Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][N:3]=1.ClC1C2C(=CC=C(C(O)=O)C=2)C(=O)NN=1.S(Cl)(Cl)=O.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41].[H-].[Na+]>O.CN(C=O)C>[F:35][C:36]([F:45])([F:46])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH:41][C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Cl:1])=[N:3][NH:4][C:5]2=[O:15])=[O:14]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2c(Cl)n[nH]c(=O)c2c1
Agent: O=C(O)c1ccc2c(=O)[nH]nc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (311 mg, 1.385 mmol), catalytic DMF and thionyl chloride (7 mL) was refluxed for 3 hours. The solution was cooled, concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (3 mL) and added dropwise to a 0° C. solution of 3-(trifluoromethyl)benzylamine (0.22 mL, 1.524 mmol), DMF (5 mL) and 60% NaH (199 mg, 8.31 mmol). The reaction was stirred at room temperature overnight, diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, brine and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide (30 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 4.62 (d, 2H), 7.65 (m, 4H), 8.10 (d, 1H), 8.47 (dd, 1H), 8.80 (d, 1H), 9.65 (t, 1H), 12.99 (s, 1H) ppm; m/z (M+1) 382.17; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide (33 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 4.63 (d, 2H), 7.65 (m, 4H), 8.38 (m, 2H), 8.46 (s, 1H), 9.63 (t, 1H), 12.98 (s, 1H) ppm; m/z (M+1) 382.24.
Reaction SMILES: [NH3:1].[CH2:2]([CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])[CH:3]=[CH2:4]>COCCOC>[OH:7][CH2:8][CH2:9][CH:5]([C:6]([NH2:1])=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC1CCOC1=O
Reactant: N
Solvent: COCCOC
Product: C=CCC(CCO)C(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In an amount of 112 mg of 3-allyldihydrofuran-2-one (WO99/36419) was dissolved in 1 ml of 1,2-dimethoxyethane, added with 1.2 ml of 28% aqueous ammonia, and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain 130 mg of 1-(2-hydroxyethyl)-3-butenecarboxamide. Physicochemical Properties of this Compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2ccn(-c3cccc(Cl)c3)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccn(-c3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.2 %

Procedure:
A mixture of the product of Step 1 (0.1 g) and LiOH (3 mL, 1N) in 15 mL of 1:1:1 THF/MeOH/H2O was stirred for two days at room temperature and heated at 55° C. for 20 h. The mixture was cooled and treated with 5 mL of 1N HCl, followed by extraction with 30 mL of EtOAc. The EtOAc extract was dried over Na2SO4, filtered and concentrated to give the crude product (0.1 g) which was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]2[C:4]=1[C:5](=N)[NH:6][C:7]2=[NH:16].[ClH:18].[CH2:19]([CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][CH2:28][C:29](=[NH:31])[N:30]=2)[CH2:22]1)[CH3:20].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH:16]=[C:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:9]=2[O:14][CH3:15])[C:5](=[C:28]2[S:27][C:26]([N:23]3[CH2:24][CH2:25][CH:21]([CH2:19][CH3:20])[CH2:22]3)=[N:30][C:29]2=[NH:31])[NH:6]1
Reactant: COc1cc(OC)c2c(c1OC)C(=N)NC2=N
Reactant: CCC1CCN(C2=NC(=N)CS2)C1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCC1CCN(C2=NC(=N)C(=C3NC(=N)c4c(OC)cc(OC)c(OC)c43)S2)C1

Procedure:
When equivalent amounts of 4,5,7-trimethoxy-1,3-diiminoisoindoline and 2-(3-ethylpyrrolidino)-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part C above, there is obtained as the product 1-imino-4,5,7-trimethoxy-3-[2-(3-ethylpyrrolidino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([Cl:18])[N:5]=2.[F-].[Cs+].[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[CH:22]1>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[NH:3]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(-c3cccc4[nH]ccc34)nc12
Yield: 63.7 %

Procedure:
In a sealed tube, to a solution of 8-bromo-2-chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (495 mg, 1.49 mmol) in CH3CN/H2O (11/1.1 mL) was added cesium fluoride (452 mg, 2.98 mmol), indole-4-boronic acid (266 mg, 1.64 mmol), and tetrakis(triphenylphosphine)palladium (172 mg, 0.15 mmol). Then the reaction was conducted under microwave irradiation at 160° C. for 30 min. The solvents were removed under reduced pressure and the crude was purified by flash column chromatography (20-100% EtOAc/cyclohexane gradient) to provide 2-chloro-8-(1H-indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (350 mg, 63.8%) as a pale yellow solid. LC-MS at 254 nm; [M+H] 369.2; Rt 1.00 min; (LCMS method 1). (400 MHz, DMSO-d6): 13.59 (s, 1H), 11.41 (s, 1H), 7.73 (dd, 1H), 7.58-7.49 (m, 2H), 7.38-7.20 (m, 2H), 5.14 (s, 1H), 4.05-4.01 (m, 1H), 3.79-3.88 (m, 1H), 3.69-3.79 (m, 1H), 3.57 (s, 1H), 3.60 (s, 1H), 1.41 (d, 3H)
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].C([N:15](CC)CC)C.[Cl:20][C:21]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:22]=1[CH2:23][N:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[S:27](=[O:35])(=[O:34])[N:26]([C:36]2[CH:41]=CC(=O)[N:38]([CH3:43])[CH:37]=2)[C:25]1=[O:44]>>[Cl:20][C:21]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:22]=1[CH2:23][N:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[S:27](=[O:35])(=[O:34])[N:26]([C:36]2[CH:41]=[N:15][C:43]([O:2][CH3:1])=[N:38][CH:37]=2)[C:25]1=[O:44]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Reactant: Cn1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)ccc1=O
Product: COc1ncc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cn1

Procedure:
The title compound (40 mg, 0.09 mmol) was prepared from (IntB2) (106 mg), 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) and triethylamine (0.07 mL, 0.50 mmol) using the methods of (132).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26]O[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1.FC1C=C(N)C=CC=1O[C:51]1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:52]([CH3:51])[CH2:26][CH2:27]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Yield: 46 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (60 mg, 0.15 mmol) was converted the title compound (30 mg, 46%) as a 2.HCl salt. 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.37 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 7.16 (m, 2H), 4.42 (br s, 2H), 3.38-3.60 (m, 10H), 2.81 (s, 3H), 2.40 (s, 3H); ).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)cc1
Yield: 107.8 %

Procedure:
In xylene (10 mL), 2-chlorobenzoxazole (1.00 g, 6.51 mmol) and ethyl 4-aminophenylacetate (1.67 g, 6.51 mmol) were heated and refluxed for 10 hours. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, ethyl 4-(2-benzoxazolylamino)phenylacetate (2.08 g, 99%) was obtained as a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([N:5]([CH2:4][C:3]([F:14])([F:2])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])[CH3:6])(=[O:30])=[O:29]
Reactant: CNCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)CCCCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
500 mg of N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylamine hydrochloride (obtained according to European Patent No. 384,842 Example 75) and then, at 0° to 5° C., 0.55 ml of triethylamine were added to a solution of 200 mg of 5-chloropentane sulfonyl chloride in 5 ml of methylene chloride, and the mixture was stirred at ambient temperature for 2 hours. Water was added and extraction was carried out with methylene chloride. The extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 378 mg of the expected product.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][NH:36]2>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][NH:36]3)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cnc23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DIPEA (0.335 mL, 1.92 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (200 mg, 0.64 mmol) and 6-chloro-9H-purine (99 mg, 0.64 mmol) in butan-1-ol (4 mL). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(9H-purin-6-yl)piperidine-4-carboxamide (141 mg, 51.1%) as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)=[O:26].[OH:38][CH:39]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=1)=O.CN(C1C=CC=CN=1)C>CN(C)C=O.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH:40]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][CH3:49])=[CH:46][CH:47]=2)[C:39](=[O:38])[C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[O:36])[CH2:30][CH2:29]1)=[O:26]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(=O)O)CC1
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)C(OC(=O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (DCC; 0.81 g, 3.92 mmol) was added in one portion to a rapidly-stirred mixture of 4-[[[(2,6-dimethylphenyl)amino]carbonyl]methyl]-1-piperazineacetic acid (1.0 g, 3.27 mmol), 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 0.88 g, 3.27 mmol) and dimethylaminopyridine (DMAP: 40 mg) in anhydrous dimethylformamide (25 mL). After 2 hours at ambient temperature, an additional equivalent of DCC and DMAP were added. The mixture was stirred further for 22 hours at room temperature before it was heated to 70° C. for 6 hours. Upon cooling, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 50% ethyl acetate in hexanes followed by ethyl acetate) afforded 0.50 g of the benzoin ester product (VI) as an off-white solid. The ester was used in subsequent reactions without additional purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31](S(C)(=O)=O)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31]([NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:15]=3)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N4CCNCC4)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(3-amino-phenyl)-piper-azine-1-carboxylic acid tert-butyl ester (from the previous step, 54 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example, 1(e) above, 80 mg, 0.19 mmol). A yellow solid was obtained (60 mg, 62%) after a preparative HPLC (32 mL/min 5-100% MeCN/H2O gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2Cl2 (1:1 v/v) to give the title compound. 1H NMR (400 MHz, CDCl3/CD3OD 10:1 v/v) δ (ppm): 9.26 (br, 1H), 8.49 (s, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.20 (s, 1H), 7.11 (11, 2H), 6.78 (br, 2H), 6.54 (m, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.98 (m, 4H), 2.29 (m, 4H), 2.96 (m, 4H), 2.14 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:5]=2[C:4](=[O:16])[NH:3]1.CC1NC2C=CC=C([N+]([O-])=O)[C:22]=2[C:21](=[O:32])NC1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>ClCCl>[C:21]([N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:5]=2[C:4](=[O:16])[NH:3][CH:2]([CH3:1])[CH2:8]1)(=[O:32])[CH3:22]
Reactant: CC1CNC(=O)c2c(cccc2[N+](=O)[O-])N1
Reactant: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CC(C)NC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (350 mg, 1.58 mmol) was dissolved in dichloromethane (5 mL) and the solution was treated with diisopropylethylamine (0.330 mL, 1.89 mmol) and trifluoroacetic anhydride (332 mg, 1.58 mmol). The reactions were allowed to stir overnight at room temperature for approximately 3 hours. The mixture was then poured over saturated NH4Cl (30 mL) and extracted with dichloromethane (3×15 mL). Combined organic extracts were dried over Na2SO4, filtered and reduced. The crude product was then isolated and purified by flash column chromatography (0% ethyl acetate/hexanes—75% ethyl acetate hexanes) to afford 370 mg of 1-Acetyl-3-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 1-Acetyl-2-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow oil. 229c) 1-Acetyl-6-amino-3-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 1-Acetyl-6-amino-2-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one. 1-Acetyl-3-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 1-Acetyl-2-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (370 mg, 1.17 mmol) was dissolved in ethanol (10 mL) and the solution was treated with Raney Nickel (50% slurry in water) (2 mL) and hydrazine hydrate (0.584 mL, 11.7 mmol). The reaction was then allowed to stir overnight at room temperature. Catalyst was removed by filtering the reaction mixture through a Celite pad and washing the pad with methanol (3×25 mL). The filtrate was dried over Na2SO4, filtered and reduced to afford 140 mg of 1-Acetyl-6-amino-3-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 1-Acetyl-6-amino-2-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a clear oil. The crude mixture was used without further purification.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:26])=[O:25]
Reactant: CCCCCCCCC=CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCCOS(C)(=O)=O

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 1-hydroxyoctadec-9-ene and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: O[Li].O.O.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:30])[CH3:28])[CH2:21][O:20][C:19]3[C:39]([C:43]([O:45]C)=[O:44])=[CH:40][CH:41]=[CH:42][C:18]1=3)=[C:11]([O:47][CH3:48])[CH:10]=[CH:9]2>CO>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:30])[CH3:28])[CH2:21][O:20][C:19]3[C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH:41]=[CH:42][C:18]1=3)=[C:11]([O:47][CH3:48])[CH:10]=[CH:9]2
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2cc(Br)ccc12
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 50 °C
Yield: 92 %

Procedure:
LiOH.H2O (31.3 mg, 746 μmol, Eq: 2.5) and H2O (1.00 mL) was added to a solution of (S)-methyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl (methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (200 mg, 298 μmol, Eq: 1.00) in MeOH (6.0 mL) and the mixture heated to 50° C. After 90 min. the mixture was concentrated, diluted with H2O and extracted with Et2O. The combined Et2O extracts were extracted with 5% NaHCO3. The combined aqueous mixture was acidified to pH 2.0 with 1 N HCl, extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated to afford the title compound (180 mg, 91%) as an off white foam which was used without purification.