Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ccc(Br)cc2N1
Reaction time: 16 h

Procedure:
To a solution of Example 112A (1.30 g, 4.23 mmol) in acetic acid (20 mL) was added N-bromosuccinimide (0.828, 4.65 mmol). The reaction stirred for 16 hours. The reaction solution was concentrated, then partitioned between NaOH (1 M) and dichloromethane. The dichloromethane layer was separated and concentrated onto silica gel. Purification via flash chromatography (30-100% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.22-7.38 (m, 6 H), 7.07 (d, J=2.37 Hz, 1 H), 7.01 (d, J=8.81 Hz, 1 H), 3.50-3.58 (m, 2 H), 3.24-3.30 (m, 1 H), 3.05-3.17 (m, 1 H), 2.91-3.01 (m, 1 H), 2.71-2.86 (m, 2 H), 2.52-2.61 (m, 1 H), 2.05-2.25 (m, 2 H), 1.90 (d, J=13.22 Hz, 1 H); MS (APCI+) m/z 386, 388 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:34]=[CH:33][CH:32]=[CH:31][C:9]=1[C:10](=[O:30])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:25]([O:27]CC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:8]1[CH:34]=[CH:33][CH:32]=[CH:31][C:9]=1[C:10](=[O:30])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:25]([OH:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1Cc1ccccc1
Temperature: 60 °C
Yield: 93.9 %

Procedure:
Dissolve 3-[(2-benzylphenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (200 mg, 0.41 mmol) in tetrahydrofuran (3 mL) and add water (3 mL). Add lithium hydroxide monohydrate (1.2 mmol) and heat at 60° C. overnight. Add addition lithium hydroxide monohydrate (1.2 mmol) and heat at 60° C. for 5 hours. Allow some of the tetrahydrofuran to evaporate and add methanol to form a homogeneous solution. Heat for 3 days, adding additional lithium hydroxide monohydrate (2.4 mmol). Dilute with water and filter. Acidify, extract into ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound as a white powder (180 mg, 97%); mp 280°-83° C.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:53])[NH:7][C@@H:8]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[C:19]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[CH:18]=2)[CH2:13][C@H:12]1[C:34]([NH:36][C@@H:37]([CH2:46][CH2:47][CH3:48])[C@H:38]([OH:45])[C:39]([NH:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:35])=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([NH:5][C:6](=[O:53])[NH:7][C@@H:8]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[C:19]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[CH:18]=2)[CH2:13][C@H:12]1[C:34]([NH:36][C@@H:37]([CH2:46][CH2:47][CH3:48])[C:38](=[O:45])[C:39]([NH:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:35])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide (2.0 g, 2.72 mmol) in methylene chloride (10 mL) was added the Dess-Martin Periodinane reagent (2.29 g, 5.44 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC analysis. Upon completion the reaction mixture was diluted with water (100 mL) and the organic layer was separated. The aqueous layer was washed with methylene chloride (2×30 mL), and the combined organic layers were washed with saturated sodium bisulfite (20 mL) followed by sodium bicarbonate solution (20 mL), and dried over sodium sulfate. The solution was filtered, the filtrate concentrated under reduced pressure, and the resulting residue was stirred with hexane (10 mL). The solid was filtered and dried to provide 1.75 g (87.8%) of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide as white solid (HPLC purity: 97.3% by area; HPLC retention time: 22.58 minutes).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[NH:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C([O:30][CH:31]=[CH:32][C:33](OCC)=O)C>FC(F)(F)C(O)=O>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[C:6]([OH:5])=[O:7])=[CH:15][CH:14]=2)[C:31](=[O:30])[CH:32]=[CH:33][N:23]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC=CC(=O)OCC
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nccc(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared form N-(2'-t-butoxycarbonylbiphen-4-yl)methylvaleramidine and ethyl 3-ethoxyacrylate (Aldrich) similarly to that in Example 10. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22](=[O:25])[NH:23][CH3:24])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>>[CH3:24][NH:23][C:22]([C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:3]=1)=[O:25]
Reactant: O=S([O-])c1ccccc1
Reactant: CNC(=O)c1cc(Br)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Agent: [Na+]
Product: CNC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Yield: 68 %

Procedure:
The product of step A and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 1:4 dichloromethane/ethyl acetate) provided tert-butyl 6-(methylcarbamoyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (41 mg, 68%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J=7.2 Hz, 2H), 7.59-7.44 (m, 3H), 7.28 (s, 1H), 4.59 (s, 2H), 3.87 (t, J=5.2 Hz, 2H), 3.10 (d, J=4.8 Hz, 3H), 3.00-2.88 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][NH:22][C:23](=[O:34])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:16]1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][NH:22][C:23](=[O:34])[N:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:7])[CH2:16]1
Reactant: CNc1ccc(F)cc1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CN(C(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)c1ccc(F)cc1
Temperature: 110 °C

Procedure:
4-Fluoro-N-methylaniline (0.007 ml) was added to a solution of Intermediate 10 (0.025 g) in anhydrous pyridine (1 ml). The mixture was heated at 110° C. in a thick walled glass vial (Reactivial) for 20 h. The mixture was evaporated to remove the pyridine, and partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The organic layer was washed with further sodium bicarbonate (10 ml×5), brine (10 ml), dried (MgSO4), concentrated in vacuo. The residue was purified by chromatography on silica gel (Trikonex flash tube 2002, 2 g), eluting with 70% ethyl acetate in cyclohexane to give the title compound as a pale yellow gum 0.014 g. LCMS (system A) Rt 2.52 min, Mass Spectrum m/z 426 [MH+].
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)C=C.C(N(CC)[C:20]1[CH:25]=CC=C[CH:21]=1)C>>[CH2:25]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:15])[CH:10]=[C:9]2[CH3:16])[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Yield: 65 %

Procedure:
Crude 7-allyloxy-4-methylcoumarin (83.5 g, 0.381 mol) was dissolved in 250 ml of diethyl aniline with heating, and the solution was allowed to reflux for two hours. After the solution had cooled and some product had precipitated, petroleum ether (b.p. 30°-60° C., 760 ml) was added. A brown precipitate formed and was collected by filtration, washed with three small portions of petroleum ether, and dried in vacuo to obtain the crude product. Recrystallization from 600 ml of 95% EtOH gave the pure product (53.5 g, 74% recovery, 65% yield) of mp 192.5°-195.0° C. (lit. 193°-194° C.). TLC showed only a single spot.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCCCC4=O)cc3OC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CCCCN1c1ccc2c(c1)OC[C@H]1[C@H](CO)OC(=O)N21
Yield: 85.7 %

Procedure:
Using compound (3R,3aS)-3-(((t-butyldimethylsilyl)oxy)methyl)-7-(2-oxopiperidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (1.016 g, 2.352 mmol), and tetra-n-butylammonium fluoride (1M, 4.7 ml) as starting materials, preparation following the method as described in Example 1(b) afforded 0.642 g white solid, yield 85.8%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:32][CH2:33][OH:34]>>[OH:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[CH2:32][CH2:33][OH:34]
Reactant: Nc1ccc(CN(CCO)CCO)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(CCO)CCO)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((di-(2-hydroxy-ethyl)-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H29N3O5
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH2:19].O>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 18 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (1 g, 7.3 mmol) in EtOH (10 mL) was added Na2CO3 (1.3 g, 12.3 mmol) and MeNH2 at 18° C. The mixture was stirred for 16 hours at 18° C. after which TLC analysis showed the reaction was complete. The reaction mixture was then concentrated to get the crude material which was treated with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to get yield the crude product which was purified by crystallized with ethanol to give the desired product (780 mg, 55.7%) as a yellow solid. LCMS (m/z): 188.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29]Br)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(C(=O)CBr)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C(=O)CN2CCOCC2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Triphenylphosphine (110 mg, 0.42 mmol) in dichloromethane (1 mL) was added slowly to an ice cooled solution of 5-(2-butoxy-5-glycoloyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 33) (150 mg, 0.35 mmol) and carbon tetrabromide (140 mg, 0.42 mmol) in dichloromethane (3 mL). The solution was allowed to warm to room temperature. After 2 h further carbon tetrabromide (25 mg, 0.075 mmol) and triphenylphosphine were added and stirring continued for 2 h. Concentration and purification of the product by flash column chromatography (gradient elution with ethyl acetate/pentane (10:90-70:30) gave 5-[2-butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one which was used without any further purification (slight contamination with triphenylphosphine oxide). 5-[2-Butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (205 mg, 0.42 mmol) was dissolved in dichloromethane and the solution cooled to 0° C. Morpholine (54 mg, 0.62 mmol) and triethylamine (84 mg, 0.83 mmol) were added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution 20% ethyl acetate/pentane:100% ethyl acetate:3% methanol/methyl acetate) gave 70 mg product.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[N:34]=[C:35]=[O:36]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:34]([C:27]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=3[O:25][CH3:24])[C:35]2=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1ccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c(OC)c1
Yield: 55.9 %

Procedure:
1-Cyclopentyl-3-(2,4-dimethoxy-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and 2,4-dimethoxyphenyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 448 [M+1]+.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=O)[CH3:2].[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]C=C.Cl>CO.CCOC(C)=O>[CH2:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCBr
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCCCCSC[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.62 g (10 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 20 ml MeOH is treated with 7.5 ml 4N NaOH and 1.63 g (10 mmol) 6-bromo-hex-1-ene. After being stirred for 1 h at rt the mixture is diluted with 50 ml EtOAc and acidified with 25 ml 1N HCl. The organic phase is washed with brine, dried with sodium sulfate and concentrated in vacuo to yield (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid as an oil which is used without purification for the next step.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[CH2:21]([O:20][C:18]([NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([OH:9])=[O:8])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-D-Orn-OH (0.50 g, 2.2 mmol) in aqueous NaOH (1M, 5 mL) at 0° C. was added benzyl chloroformate (0.37 mL, 2.6 mmol, 1.2 equiv) followed by aqueous NaOH (1M, 5 mL). After stirring for 2 hours at room temperature, the reaction mixture was poured to separatory funnel and extracted with ether. The aqueous layer was acidified to pH 3 with aqueous 10% citric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.2.1a (0.57 g, 72%) which was used for the next step without further purification. MS m/z (M+Na) 389.2. 1H NMR (400 MHz, DMSO-d6) 12.37 (br-s, 1H), 7.35-7.25 (m, 5H), 7.20 (t, J=5.31 Hz, 1H), 7.01 (d, J=8.02 Hz, 1H), 4.97 (s, 2H), 3.83-3.77 (m, 1H), 2.94 (dd, 2H), 1.67-1.56 (m, 1H), 1.53-1.37 (m, 3H), 1.34 (s, 9H).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:39]=[CH:38][C:37](=[O:40])[C:36]([C:41]([NH2:43])=[O:42])=[CH:35]1)(=O)C1C=CC=CC=1>N>[C@H:11]1([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[C:36]([C:41]([NH2:43])=[O:42])=[CH:35]2)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: NC(=O)c1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)ccc1=O
Agent: N
Product: NC(=O)c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)ccc1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
Compound 33 (0.5 g, 0.86 mmol) was dissolved in dry methanolic ammonia (50 mL) and stirred for 15 h in a bomb at room temperature. The solution is then concentrated to a small volume and cooled overnight at 4° C. The crystalline product formed was filtered off, washed with cold methanol. The solid was recyrstallized from absolute ethanol to give 0.23 g (87%) of pure product: mp 209-211° C.; 1H NMR (Me2SO-d6) δ 3.60 (m, 2H, C5'H), 3.93 (m, 1H, C4'H), 4.09 (m, 1H, C3'H), 4.34 (m, 1H, C2'H), 5.11 (m, 1H, C5'OH, D2O exchangeable), 5.22 and 5.47 (2m, 2H, C2',3' OH, D2O exchangeable), 5.84 (d, 1H, J1',2' =6.3 Hz, C1'H), 7.21 (m, 2H, PhH), 7.64 (m, 2H, PhH and CONH2) and 8.44 (s, 1H, CONH2). Anal. Calc. for C11H14N2O6 (270.24): C, 48.89; H, 5.22; N,10.37. Found: C, 48.89; H, 5.42; N, 10.51.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17](Br)=[C:16]([N:19](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:15]3[N:36]=[CH:37][C:38]([C:39]4[CH:40]=[N:41][C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[C:14]3[N:13]=2)[CH2:8][CH2:7]1)C.[Sn]([C:63]#[N:64])(CCCC)(CCCC)CCCC.Cl>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:19][C:16]1[N:15]2[N:36]=[CH:37][C:38]([C:39]3[CH:40]=[N:41][C:42]4[C:47]([CH:48]=3)=[CH:46][CH:45]=[CH:44][CH:43]=4)=[C:14]2[N:13]=[C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:3])=[O:49])[CH2:7][CH2:8]2)[C:17]=1[C:63]#[N:64]
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A degassed mixture of (4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexyl)-acetic acid ethyl ester (0.078 mmol, 60 mg), Bu3SnCN (50 mg, 0.156 mmoL), Pd[P(t-Bu)3]2 (8.3 mg, 0.016 mmoL) in Dioxane (1 mL) was heated at 100° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in 2:1 MeOH:H2O (1.5 mL) and was treated with 2N NaOH(aq) (0.5 mL). The resulting reaction mixture was stirred at room temperature for 18 hours. Aqueous hydrochloride solution (1.0 N, 2 ml) was added to the reaction mixture and the resulting solution was stirred at 65° C. for 2 h. The solution was concentrated and purified by prep-LC to afford the title compound (8.8 mg) as a mixture of cis and trans isomers: LC/MS RT=3.88 min. Mass calculated for, M+H 427.18, observed 427.18.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4Cl)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31].CN1CCOCC1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4[NH:28][C@H:29]([CH2:30][OH:31])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of 3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-chloro-1H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (0.78 mg, 5.2 mmol) and N-methyl morpholine (2 mL). The reaction mixture was heated to 80° C. for 12 h, cooled to room temperature and concentrated with high vacuum. The residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (0.90 g, 69%). 1H NMR (400 MHz, CD3OD) δ 7.36 (1H, s), 7.02–7.23 (6H, m), 6.80 (1H, s), 5.98 (1H, d, J=7.5 Hz), 4.10–4.12 (3H, m), 3.67–3.78 (6H, m), 3.06–3.11 (3H, m), 2.90 (1H, dd, J=7.8, 13.6 Hz), 2.54 (3H, s), 2.12 (3H, s). LCMS (M+H)+ m/z 501 (t=1.30 min.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[CH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(C)(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N=CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Step-2. L-Alanine ethyl ester from step-1 (9 g) was dissolved in 150 ml anhydrous CH2Cl2. The solution was cooled to 0° C. MgSO4 (10.17 g) was added to the solution followed by addition of pivalaldehyde (6.95 g). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and the filtrate was evaporated to give 11.2 g of N-neopentylidene-L-alanine ethyl ester. The product was used for next step without further purification. MS: 186 (MH+).