Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]#[N:14])=[CH:7][CH:6]=1.Cl.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][N:20]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:25]([C:22]3[CH:21]=[N:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[N:26]=[C:13]([NH2:14])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(NN)cn1
Reactant: COCOc1ccc(C=CC#N)cc1
Agent: Cl
Product: COCOc1ccc(C2CC(N)=NN2c2ccc(OC)nc2)cc1
Yield: 41.2 %

Procedure:
The title compound (1.63 g, 41.2%) was prepared as a powder from 3-(4-methoxymethoxyphenyl)acrylonitrile and 2-methoxy-5-pyridinylhydrazine dihydrochloride in a similar manner to that of Example 14-1.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:30][NH:31][C:32](=O)[CH2:33][N:34]([CH3:36])[CH3:35].C[O-].[Na+]>CO>[CH3:35][N:34]([CH2:33][C:32]1[NH:31][N:30]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:36]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)(C)C)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)CC(C)(C)C)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to the procedure described in Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3,3-dimethylbutanamide hydrochloride (0.360 g, 0.87 mmol), N-amino-2-(dimethylamino)acetamide (0.304 g, 2.60 mmol) and sodium methoxide in methanol (0.398 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.093 g, 25% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.16 (t, 1H), 8.08 (dt, 1H), 7.75 (dt, 2H), 7.66 (d, 1H), 7.50 (t, 1H), 3.71 (s, 2H), 2.37 (s, 6H), 2.30 (s, 2H), 1.12 (s, 9H); ES-MS (m/z) 432 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][OH:13].[NH2:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[CH3:20][N:17]1[CH:18]=[CH:19][C:15]([NH:14][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][C:2]4[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=4[CH2:12][OH:13])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[N:16]1
Reactant: OCc1cccc(C(F)(F)F)c1F
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(CO)cccc4C(F)(F)F)cc23)n1

Procedure:
The compound of Example 142 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-fluoro-3-(trifluoromethyl)-benzenemethanol, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of Example 17A (19.9 g, 66 mmol) and triethylamine (9.5 mL, 70 mmol) in THF (200 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (15.08 g, 132 mmol) drop wise over 30 minutes. The mixture was allowed to warm up to room temperature, stirred for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to a yellow oil. The yellow oil was purified using a Biotage 65+ eluting with 100% ethyl acetate to provide the titled compound. MS (ESI) m/e 380 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.44 (m, 9H) 2.22 (m, 1H) 2.65 (m, 1H) 3.05 (m, 1H) 3.14 (d, 3H) 3.17 (m, 1H) 3.74 (m, 3.73 Hz, 1H) 3.81 (m, 2H) 4.00 (m, 1H) 4.53 (m, 1H) 4.70 (m, 2H) 5.32 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=2[NH:16][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)c1ccc(N)c(C2=CCCCC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a mixture of 2-cyclohex-1-enyl-4-isopropyl-phenylamine (as prepared in the previous step, 30.0 mg, 0.139 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 43.0 mg, 0.141 mmol) and PyBroP (65.0 mg, 0.139 mmol) in 1.5 mL of DMF was added DIEA (73 μL, 0.417 mmol). The resulting mixture was stirred at RT for 16 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (2×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (DCM) gave 55.4 mg (86%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C26H36N4O2Si, 465.3 (M+H), found 464.9.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]2)=[CH:7][CH:6]=1)#[N:4].Cl>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=2)=[O:31])[CH2:15][C@@H:16]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
LiOH (143 mg, 5.96 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate (1200 mg, 2.98 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust pH to about 3, extracted with ethyl acetate (2×50 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 1150 mg (99%). LC-MS: 389.2, 387.3 (t=2.1 min).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH:20](OC)OC)=[O:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.CO.[OH-].[K+]>C(Cl)(Cl)Cl>[S:6]1[C:10]2[CH:11]=[C:12]([N:15]3[CH:20]=[CH:19][NH:18][C:16]3=[O:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: COC(CNC(=O)Nc1ccc2ncsc2c1)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ccn1-c1ccc2ncsc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
1N H2SO4 (2 mL) was added to 1-benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (I-142a: 300 mg) and the resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was heated to 50° C. for 2 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to 0° C. and basified with 10% KOH solution. The precipitate was collected, washed with water and dried under reduced pressure to afford 170 mg of 1-Benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (73.59% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CNS(=O)(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred room temperature solution of 4-bromomethyl-N-methyl-benzenesulfonamide (2.70 g, 10.0 mmol) in DMF (15 mL) was added sodium azide (0.90 g, 13 mmol). The mixture was stirred at 40° C. for 16 hours. The solution was poured into water (60 mL) and diluted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to afford 4-azidomethyl-N-methyl-benzenesulfonamide
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Fc1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(F)c(F)c2)C1

Procedure:
The title compound was prepared from (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine and 4-bromo-1,2-difluorobenzene using the procedure outlined for Description 11.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu].C(O)(=O)C>[NH2:20][C:16]1[CH:15]=[C:14]([NH:21][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 6.25 h

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid 16 (150.0 g, 744 mmol), 1,3-phenylenediamine 17 (150.0 g, 1.387 mol), anhydrous potassium carbonate (309.0 g, 2.236 mol ), copper powder (2.0 g, 31.5 mmol), cupric sulfate (10 mg) and water (2.0 L) was heated to reflux with stirring for 6.25 hr under argon. It was then allowed to stand overnight at room temperature. Glacial acetic acid was added to the reaction mixture with stirring until pH 5 and the flask cooled in ice water. The mustard yellow solid was collected, washed with ice-cold water (3×100 mL), and redissolved in hot dilute ammonia (300 mL 0.88 s.g. ammonia and 2.7 L water). Charcoal (2.0 g) was added, the mixture refluxed briefly, and then filtered through a fluted paper. On cooling to room temperature the mixture was acidified to pH 5 by adding glacial acetic acid and the flask cooled in ice-water. The product was collected and washed with ice-cold water (2×100 mL) followed by ice-cold ethanol (2×100 mL), dry ether (2×100 mL) and finally hexane (100 mL). The product was dried over P2O5 under vacuum to yield the product AR-ACO-06 (155.10 g, 76%) as brown solid.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[C:43]([CH3:44])=[CH:42][C:14]([CH2:15][C@@H:16]([CH2:21][C:22](=[O:41])[N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:40])[CH2:25][CH2:24]2)[C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:45])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:3]([O:10][C:11]1[C:43]([CH3:44])=[CH:42][C:14]([CH2:15][C@@H:16]([CH2:21][C:22](=[O:41])[N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:40])[CH2:25][CH2:24]2)[C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:45])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (8.35 mmol) LiOH in 40 mL water was added to a solution of 2.43 g (4.16 mmol) methyl(S)-2-(4-benzyloxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 80 mL THF and the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 100 mL water and acidified with 2 M HCl with stirring. The precipitate formed was separated off and dried at 40° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:29][CH2:30][C:31](Cl)=[O:32]>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[C:31](=[O:32])[CH2:30][Br:29])[CH3:2]
Reactant: CCOC(CCNCC1OCCO1)OCC
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CCN(CC1OCCO1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: CC(C[O-:5])C.[K+].[C:7]1([CH3:14])[C:8](C)=[CH:9]C=C[CH:12]=1.[CH3:15][C:16]([CH3:18])=[O:17].C#C>O>[CH3:12][CH:7]([CH2:8][CH3:9])[C:14]#[C:15][C:16]([CH3:18])([OH:5])[OH:17]
Reactant: CC(C)=O
Reactant: CC(C)C[O-]
Reactant: Cc1ccccc1C
Agent: C#C
Agent: [K+]
Solvent: O
Product: CCC(C)C#CC(C)(O)O
Yield: 90 %

Procedure:
529 g of a potassium isobutoxide/xylene suspension (4.5 mol/kg), 127 g of acetone and 29 g of acetylene gas were metered continuously and synchronously over a period of one hour into a reaction mixing pump having a nominal capacity of 20 ml. The reaction mixture which was mixed very well in the reaction pump was conveyed via a pump circuit in which a heat exchanger was located. The reaction temperature in the pump was 35° C., that upstream of the heat exchanger was 32° C. and that downstream of the heat exchanger was 28° C. The volume flow in the pumped circuit was in the range from 80 to 100 l/h. From the pump circuit, an after-reaction section led to a hydrolysis vessel where the reaction mixture was hydrolyzed by means of 500 g/h of water. After the organic phase had been separated off and neutralized by means of 22.8 g of phosphoric acid, dimethylhexynediol was obtained at a conversion of 98% and in a yield of 90%. Methylbutynol in a yield of 2.3% was identified as by-product.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[N:42]([Sn](CCCC)(CCCC)CCCC)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[N:42]=[N:43][NH:44][N:17]=2)[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC#N)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1nn[nH]n1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 100 °C

Procedure:
To a solution of (S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetonitrile (0.1 mmol) in toluene (6 mL), add azidotributyltin (0.1 mmol) and heat at 100° C. After heating for 14 h, cool to room temperature and dilute with ethyl acetate (20 mL). Wash the reaction with concentrated sodium fluoride (2×20 mL), dry the organic phase over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-5%), to afford the title compound as a colorless foam. MS (ES+): 633 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(F)cc23)cc(OC)c1OC
Yield: 59.2 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-fluoroindole-3-carboxaldehyde (1.63 g) to give Compound 29 (2.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CS(C)=O.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:34][C@H:35]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc2cc(-c3cnc4ccc(Cl)nn34)sc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 33 mg of the yellow solid, 75%.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:47][C@H:48]([C:56]([O:58][CH2:59][C:60]#[N:61])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:47][C@H:48]([C:56]([O:58][CH2:59][C:60]#[N:61])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: N#CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
300 mg (0.69 mmole) of Z-Tyr-Gly-Gly-OH was dissolved in 5 mL dry THR, and the temperature was lowered to -10° C. in a dry ice/ethylene glycol bath. One equivalent of N-methyl morpholine and 1 equivalent of isobutyl chloroformate was added with stirring. One equivalent of H-L-Phe-OCH2CN, HCl (166 mg), and 1 equivalent of N-methyl morpholine dissolved in 2 mL DMF was added and the solution stirred for 5 minutes. The reaction was allowed to come to room temperature, then diluted with six volumes of ethyl acetate. The ethyl acetate was washed with cold water (2x), 0.1 N HCl (3x), 0.2 M Na2CO3 (2x), water (2x) and concentrated brine (1x). The ethyl acetate as concentrated carefully under vacuum, and the residue was recrystallized from CH2Cl2 /hexanes to give 260 mg (62%) of Z-Tyr-Gly-Gly-Phe-OCH2CN. Amino acid analysis: tyr1.0, gly1.9, phe0.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:11]>CO.[Cu]Br>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH2:11])[CH:7]=[N:6][CH:5]=1
Reactant: COc1cncc(Br)c1
Reactant: [NH4+]
Agent: [Cu]Br
Agent: [OH-]
Solvent: CO
Product: COc1cncc(N)c1
Temperature: 171 °C

Procedure:
Crude 5-bromo-3-methoxypyridine (3.50 g, 18.62 mmol) was dissolved in methanol (50 mL) and added to concentrated ammonium hydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.67 g, 18.62 mmol) in a heavy-walled glass pressure-tube apparatus. The tube was flushed with nitrogen and sealed. The mixture was stirred and heated at 170-172° C. (oil bath temperature) for 24 h. After cooling, the solution was concentrated by rotary evaporation to a gummy residue. The residue was diluted with sodium carbonate solution (17.6%, 200 mL) and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to give 1.26 g of a cream-brown solid. The aqueous phase was re-extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were similarly dried and concentrated to give an additional 0.34 g of a cream-brown solid, bringing the total yield to 1.60 g (69.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[C:11](=[O:13])[N:14]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21])[C:5]2=[O:7]
Reactant: NC1CCCNC1=O
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Solvent: CN(C)C=O
Product: Nc1cccc2c1C(=O)N(C1CCCNC1=O)C2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
To a solution of 3-aminophthalic acid (0.100 g, 0.552 mmol) in DMF (1.1 mL) was added 3-aminopiperidine-2-one (0.063 g, 0.552 mmol) and the reaction was stirred at 90° C. over 18 h. Volatiles were removed in vacuo and the dark-brown crude residue was purified by preparative reverse phase HPLC to give the desired product 28 (0.050 g, 35%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 7.83 (s, 1H), 7.43 (dd, J=8.3, 7.1 Hz, 1H), 7.07-6.87 (m, 2H), 6.47 (br s, 2H), 4.49 (dd, J=11.9, 6.3 Hz, 1H), 3.27-3.10 (m, 2H), 2.19 (dt, J=12.0, 7.7 Hz, 1H), 2.05-1.72 (m, 3H). MS (ESI) m/z calcd for C13H14N3O3 [M+H]+ 260.3, found: 260.9.