Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[S:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[ClH:10].[Br:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[S:5][C:6]=1[S:7]([NH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:9])=[O:8]
Reactant: NCCN1CCOCC1
Reactant: NS(=O)(=O)c1cc(Br)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cl
Product: NS(=O)(=O)c1cc(Br)c(S(=O)(=O)NCCN2CCOCC2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Step A (2.3 g, 6.0 mmol) in THF (5 mL) was added dropwise to a cooled solution (0° C.) of triethylamine (1.5 g) and 4-(2-aminoethyl)-morpholine (1.95 g, 15 mmol) in THF (15 mL). The solution was stirred at 0° C. for 1 h and then was warmed to ambient temperature for an additional hour. The reaction mixture was concentrated, the residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried and concentrated to furnish the desired product as a white solid. The material was dissolved in ethanol and treated with ethanolic HCl and the resultant solid was isolated by filtration and dried. The desired product was obtained as a white solid: mp 180°-182° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: FC(F)(F)Sc1ccc(OCCCI)c(Cl)c1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Product: CCC1(C(=O)O)Cc2cc(OCCCOc3ccc(SC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the phenol prepared in Example 4, Step 1 and the iodide prepared in Step 2.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([O-:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O.N[CH:28]1[CH:32]([CH3:33])[S:31][S:30][CH:29]1[CH3:34]>O.O1CCCC1>[CH3:34][CH:29]1[CH:28]([N:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[C@@H:2]([C:3]([OH:5])=[O:4])[CH3:1])[CH:32]([CH3:33])[S:31][S:30]1
Reactant: CC1SSC(C)C1N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1SSC(C)C1N(C(=O)OC(C)(C)C)[C@H](C)C(=O)O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Under anhydrous conditions, to a mixture of 1.7 g (8.9 mmole) of N-t-Boc-D-alanine obtained in Part A, 1.98 g (19 mmole) triethylamine and 40 ml of tetrahydrofuran, cooled to -10° C. is added dropwise 0.96 g (8.9 mmole) ethyl chloroformate and the resulting mixture is stirred at this temperature for 20 minutes. To this is added 1.1 g (7.5 mmole) of mixed cis- and trans-isomers of 4-amino-3,5-dimethyl-1,2-dithiolane and the resulting mixture is stirred at -10° C. for 10 minutes, then allowed to warm to room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dilute hydrochloric acid, water, brine, then dried (Na2SO4) and the solvent is evaporated at reduced pressure to obtain the desired product which is used in the next step.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29](=O)[C:28]4[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=4[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[NH2:42][NH2:43]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29]4=[N:42][NH:43][C:31](=[O:33])[C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=54)[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1ccncc1)N2
Solvent: CO
Solvent: O
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
A mixture of methyl 3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg, 0.26 mmol) in 85% hydrazine monohydrate (10 mL) and methanol (3 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give compound 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield 8%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.11-1.13 (m, 6H), 2.95-2.98 (m, 1 H), 3.26-3.68 (m, 8H), 4.40-4.42 (d, J=8.4 Hz, 1H), 4.82-4.84 (d, J=8.4 Hz, 1H), 7.19-7.32 (m, 4H), 7.36-7.39 (m, 3H), 7.59-7.68 (m, 2H), 8.41-8.42 (d, J=6.0 Hz, 2H); LC-MS (ESI) m/z: 523 (M+1)+.
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
7-Fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-193) (230 mg, 0.68 mmol) was dissolved in DMSO (5 ml), then triethylamine (195 μl, 1.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (181 μl, 1.43 mmol) were added, followed by stirring at 150° C. for 4 hours. After cooling, concentration under reduced pressure, dilution with ethyl acetate and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (32 mg, 11%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1)(=[O:30])=[O:31]
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-naphthalene-sulfonyl chloride (79.8 mg; 0.41 mmol) to obtain 50.0 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.31 (br s, 1H), 8.23 (m, 2H), 8.13 (m, 1H), 7.84 (m, 1H), 7.77 (m, 2H), 7.37 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.83 (m, 2H), 5.90 (br s, 2H), 3.82 (br d, J=11.2 Hz, 2H), 3.11 (br d, J=12.0 Hz, 2H), 2.87 (m, 2H), 2.64 (m, 2H). ESIMS+436.0 m/z
Reaction SMILES: C(OC([N:11]1[CH:23]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.Br.CCOCC>C(O)(=O)C>[NH:28]1[C:24]([CH:23]2[CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][NH:11]2)=[N:25][N:26]=[N:27]1
Reactant: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2CC1c1nnn[nH]1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: c1ccc2c3c([nH]c2c1)CNC(c1nnn[nH]1)C3
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3RS)-2-Benzyloxycarbonyl-3-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-β-carboline (0.3 g) is dissolved in acetic acid (1 ml) and thereto is added dropwise a 25% solution of HBr in acetic acid (2 ml). The mixture is stirred at room temperature for 20 minutes, and thereto is added ether. The precipitates are collected by filtration, washed with ether and dried to give the title compound (0.257 g, quantitatively) as pale yellow powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1CCC[C:16](=O)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH2:16][C:3](=[CH2:4])[CH2:2][CH2:1]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1 g methyltriphenylphosphoniumbromide (MW: 357.22, 2.79 mmol) in 20 ml of tetrahydrofuran was treated at −78° C. with 1.22 ml of a 2.3 M n-butyl lithium solution in N-hexane (2.8 mmol). The reaction mixture was stirred at −78° C. for ten minutes, then at 0° C. for one hour. The yellow suspension was cooled to −78° C. and treated with a solution of 595 mg 4-oxo-azepane-1-carboxylic acid tert-butyl ester (WO 2000044376) (MW: 213.279, 2.78 mmol) in 10 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for one and half hour. The reaction mixture was quenched with 30 ml of a saturated aqueous solution of ammonium chloride, diluted with 30 ml of ethyl acetate. The organic layer was successively washed with 30 ml water and 30 ml brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography over silica. (cyclohexane:ethyl acetate 1:1). Yield: 487 mg, 83%. NMR (CDCl3): 1.35 ppm (s, 9H, tert-but.); 1.6 ppm (m, 2H, —CH2—), 2.14 ppm (m, 2H), 2.33 ppm (m, 2H); 3.29 ppm (m, 4H, N-—(CH2); 4.67 ppm (m, 2H, vinyl-CH2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](O)=O)[CH:7]=1)[CH3:2].Cl.[NH2:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[SH:27]>>[Cl:25][C:24]1[C:19]2[N:18]=[C:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:11]=[CH:10][CH:9]=3)[S:27][C:20]=2[CH:21]=[CH:22][C:23]=1[Cl:26]
Reactant: Nc1c(S)ccc(Cl)c1Cl
Reactant: CCOC(=O)Cc1cccc(CC(=O)O)c1
Agent: Cl
Product: CCOC(=O)Cc1cccc(Cc2nc3c(Cl)c(Cl)ccc3s2)c1
Yield: 56.3 %

Procedure:
The procedure of Example 16-i) was repeated using 1,3-phenylene diacetic acid monoethyl ester (847 mg, 3.3 mmol) and 2-amino-3,4-dichlorothiophenol hydrochloride (831 mg, 4.3 mmol) to obtain ethyl 3-[(4,5-dichlorobenzothiazol-2-yl)methyl]phenylacetate (706 mg, 56%) as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26]O)=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:28]1[C:29](=[O:57])[N:30](COCC[Si](C)(C)C)[CH:31]=[C:32]([NH:34][C:35]([C:37]2[CH:38]=[N:39][N:40]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:41]=2)=[O:36])[CH:33]=1)=O)(C)(C)C.CS(Cl)(=O)=O.[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[NH:65]1>ClCCCl.C(OCC)(=O)C>[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[N:65]1[CH2:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][C:18]([C:28]1[C:29](=[O:57])[NH:30][CH:31]=[C:32]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:41]=3)=[O:36])[CH:33]=1)=[CH:19]2
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(NC(=O)c3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2cc(CO)ccc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc2[nH]c(-c3cc(NC(=O)c4cnn(Cc5ccccc5)c4)c[nH]c3=O)cc2c1
Temperature: 0 °C

Procedure:
The title compound was prepared by the route outlined in Scheme 8, following the same experimental procedures as for Example 51, with the following modification. Deprotection of intermediate (8e), 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, in the usual manner, yielded 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester. DIPEA (153 μL, 0.9 mmol) and 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (0.2 g, 0.3 mmol) were stirred in 1,2-dichloroethane (5 mL) and cooled to 0° C. Methanesulfonyl chloride (27 μL, 0.36 mmol) was added drop wise at 0° C. and stirred for a further 2 hours at 0° C. cis-2,6-Dimethylpiperidine (118 μL 0.9 mmol) was added drop wise at 0° C. and then the reaction was allowed to attain ambient temperature. The reaction mixture was heated at reflux overnight followed by cooling to ambient temperature. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was taken up in methanol (1 mL) and loaded onto a 5 g SCX column. The column was flushed with methanol and then eluted with ammonia solution 7N in methanol. The eluent was concentrated in vacuo to afford the title compound as a light brown solid, 120 mg, 53%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O=[C:18]1[CH2:25][CH:24]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]([CH2:21][O:22][CH2:23]2)[CH2:19]1>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[C:18]1[CH2:19][CH:20]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]([CH2:23][O:22][CH2:21]2)[CH2:25]1)[CH3:4].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][C:18]1[CH2:19][CH:20]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]([CH2:23][O:22][CH2:21]2)[CH:25]=1)[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CC2COCC(C1)N2C(=O)OC(C)(C)C
Product: CCOC(=O)CC1=CC2COCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %
Yield: 30.8 %

Procedure:
To a suspension of sodium hydride (396 mg, 60% dispersion in mineral oil, 9.9 mmol) in dry THF (5 ml) was added 2-diethoxyphosphorylacetic acid ethyl ester (2.40 g, 10.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 10 mins, and then heated at 80° C. for 20 mins. The reaction mixture was cooled down to room temperature. To the reaction mixture was added a solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.00 g, 8.3 mmol) in dry THF (20 ml). The resulting mixture was stirred at 80° C. overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic phase was dried, concentrated and purified by silica gel chromatography to give tert-butyl 7-(2-ethoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 123b (1.20 g, 46.5%) and tert-butyl 7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate 123e (0.800 g, 30.8%). Compound 123b: 1H NMR (400 MHz, CDCl3): d=5.72-5.66 (m, 1H), 4.29-4.23 (m, 1H), 4.15 (d, J=7.3 Hz, 3H), 4.05-3.97 (m, 1H), 3.88-3.77 (m, 2H), 3.76-3.65 (m, 2H), 2.77-2.61 (m, 1H), 2.38 (d, J=15.3 Hz, 2H), 1.53-1.48 (m, 9H), 1.30-1.26 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Yield: 87.4 %

Procedure:
A solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (3.0 g, 10.52 mmol), 3-hydroxybenzaldehyde (1.41 g, 1.1 eq) and potassium carbonate (3.0 g, 3.0 eq) in a mixture of acetonitrile (CH3CN, 30 mL)/H2O (5 mL) was refluxed for 15 hours. After concentration in a vacuum to remove the reaction solvent, the residue was stirred in water (50 mL) and the aqueous layer was extracted twice with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. Purification by silica gel chromatography afforded (E)-methyl 2-(2((3-formylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (3.0 g, yield 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.CCN(C(C)C)C(C)C.Cl[C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C1C=CN=CC=1)C.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:2]=1[NH:1][C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCC(=O)Nc1ccc(I)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-amino-5-iodobenzoate (i-a) (15 g, 54 mmol) was added 200 mL of CH2Cl2, followed by DIEA (9.4 mL, 54 mmol) and a catalytic amount of DMAP. Ethyl 4-chloro-4-oxobutanoate (Rc═Rd═H) (8.5 mL, 60 mmol) was added, and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then poured into 250 mL H2O, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford ii-a (22 g, 99%) as a pale yellow solid: MS m/z=406 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([N:14]=[C:15]=[S:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:11]=[CH:12][CH:13]=1
Reactant: NCC(N)=O
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of glycinamide hydrochloride (6.1 g), 3-chloro-2-methylphenyl-isothiocyanate (10.1 g), triethyl amine (5.6 g), and chloroform (200 mL) was heated at reflux for 3 hours then cooled to ambient temperature. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide (12.5 g), m.p. 162°-164° C. (dec.). This compound was used without further purification for the preparation of the title compound of step 2.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[NH3:7].[NH2:8][C:9]1[N:10]=[N:11][C:12]([Br:15])=[CH:13][N:14]=1>>[NH2:8][C:9]1[N:10]=[N:11][C:12]([Br:15])=[C:13]([NH2:7])[N:14]=1
Reactant: Nc1ncc(Br)nn1
Reactant: N
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1nnc(Br)c(N)n1
Temperature: -33 °C

Procedure:
A solution of 6.0 grams (0.038 mole) of potassium permanganate in about 300 mL of liquid ammonia (-33° C.) is stirred, and 5.3 grams (0.030 mole) of 3-amino-6-bromo-1,2,4-triazine is added portionwise. Upon completion of addition, the reaction mixture is maintained at -33° C. for 15 minutes. Ammonia is then evaporated and the residue is extracted with about 150 mL of hot 1-methylethanol. The solution is concentrated under reduced pressure, yielding 3,5-diamino-6-bromo-1,2,4-triazine.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[O:19]=[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC1Oc2ccccc2NC1=O
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1Oc2ccc(C(=O)CCC(=O)O)cc2NC1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazine (11.4 g) and succinic anhydride (7 g) were added to 93 g of aluminum chloride and 15.3 ml of dimethylformamide. The mixture was stirred at 70° C. for 2.5 hours and then poured onto ice, giving a solid which was collected by filtration and washed with water. Drying under vacuum gave 16.5 g of the title compound (90% yield), mp 198°-200° C.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=O)[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].CCN(CC)CC>C(Cl)Cl>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([NH:37][CH2:35][CH3:36])=[O:20])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN
Reactant: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 0.037 g (0.08 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine and 0.06 mL (0.12 mmol) of ethylamine in 2 mL of CH2Cl2 at rt was added 0.031 g (0.12 mmol) of BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride, Aldrich) and 0.045 mL Et3N and the reaction mixture was stirred for 18 h. The reAction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.85-7.90 (m, 3H), 7.45-7.56 (m, 4H), 7.09-7.19 (m, 2H), 6.96-7.03 (m, 2H), 3.94-4.49 (m, 4H); Mass Spectrum (ESI) m/e=488 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[OH:22])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH3:23]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[NH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)c2cc(F)ccc2O)cc1OC
Reactant: N
Solvent: CO
Product: COc1ccc(CCC(=N)c2cc(F)ccc2O)cc1OC
Temperature: 60 °C
Yield: 32 %

Procedure:
A mixture of 1.72 g (5.6 mmol) 3-(3,4-dimethoxy-phenyl)-1-(5-fluoro-2-hydroxy-phenyl)-propan-1-one and 24 mL NH3 (7N) in methanol was heated to 60° C. for 16 h in a sealed tube. The mixture was concentrated and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 0.693 g (32%) of the title compound. MS (m/e): 304.1 (MH+).