg, 0.084 mmol) was dissolved in dichloromethane (2 ml) and methanol (2 ml), to which hydrazine (0.020 ml, 0.624 mmol) was then added and stirred for 18 hours. The solvent was distilled off under reduced pressure and the residue was purified by preparative HPLC to give N-(benzylsulfonyl)-D-isoleucyl-N1-{4-[hydrazino(imino)methyl]benzyl}-L-methioninamide (29 mg, 0.051 mmol; yield 61%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Li])CCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>O1CCCC1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([B:25]([OH:26])[OH:24])=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCNc1ccc2ncc(B(O)O)n2n1
Temperature: -78 °C
Yield: 57.7 %

Procedure:
A precooled (−78° C.) solution of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (200 mg, 0.74 mmol) and tetrahydrofuran (4 mL) was treated dropwise with n-butyllithium (1.2 mL, 1.6 M, 1.9 mmol). The resulting reaction mixture was maintained at −78° C. for 5 min, then treated dropwise with tris(isopropyl)borate (0.21 mL, 0.89 mmol) and maintained at −78° C. for 2.5 h. The reaction was quenched with H2O (1 mL) and allowed to warm to RT. The organic volatiles were removed under reduced pressure, and the aqueous layer was acidified with 1 N HCl until a white precipitate formed. The solid was collected by filtration to afford (6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid (100 mg, 58%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 (d, J=9.9 Hz, 1H), 7.39 (s, 1H), 6.66 (d, J=9.9 Hz, 1H), 3.25-3.35 (m, 2H), 1.60-1.75 (m, 1H), 1.37-1.58 (m, 1H), 0.94-1.08 (m, 1H); LCMS (ESI) m/e 235.2 [(M+H)+, calcd for C10H15BN4O2 235.1].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc2ccccc2n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccc2ccccc2n1)c1ccccc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
A solution of 2-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. More acetonitrile (60 ml) was added and the solution was heated at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.33 g, 40% yield) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>C(=S)=S>[Cl:17][C:18]1[C:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)=[CH:23][CH:24]=[CH:25][N:26]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: O=C(c1ccc(-c2ccccc2)cc1)c1cccnc1Cl

Procedure:
26.7 g AlCl3 is added slowly while stirring to a solution of 9.2 g biphenyl and 10.6 g 2-chloronicotinoyl chloride in 170 ml carbon disulfide. The mixture is refluxed 5 hrs. After cooling, the S2C layer is poured off, and the residue is added to acidic ice:water, basified and extracted with methylene chloride. The combined extracts are washed, dried (MgSO4) and solvent removed in vacuo. The crude product is chromatographed on a silicagel column and eluted with benzene:ethyl acetate 15:1 Yield: 5 g of title product, m.p. 128°-32° C.; UV (ethanol): λmax. 295 nm, ε: 27,260; Cl 11.96 (12.07).
Reaction SMILES: ON[C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]3[C:15](=[O:32])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]5=[O:31])=[CH:21][CH:20]=4)[CH2:17][CH2:18][C:13]=3[C:12]([C:33]([F:36])([F:35])[F:34])=[N:11]2)[CH:5]=1.[OH-:38].[Na+].OO>ClCCl>[O:32]=[C:15]1[C:14]2[N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([NH2:37])=[O:38])[N:11]=[C:12]([C:33]([F:34])([F:36])[F:35])[C:13]=2[CH2:18][CH2:17][N:16]1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]2=[O:31])=[CH:21][CH:20]=1
Reactant: [OH-]
Reactant: N=C(NO)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 116, part A (0.05 g) was dissolved in dichloromethane (10 mL). To this was added sodium hydroxide (1N, 5 mL), hydrogen peroxide (3 mL), and tetrabutylammonium-hydroxide (0.01 g). The reaction mixture was stirred at rt for 24 h and concentrated, quenched with water (50 mL) and the organics extracted with ethylacetate (2×50 mL), dried (MgSO4) and concentrated. The crude was purified via prep HPLC to a colorless solid. ESI mass spectrum 494(M+H) and 492(M−H).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]=1[NH2:15])#[N:2].C(N(CC)CC)C.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:5][C:4]=1[N:15]1[CH2:24][CH2:25][CH2:26][C:27]1=[O:28])#[N:2]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1c(-c2ccccc2)[nH]c(N)c1C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)[nH]c(N2CCCC2=O)c1C#N
Temperature: -50 °C
Yield: 22.8 %

Procedure:
To a solution of 3-cyano-4-methyl-2-amino-5-phenylpyrrole (4.9 g) in THF (80 ml) was added triethylamine (2.5 g) and while the mixture was stirred at -50° C., 4-chlorobutyryl chloride (3.5 g) was added. This reaction mixture was then stirred at room temperature for 1.5 hours, after which the insoluble matter was filtered off. The filtrate was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous solution of sodium hydrogen carbonate, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from benzene/n-hexane. The crystals were suspended in ethanol (40 ml), and potassium tert-butoxide (1.32 g) was added thereto. The mixture was stirred at room temperature overnight and the resulting crystals were collected by filtration, washed with water, and air-dried. The crude crystals thus obtained were recrystallized from ethanol to provide the title compound as light-yellow needles (1.5 g). m.p. 140-141° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:32]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:32])[C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3C)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 525 and methyl iodide (10 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (9 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:32](=[CH:33][CH:34]=[CH:35][C:28]=2[Cl:27])[O:36]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 24.4 %

Procedure:
(E)-4-Oxo-but-2-enoic acid ethyl ester (4.60 mL, 38.32 mmol), 2-nitrobenzoic acid (1.08 g, 6.39 mmol), and pyrrolidine (0.53 mL, 6.39 mmol) were added simultaneously to a solution of commercially available 2-chloro-6-hydroxy-benzaldehyde (5.0 g, 31.93 mmol) in dimethysulfoxide (30 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel Flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (2.08 g, 49.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23](OC)=[O:24])=[N:21][CH:22]=1)(=[O:16])=[O:15].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][N:21]=1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Reactant: Nc1ccccc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added to trimethylaluminum (2.0 M 4.6 mL) then methyl 5-(methylsulfonyl)picolinate 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction mixture was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[CH2:28][O:29][C:30]([NH:32][C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2[CH2:42][C:43](O)=[O:44])=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:43](=[O:44])[CH2:42][N:37]1[CH:36]=[N:35][C:34]2[C:38]1=[N:39][CH:40]=[N:41][C:33]=2[NH:32][C:30]([O:29][CH2:28][C:27]1[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:31])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1OC
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)c(OC)c3)ncnc21
Yield: 97.6 %

Procedure:
The title compound (6.28 g, 96%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (3.26 g, 9.5 mmol) and [6-N-(3,4-dimethoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (3.50 g, 9.03 mmol) as per the procedure of Example 27. 1H NMR (500 MHz; DMSO-d6) δ 10.58 (s, 1H), 8.98 (brs, 0.6H), 8.77 (brs, 0.4H), 8.57 (s, 0.4H), 8.53 (s, 0.6H), 8.29 (d, 1H), 8.27 (m, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 7.08 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 5.35 (s, 1.2H), 5.15 (s, 0.8H), 5.12 (s, 2H), 4.45 (s, 0.8H), 4.18 (q, 0.8H), 4.07 (s, 1.2H), 4.01 (q, 1.2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (t, 1.2H), 3.48 (t, 1.2H), 3.42 (t, 0.8H), 3.22 (t, 0.8H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (2 g, 5.7 mmol) in 1,4-dioxane (40 mL) and H2O (8 mL) under nitrogen was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.48 g, 6.30 mmol), and potassium carbonate (2.39 g, 17.0 mmol). Upon completion of addition, the reaction mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.46 mg, 0.050 mmol) was added. The reaction mixture was again degassed for 10 min with nitrogen. At the conclusion of this period, the reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using 2.7% MeOH in DCM as eluent to afford 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinaldehyde (1.8 g, 100% yield) as an off-white solid. LCMS Method Y: retention time 1.99 min; [M+1]=418.4.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[N:25]=[N:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:9][CH2:10]1)[C:29](=[O:30])[CH2:28][C:26]1[N:25]=[N:24][NH:23][CH:27]=1
Reactant: O=C(O)Cc1c[nH]nn1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)Cc1c[nH]nn1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (100 mg, 0.290 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (55.2 mg, 0.434 mmol), T3P® (50% solution in DMF) (338 μl, 0.579 mmol) and Huenig's base (101 μl, 0.579 mmol) in DMF was stirred at room temperature for 18 hours. The resulting mixture was concentrated under pressure. The crude residue was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[N:31]=1>>[CH3:40][C:37]1([CH3:41])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CC1(C)CCc2nc(CNS(C)(=O)=O)nc(Cl)c2C1
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CNS(C)(=O)=O)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and N-((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)methanesulfonamide (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br s, 1H), 8.05 (br s, 1H), 7.74 (d, 1H), 7.56 (dd, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 4.68 (s, 2H), 4.37-4.31 (m, 2H), 4.12 (d, 2H), 3.93-3.87 (m, 2H), 2.85 (s, 3H), 2.71 (t, 2H), 2.54 (s, 3H), 2.47 (s, 2H), 1.60 (t, 2H), 0.85 (s, 6H); MS (EI) for C28H33N7O3S: 548 (MH+).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=1.[K].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18]Cl>C(O)C>[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18][O:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cnc([N+](=O)[O-])c(O)c1
Reactant: Cc1cccc(C)c1CCl
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc([N+](=O)[O-])c(OCc2c(C)cccc2C)c1
Yield: 81.1 %

Procedure:
To 0.52 g (8.02 mmol) of 87% KOH and 0.15 g q-iodide in 6 ml 95% ethanol was added a solution of 3-hydroxy-5-methyl-2-nitropyridine (1.2 g, 7.79 mmol) in 25 ml of ethanol. To the resulting suspension of the potassium salt was added dropwise a solution of 2,6-dimethyl benzylchloride (1.24 g, 8.02 mmol) in 13 ml of ethanol. The reaction mixture was refluxed for 1 h. More 87% KOH (0.16 g) and 2,6-dimethylbenzylchloride (0.38 g) were added. The reaction mixture was refluxed for additional 70 min. The mixture was filtered and the inorganic salts were washed with ethanol and methylene chloride. The organic layer was evaporated in vacuo. The residue was dissolved in methylene chloride, washed with aqueous NaHCO3, dried and evaporated in vacuo. The residue was suspended in ether/isopropanol and filtered to give 1.72 g (81%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[NH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Add trifluoroacetic acid (10 mL) dropwise to a solution of {2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.7 g, 10 mmol) in dichloromethane (50 mL) at 0° C. Warm to room temperature and stir overnight. Concentrate on a rotary evaporator, dissolve residue in methanol then apply to a strong cation exchange column (Varian, 0.79 meq/g), and wash with methanol. Elute the product with 2M ammonia in methanol then concentrate on a rotary evaporator to yield N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (2.3 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.97 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.19 (d, 2H, J=7.9 Hz), 6.92 (dd, 4H, J=21.3, 8.1 Hz), 3.60-3.05 (m, 3H), 2.73-2.55 (m, 3H), 2.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min). Title compound isolated (70 mg, 47%) as an off-white solid. MP 233-234, LCMS 492.27 (M+H), HPLC purity 98%, 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, 7.9 Hz, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30-7.21 (m, 2H), 7.18-7.09 (m, 3H), 6.08 (bt, J=5.1 Hz, 1H), 4.93 (s, 2H), 4.88-4.82 (m, 1H), 4.39-4.33 (m, 1H), 3.83-3.78 (m, 1H), 3.82-3.75 (m, 1H), 3.08-3.02 (m, 1H), 2.81-2.74 (m, 1H), 2.64-2.59 (m, 1H), 1.83 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methane sulfonate (930 mg, 3.70 mmol, Example 316) in dimethylformamide (20 mL), sodium azide (962 mg, 14.8 mmol, Aldrich) was added and the mixture was stirred at 90° C. overnight. The mixture was poured into water and extracted with ethyl acetate (5×10 mL) and the extracts were combined, washed with water, brine and dried with sodium sulfate. The solvent was removed to give a clear oil. 710 mg, 97%. The compound was directly used for the next step.