Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[C:14]#[CH:15]>C1(C)C(C)=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: C#CC(=O)OCCCC
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
2.0 g (0.126 mole) of 3-diazo-oxindole is taken up in xylene (85 ml), treated with 1.2 equivalents of n-butyl propiolate (1.9 g) and refluxed under a stream of nitrogen for 17 hours in an oil bath. The light coral-colored precipitates that form are cooled and filtered off and washed with ether. Yield: 3.0 g, m.p. 190°-195°; 83.57% crude yield. The crude product is taken up in boiling absolute ethanol (250 ml), treated with activated carbon, filtered and concentrated down on a steam bath to a volume of ~75 ml. After cooling, tan-colored precipitates are filtered off and dried in a vacuum oven at room temperature for 4 hours. Yield: 2.2 g, m.p. 198°-200°.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[O:17])[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CN(C)C=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:17])[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)c2ccc(OCC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution of 4′-hydroxy-4-methoxy-chalcone, 7 (15 g, 59 mmol) in dry dimethyl formamide (170 mL) was added 50% sodium hydride (5.6 g, 236 mmol) at 0-5° C. and after 30 minutes, excess of epichlorohydrin (13.8 mL, 177 mmol) was added and stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with chloroform. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness. The crude product was purified by column chromatography to afford 13. Yield 11 g (60%); mp 85-87° C.; MS (FAB) 311 (M++1); IR (KBr) 1655; 1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 2H), 7.77 (d, J=15.6 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.32 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.01 (dd, J=11.1 Hz, 5.7 Hz, 1H), 3.84 (s, 31H), 3.40-3.35 (m, 1H), 2.92 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.77 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:33])[CH2:3][N:4]([CH2:29][CH:30]([OH:32])[CH3:31])[C:5]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:1][CH:2]([CH3:33])[CH2:3][N:4]([CH2:29][CH:30]([O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH3:31])[C:5]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:8])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])(=[O:37])=[O:36]
Reactant: CC(O)CN(CC(C)O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Product: CC(CN(CC(C)OS(C)(=O)=O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-])OS(C)(=O)=O
Yield: 100 %

Procedure:
Reaction of 18 with MsCl as above gave 1-methyl-2-[{2-[(methylsulfonyl)oxy]propyl}-2,4-dinitro-6-({[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}carbonyl)anilino]ethyl methanesulfonate (19) (2.52 g, 100%): as a yellow foam; which was used directly for the next step.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]([N:28]([CH2:32][CH2:33][CH3:34])[C:29]([NH2:31])=[S:30])[CH2:25][O:26][CH3:27].C(N(CC)CC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:31]=[C:29]([N:28]([CH:24]([CH2:25][O:26][CH3:27])[C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:32][CH2:33][CH3:34])[S:30][C:2]=1[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(COC)c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(COC)c1ccc2ccccc2c1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
0.93 g of 2-bromo-1-(2,4-dichlorophenyl)propan-1-one, 1 g of N-(1-naphth-2-yl-2-methoxyethyl)-N-propyl-thiourea and 0.47 ml of triethylamine are dissolved in 20 ml of ethanol and the reaction mixture is heated for 3 hours at 70° C. The ethanol is removed by evaporation and then, successively, water is added, extraction is carried out with methylene chloride and the organic phases are washed, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a column of silica gel, using a 9/1 (v/v) cyclohexane/ethyl acetate mixture as eluent, to provide 0.9 g of the expected product, the hydrochloride of which is prepared; M.p.=50° C. 1H NMR (DMSO): 0.73 (m, 3H), 1.12-1.59 (m, 2H), 2.09 (s, 3H), 3.35 (s, 3H), 3.31-3.46 (m, 2H), 3.97-4.23 (m, 2H), 5.48-5.60 (m, 1H), 7.48-7.95 (m, 10H).
Reaction SMILES: CC(C)([O-])C.[K+].N[CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CO[CH:18](OC)[CH2:19][C:20]#[N:21].Cl>C(COC)OC>[F:12][C:11]([F:14])([F:13])[C:10](=[O:15])[CH:9]=[CH:8][CH:18]=[CH:19][C:20]#[N:21]
Reactant: COC(CC#N)OC
Reactant: NC=CC(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: N#CC=CC=CC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml of dimethoxyethane under N2 and the solution was cooled to 0° C. 4-Amino-1,1,1-trifluoro-3-buten-2-one, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min and then 60.3 g (0.525 mol) of 3,3-dimethoxypropionitrile were added dropwise. The mixture was then stirred at 30° C. for 3-4 h. The reaction mixture was added to ice and acidified to pH 3-4 using HCl. The precipitate was filtered off and washed with water. 71 g of product (75%), mp: 123-126° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I-:15].[Na+]>C(C(C)=O)C>[CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(C)CCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)CC(C)(C)CCCCI

Procedure:
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87°C. (0.18 Torr).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[Cl:35][CH2:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41]>C1COCC1>[Cl:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:41]
Reactant: O=C=NCCCCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 99 %

Procedure:
A solution of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 3-chloropropyl isocyanate (111 μL, 1.089 mmol) in THF (2.5 mL) was heated at 120° C. for 3 hr using microwave irradiation. The reaction mixture was concentrated in vacuo then subjected to flash chromatography eluting with a gradient of 25-100% EtOAc in cyclohexane to give the title compound (125 mg).
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:11])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[Na+].[OH:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][C:17]([O-:19])=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:19][C:17](=[O:18])[CH2:16][CH2:15][CH:14]([OH:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)=CCCC(C)=CCCl
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCC(O)CCC(=O)OCC=C(C)CCC=C(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
A mixture of 155 g 1-chloro-3,7-dimethyl-octa-2,6-diene, 202 g 4-hydroxy-undecanoic acid sodium salt and 5 g tetrabutylammoniumbromide in 800 ml of dimethylfornamide was heated to 50° C. After stirring for 24 hours, the mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with ether, washed with water, 2N HCl, saturated sodium bicarbonate and brine. The organic phase was dried and evaporated to dryness. The resulting yellow oil was purified by wipe film distillation to yield 96.6 g of a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:1]([NH:8][C:9]([NH:10][C@H:11]([C:12]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)NNCc1ccccc1

Procedure:
(L)-tert-Leucine (0.500 g, 3.81 mmol) was dissolved in dioxane (23 mL) and 2M NaOH (6.3 mL, 12.6 mmol) was added. After stirring for 10 min, phenylisocyanate (0.900 mL, 7.29 mmol) was added drop wise to yield a clear solution. The reaction mixture was stirred at room temperature for 18 h and then made acidic by addition of concentrated HCl and thereafter extracted with EtOAc. The organic phase was dried and evaporated to afford (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.36 g, 36% yield), which was analysed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.646 g, 2.44 mmol), EDAC (0.515 g, 2.67 mmol), HOBT (0.363 g, 2.69 mmol), NMM (0.300 mL, 2.73 mmol), benzylhydrazine×2HCl (0.528 g, 2.71 mmol) and Et3N (0.753 mL, 5.38 mmol). The product was filtered through a short silica column (CHCl3/MeOH, 100:0-95:5) and then used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].Cl[CH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:40][CH:41]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Reactant: O=C(NCc1ccccn1)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCc1ccccn1)c1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
8-(2-nitrobenzenesulfonyl)amino-5,6,7,8-tetrahydroquinoline (402 mg, 1.20 mmol), 4-Chloromethyl-N-pyridin-2-ylmethyl-benzamide (314 mg, 1.20 mmol), and K2CO3 (498 mg, 3.60 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 50% ethyl acetate in CH2Cl2, afforded the title compound (603 mg, 90%) as white foam. 1H NMR (CDCl3) δ 1.56-1.61 (m, 1H), 1.74-2.05 (m, 2H), 2.32-2.36 (m, 1H), 2.58-2.64 (m, 2H), 3.95 (d, 1H, J=16.2 Hz), 4.74 (d, 2H, J=4.5 Hz), 4.85 (d, 1H, J=15.9 Hz), 5.30 (dd, 1H, J=11.1, 17.4 Hz), 7.05 (dd, 1H, J=4.5, 7.5 Hz), 7.22-7.29 (m, 2H), 7.34 (dd, 2H, J=7.5, 7.8 Hz), 7.48-7.73 (m, 8H), 8.12-8.15 (m, 1H), 8.20-8.24 (m, 1H), 8.45-8.59 (m, 1H); ES-MS m/z 558.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=O)[CH:4]([CH2:7][Br:8])[CH2:5][Br:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:6][CH2:5][CH:4]([CH2:7][Br:8])[CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: CN(C)C(=O)C(CBr)CBr
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CN(C)CC(CBr)CBr
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-3-bromo-2-(bromomethyl) proprionic amide (44 g) in CH2Cl2 (300 mL) was added DIBAL (450 mL, 1.0 M in toluene) at −40° C. over 30 minutes. The mixture was allowed to warm to −10° C. over 3 hours and the diluted with CH2Cl2 (1500 mL). The reaction was quenched with a mixture of water (300 mL) and methanol (100 mL) at −10° C., followed by stirring at a temperature less that 10° C. for 2 hours. The suspension was filtered, dried, and concentrated to ca. 300 mL. The product crystallized upon standing overnight at room temperature. The crystals were separated from the solution and dried (19 g, 66%). MS(M+1): 178.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH:14]([C:16]([OH:18])=[O:17])[CH3:15])[C:4]1=[O:19].[CH2:20]([CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[ClH:1].[C:16]([CH:14]([N:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][CH2:9][CH:3]([NH:2][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:4]1=[O:19])[CH3:15])([OH:18])=[O:17]
Reactant: CC(C(=O)O)N1C(=O)C(N)CCc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(C(C)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-(1-carboxyethyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride (3 g) and ethyl benzylpyruvate (6.5 g) in acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.8 g) in methanol (10 ml) was added over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Cencentrated hydrochloric acid (2 ml) was added and the mixture was stirred for 1 hour. The solvents were removed at reduced pressure and the residue was partitioned between water (50 ml) and ether (30 ml). The pH was adjusted to 9.4, the ether layer was separated and discarded. The aqueous solution was adjusted to pH 4.3 and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate solutions were dried over magnesium sulfate and the solvent removed under reduced pressure. Hydrogen chloride was bubbled into a solution of the crude product in methylene chloride (10 ml) for 2 minutes. The solution was evaporated to give 1-(1-carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride, as a mixture of diastereomers, m.p. 87°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: N#Cc1cc(CCl)ccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(C#N)c1
Temperature: 80 °C
Yield: 4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (600 mg, 2 mmol), (prepared as described for the starting material in Example 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 3 mmol) and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) was heated at 80° C. for 30 minutes. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane, the solid product collected by filtration and purified by column chromatography eluting with ethyl acetate and further chromatography eluting with methylene chloride/methanol (99/1). The purified product was recrystallised from ethyl acetate/hexane to give 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline (35 mg, 4%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[NH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(#N)C>[CH3:21][O:20][C:18]([CH2:17][N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:5][CH:4]=1)[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:19]
Reactant: ClCc1ccc(CCl)cc1
Reactant: COC(=O)CNCC(=O)OC
Solvent: CC#N
Product: COC(=O)CN(CC(=O)OC)Cc1ccc(CN(CC(=O)OC)CC(=O)OC)cc1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of α,α'-dichloro-p-xylene (87.5 g, 0.5 mol) in acetonitrile (300 ml) was added dimethyl iminodiacetate (328.7 g, 2.04 mols), and stirred at 65° to 70° C. for 8 hours. 250 ml of acetonitrile was added thereto, and crystals formed were removed by filtration, followed by concentrating the solution. After dissolving the residue in 600 ml of ethyl acetate, the solution was washed with water (400 ml×3), then concentrated. Recrystallization of the residue from a hexane-ethyl acetate mixture solvent gave the end product (170.0 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N+:27]([C:30]1[C:35]2=[N:36][O:37][N:38]=[C:34]2[C:33](N)=[CH:32][CH:31]=1)([O-:29])=[O:28].O>C1COCC1>[CH3:7][CH:5]([CH3:6])[CH2:4][C@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:2][NH:1][C:33]1[C:34]2=[N:38][O:37][N:36]=[C:35]2[C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1ccc([N+](=O)[O-])c2nonc12
Reactant: CC(C)C[C@@H](CN)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](CNc1ccc([N+](=O)[O-])c2nonc12)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-aminomethyl-3-methyl-butyl)-amide (30 mg, 83.2 μmol) in THF (555 μl) was added 7-nitro-2,1,3-benzoxadiazol-4-amine (CAN 10199-91-4, 19.9 mg, 100 μmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring at reflux temperature for 2 hours. After cooling to room temperature the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine; and the aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The black, solid residue was purified by flash chromatography (basic silica gel, 10 g, 0% to 100% ethyl acetate in a 1:1 mixture of dichloromethane and heptane) to give the title compound (25 mg, 57%) as brown solid; LC-MS (UV peak area/ESI) 100%, 524.2609 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.S(Cl)([Cl:15])=O>>[S:1]1[C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2s1
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
1.0 g of benzo[b]thiophene-2-carboxylic acid was reacted with 2 ml of thionyl chloride under reflux overnight, and then excess thionyl chloride was distilled off under reduced pressure to obtain benzo[b]thiophene-2-carbonyl chloride as a solid product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:3][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Oc3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The compound (500 mg) prepared in Step 1, N-Boc-piperazine (500 mg) and tassium carbonate (2.0 g) were dissolved in dimethylformamide (3 ml), and stirred at 90° C. for 2 hours. The dimethylformamide of the mixed solution was removed by distillation under reduced pressure, and extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, and water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The solvent-removed mixture was purified by column chromatography to obtain a yellow target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:2]=1
Reactant: NCc1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCc1cccnc1
Yield: 102.9 %

Procedure:
Prepared according to Plater et al. Org. Biomol. Chem. 2009, 7, 1633. To a solution of pyridin-3-ylmethanamine (9.42 ml, 92 mmol) in water (103 ml) at 10° C. was added acetic anhydride (10.47 ml, 111 mmol), stirred at a rate where the internal temperature did not rise above 25° C. After an additional 18 h of stirring, the solution was concentrated in vacuo then co-evaporated with toluene (3×) to afford the title compound (14.22 g, quantitative) as a clear oil. LCMS: Rt=0.12 min, m/z=151.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.4 Hz, 2H) 7.65 (dd, J=7.8, 1.6 Hz, 1H) 7.30-7.24-(m, 1H) 6.59-6.49 (m, 1H) 4.43 (d, J=6.0 Hz, 2H) 2.02 (s, 3H).