Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C=CC=CC=2NC2=CC(C(O)=O)=NN12.F[C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24]3=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[N:31][N:23]3[C:22](=[O:35])[C:21]=2[CH:20]=1>N1C=CC=CC=1.S(Cl)(Cl)=O>[O:35]=[C:22]1[C:21]2[CH:20]=[CH:19][CH:28]=[CH:27][C:26]=2[NH:25][C:24]2=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[N:31][N:23]12
Reactant: NC(=O)c1cc2[nH]c3ccc(F)cc3c(=O)n2n1
Agent: O=C(O)c1cc2[nH]c3ccccc3c(=O)n2n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: NC(=O)c1cc2[nH]c3ccccc3c(=O)n2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4,9-dihydro-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (5 g; 0.022 mole), thionyl chloride (250 ml) and four drops of pyridine is stirred at room temperature for 24 hrs. The reaction mixture is evaporated to dryness under reduced pressure in a water bath at 30°-40° C. The residue is treated with cold (0° C.) concentrated ammonium hydroxide solution (200 ml) and allowed to come to room temperature. The product is filtered off, washed with ether and used in the next step without further purification. Yield 3.2 g; mp 315°-325° C. An analytical sample, recrystallized from dimethylformamide, melts at 335°-340° C. By the same procedure, starting with the corresponding 7-fluoro compound, the product obtained is 4,9-dihydro-7-fluoro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12
Reactant: O=S(Cl)Cl
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Solvent: c1ccccc1
Product: CN1Cc2c(CCl)ncn2-c2ccccc2C1=O

Procedure:
6 g (24.6 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 4.45 g of thionyl chloride are heated to boiling under reflux for 2 hours in 50 ml of benzene. The mixture is evaporated to dryness, the residue is taken up in chloroform and washed with 2 N sodium hydroxide. The organic phase is dried over magnesium sulphate and, after removal of the solvent, there is obtained 3-(chloromethyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 277°-280°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[N:3]1.[NH2:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O>>[Cl:28][C:26]1[CH:27]=[C:19]2[C:20]([C:21](=[O:23])[N:10]([S:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:9])=[O:8])[C:11](=[O:12])[NH:18]2)=[CH:24][CH:25]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)N=C=O
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 35.3 %

Procedure:
1.26 g (4.89 mmol) of 1-methyl-4-ethoxycarbonylpyrazol-5-sulfonylisocyanate and 839 mg (4.89 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 712 mg of the above-identified compound (yield 35.3%). Properties: colorless crystal, Melting point: 222°-224° C., PMR (δppm, DMSO-d6):1.05 (3H,t), 2.09 (3H,s), 4.04 (2H,q), 4.25 (2H,s), 7.15 (1H,s), 7.29 (1H,s), 7.91 (1H,d), 8.02 (1H,s), 11.92 (1H,br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH2:19][CH2:20][CH3:21])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:22]([O:24]C)=[O:23])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][CH2:29]I>O1CCCC1>[CH2:28]([N:18]([CH2:19][CH2:20][CH3:21])[C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[CH3:29]
Reactant: CCCNc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(propylamino)quinoxaline-6-carboxylate (70 mg, 0.21 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (32 mg, 1.32 mmol) and CH3CH2I (1.5 mL), and the reaction was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.03% NH3H2O and CH3CN (10% CH3CN up to 35% in 8 min); Detector, UV 220 nm] to afford 3-(ethyl(propyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (45.0 mg, 62.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][O:37][CH2:38][CH2:39][N:34]2[CH2:33][C@@H:32]([CH2:40]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][O:37][CH2:38][CH2:39][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@@H]1CN2CCOC[C@H]2CO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CN2CCOC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-yl]methanol (prepared as described in PCT Int. Appl. 2004006846) following General Procedure J.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)[CH:10]=[N:9]1)[C:3](OC)=[O:4].[CH2:31]([CH2:33][NH2:34])[OH:32]>CO>[OH:1][C@@H:2]([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)[CH:10]=[N:9]1)[C:3]([NH:34][CH2:33][CH2:31][OH:32])=[O:4]
Reactant: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Reactant: NCCO
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@H](O)C(=O)NCCO)c2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Methyl (2S)-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (40 mg, 0.10 mmol) in methanol (1 mL) was treated with ethanolamine (0.03 mL, 0.48 mmol). The mixture was stirred overnight at 70° C. Upon cooling to room temperature, the mixture was filtered and purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier) to afford (2S)-2-hydroxy-N-(2-hydroxyethyl)-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanamide. MS ESI calcd. for C20H21F3N6O3 [M+H]+ 451. found 451. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.80 (d, J=4.9 Hz, 1H), 7.94 (s, 1H), 7.84 (t, J=5.6 Hz, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.33 (s, 1H), 7.23 (d, J=6.3 Hz, 1H), 7.05 (s, 1H), 4.39 (dd, J=2.9 Hz, 13.7 Hz, 1H), 4.26 (d, J=7.7 Hz, 1H), 4.17-4.12 (m, 1H), 3.38 (t, J=5.9 Hz, 2H), 3.16 (q, J=6.1 Hz, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([C:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)C.[OH-].[K+]>CCOCC>[C:5]([C:9]1[CH:13]=[CH:12][C:11](=[C:2]([CH3:4])[CH3:1])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)=C1C=CC(C(C)(C)C)=C1

Procedure:
Dry acetone (99.3 mmol, 5.77 g, 7.3 mL) and t-butylcyclopentadiene (50.6 mmol, 6.17 g) were mixed in a dropping funnel and added at room temperature to an ethanol solution (10 mL) of KOH (10.3 mmol, 0.58 g) stirring under nitrogen. After stirring overnight, the golden solution was diluted with ether, washed with 2 N HCl, water, and dried over sodium sulfate. A sample of the crude organic fraction (7.4 g) was taken for analysis (GCMS) showing 90% conversion to the title compound. The product was submitted to distillation. 1H-NMR (CDCl3): δ 1.38 (s, 9H), 2.28 (s, 6H), 6.24 (m, 1H), 6.63 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[S:4]([C:7]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10]2[N:11]=C(C3C=CC=CC=3)[O:13][C:9]=2[CH:8]=1)(=[O:6])=[O:5])[CH3:2].[OH-].[K+]>C(O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10]([NH2:11])=[C:9]([OH:13])[CH:8]=1)(=[O:6])=[O:5])[CH3:27]
Reactant: CCN(CC)S(=O)(=O)c1cc2oc(-c3ccccc3)nc2c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)S(=O)(=O)c1cc(O)c(N)c2ccccc12
Yield: 152.9 %

Procedure:
A mixture of N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide (38.1 g, 100 mmol), 20% KOH (140 ml) and ethanol (180 ml) was refluxed for 2 h under nitrogen and the product was extracted with ethyl acetate (3×500 ml). The combined extracts were dried over anhydrous sodium sulfate and the solvent evaporated to give 45 g crude N,N-diethyl-4-amino-3-hydroxy-1-naphthalenesulfonamide as a black sticky oil (50% pure by NMR). An analytical sample was prepared by column chromatography (chloroform) to give pure N,N-diethyl-4-amino-3-hydroxy-1-naphthalenesulfonamide as a glassy material which upon titration with ether gave a black solid, m.p. 120°-122° C.
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28])[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)(=O)C.[OH-].[Li+].CO.C(Cl)(Cl)Cl>O.CO>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24][CH2:23][N:12]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][OH:7])=[CH:31][CH:32]=1
Reactant: CC(=O)OCCCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: O=C(NCCCN(CCCCO)C1CCCc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
Lithium hydroxide monohydrate (11 mg, 0.26 mmol) was added to a solution of 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butyl acetate (67 mg, 0.13 mmol) in 10% water/methanol (1.1 ml). After stirring at RT for 16 h, additional lithium hydroxide monohydrete (22 mg, 0.52 mmol) was added. The reaction mixture was stirred at RT for 17 h, and then concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica get and then developed with 10% methanol/chloroform to afford 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-butanol (48 mg, 77%): MS(ES+) m/e 476 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.36 (m, 4H), 7.11-7.03 (m, 3H), 6.10 (br, 1H), 4.33 (br, 1H), 3.90 (m, 1H), 3.37 (m, 2H), 3.13 (m, 1H), 3.02 (m, 1H), 2.67 (m, 2H), 2.54-2.47 (m, 4H), 1.93 (m, 2H), 1.58 (m, 4H), 1.44 (m, 4H).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:33]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1noc(C)c1COc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 35%. MS (ES) 455 (M+, 100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:33])[C:21]3[CH:26]=[CH:25][C:24]([CH:27]4OCCC[O:28]4)=[CH:23][CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=3)=[O:33])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(C2OCCCO2)cc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
4-[1-(6-Bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carbonyl]-benzaldehyde was synthesized analogous to example 10 with 90 mg (0.18 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-[1,3]dioxan-2-yl-benzoyl)-1H-quinolin-4-one, 4 mL of 4 N HCl in dioxane. The crude product obtained was used directly for next step with 84 mg (0.4 mmol) of sodium triacetoxyborohydride, 0.2 mL (2.0 M, 0.4 mmol) of methylamine in THF, 2 mL of DCM. The crude product was purified by flash chromatograph to yield 35 mg of colorless solid. LC-MSD, m/z for C24H20N3O2Br [M+H]+: 462.3, [M+2H]+: 463.3. Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 0.581 min.
Reaction SMILES: [CH2:1]([C:4]([CH:11]([C:16](=[O:37])[NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19]1)[CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]=[CH2:10])[C:5](O)=[O:6])[CH:2]=[CH2:3].C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([C:4]([CH2:8][CH:9]=[CH2:10])([CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:16]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:19]1)=[O:37])[C:5]([NH2:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)(C(=O)O)C(CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC(CC=C)(C(N)=O)C(CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 30 (250 mg, 0.5 mmol) in 30 ml DMF was added HATU (250 mg, 0.66 mmol) and DIEA (400 uL, 2.2 mmol). After stirring for 2 hrs, ammonia gas was bubbled into the solution for 5 minutes using a glass inlet tube. The mixture was then stirred at ambient temperature overnight. Water was added (10 mL) and the solvent was removed under vacuum to give a yellow oil which was taken up in ethyl acetate and water (1:1). The organic layer was washed twice with water and then brine, and dried over Na2SO4. After filtration and concentration, the crude product was purified using silica gel chromatography (CH2Cl2/methanol 10:0.5) to give compound 31 (120 mg) as a white solid (48%). 1H NMR (CDCl3) 0.95-0.88 (dd, 6H), 1.32-1.28 (m, 1H), 1.64-1.50 (m, 1H), 1.90-1.80 (m, 1H), 2.35-2.00 (m, 1H), 2.80-2.54 (m, 4H), 3.48 (s, 3H), 5.38-5.14 (m, 5H), 5.54-5.51 (d, 1H), 5.90-5.78 (m, 2H), 7.65-7.25 (m, 9H), 8.52 (s, 1H). ESI ES+=523.2 (M+Na).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:15](/B(O)O)=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20].[ClH:24]>CCOCC>[ClH:24].[CH:15](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCO)nn12
Yield: 53 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (45 mg, 53%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.91 (s, 1H), 7.88 (d, J=9.8 Hz, 1H), 7.22 (d, J=9.8 Hz, 1H), 6.88 (dt, J=7.0, 16.2 Hz, 1H), 6.67 (d, J=16.2 Hz, 1H), 3.81 (t, J=5.7 Hz, 2H), 3.55 (t, J=5.7 Hz, 2H), 2.36-2.32 (m, 2H), 1.55-1.49 (m, 2H), 1.46-1.40 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.3, 139.2, 133.2, 130.2, 121.0, 120.8, 117.6, 114.2, 60.5, 45.0, 34.3, 32.3, 23.3, 14.3; HPLC tR=10.8 min (Luna), 98.8%; ES-MS: (M+H)=261 m/z.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[N:19](COC)[C:18]=3[CH:27]=2)[CH2:9]1)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:7][C@@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:27]=2)[C:11](=[O:13])[CH2:12]1
Reactant: COCN1C(=O)COc2ccc(N3C[C@@H](NC(=O)OC(C)(C)C)CC3=O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 29.8 %

Procedure:
To a solution of {(3S)-1-[4-(methoxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-5-oxopyrrolidin-3-yl}carbamic acid tert-butyl ester (1.79 g, 4.57 mmol) in tetrahydrofuran (24 ml) was added 6N Hydrochloric acid (11.9 ml) and the mixture was stirred at 80° C. for 1.5 hours. After cooling, the reaction solution was basified by adding a saturated sodium hydrogen carbonate aqueous solution and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol) to yield 337 mg (30%) of the title compound in the form of a light yellow solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][CH2:10]C)=[O:8].Cl>CO>[CH3:10][O:9][C:7]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)=[O:8]
Reactant: CCOC(=O)C1SCCCS1
Agent: Cl
Solvent: CO
Product: COC(=O)C1SCCCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 192 g (1 mole) of ethyl 1,3-dithiane-2-carboxylate in 1 L of methanol and add 5 ml of concentrated hydrochloric acid. Stir at room temperature for 18 hours. Neutralize the mixture with 1 N sodium hydroxide and remove the methanol under reduced pressure. Take up the residue in 1 L of ether, wash with water, dry over magnesium sulfate and evaporate. Distil the residue under reduced pressure to obtain methyl-1,3-dithiane-2-carboxylate.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13](NC(=O)NCC(N2[C@@H](CC(C)C)CC[C@H]2C(OC(C)(C)C)=O)=O)[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([OH:10])(=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)C[C@H]1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1

Procedure:
A The reaction is carried out in a way similar to that described in Example 1 A, but starting from 1.65 g of tert-butyl (2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-isobutylpyrrolidine-2-carboxylate and 0.25 g of 10% palladium-on-charcoal in 50 cm3 of ethanol. After treatment, there is obtained 0.57 g of (2S,5R)-3-3-2-(2-tert-butoxycarbonyl-5-isobutyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, the optical rotation of which is [α]D20 =-36.8° (c=1.0; methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:11]=[C:10]([OH:20])[CH:9]=3)[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN1CCN(c2ccnc(-c3cc(O)nc(-c4ccccn4)n3)c2)CC1

Procedure:
A mixture of 3.51 g (12.3 mmol) of 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol, 27.4 ml (303 mmol, 20 equivalents, 30.38 g) of 1-methyl-piperazine and 84 mg (0.05 mmol, 0.05 equivalent) of zinc(II) chloride in 50 ml of 2-methyl-2-butanol is refluxed for 22 hours and concentrated to dryness using a rotary evaporator. 50 ml of water are added, 3.6 g of EDTA are added, and the pH is adjusted to 9 using dilute sodium hydroxide solution. Extraction is carried out three times using 150 ml of chloroform each time, and the organic extracts are combined and dried (sodium sulfate). Concentration is carried out using a rotary evaporator and the crude product is recrystallised from toluene. 6-[4-(4-Methyl-piperazin-1-yl)-pyrid-2-yl]-2-pyrid-2-yl-pyrimidin-4-ol is obtained in the form of a whitish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Nc1cccc(Cl)c1C(=O)NC1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.7 %

Procedure:
A mixture of 2-amino-6-chlorobenzoic acid (3.0 g, 17 mmol) and CDI (2.6 g, 16 mmol) in acetonitrile (40 mL) was stirred at room temperature for 1.5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.6 g, 16 mmol) and sodium hydrogen carbonate (1.8 g, 21 mmol), and the mixture was heated at 50° C. for 21 hours. The suspension was cooled to room temperature for 1 hour. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL). The solid was dried in a vacuum oven overnight to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-chloro-benzamide as a white solid (1.7 g, 35% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 5/95 grad to 95/5 for 5 min CH3CN/0.1% H3PO4, 4.01; 1H NMR (DMSO-d6) δ 1.92-1.98 (m, 1H, CHH), 2.05-2.20 (m, 1H, CHH), 2.49-2.57 (m, 1H, CHH), 2.76-2.88 (m, 1H, CHH), 4.67-4.76 (m, 1H, NCH), 5.61 (s, 2H, NH2), 6.57 (d, J=8 Hz, 1H, Ar), 6.63 (d, J=8 Hz, 1H, Ar), 7.04 (t; J=8 Hz, 1H, Ar), 8.83 (d, J=8 Hz, 1H, NH), 10.95 (s, 1H, NH); 13C NMR (DMSO-d6) δ 23.50, 30.96, 49.31, 113.29, 115.51, 120.97, 130.03, 130.19, 147.03, 165.60, 172.92, 172.97; LCMS: MH=282, 284.