Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:12][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]#[CH:15]>CN(C=O)C.CCN(CC)CC.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.[Cu]I>[C:19]([O:18][C:17]([NH:16][CH:13]([CH3:12])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CC(C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#CC(C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 51.2 %

Procedure:
Pd(Ph3P)4 (683 mg, 0.591 mmol), CuI (938 mg, 49.2 mmol), methyl 2-iodobenzoate (25.8 g, 98.49 mmol), tert-butyl but-3-yn-2-ylcarbamate (intermediate 3.2, 25 g, 147.75 mmol) in DMF (30 ml) and Et3N (27 ml) were mixed in DMF (125 ml) and the mixture was heated to 60° C. under nitrogen atmosphere for 12 hrs. The mixture was quenched with water and the product extracted with EtOAc. The collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual was purified by column chromatography over silica gel (Hex/EtOAc 9:1) to give the title compound (15.3 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(C(O)c2cccc(F)c2)ccc2cccnc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1cccc(F)c1)c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
MnO2 powder (0.87 g, 10 mmol) was added to a solution of (3-fluoro-phenyl)-(8-nitro-quinolin-7-yl)-methanol (Intermediate 344) (0.3 g, 1.01 mmol) in DCM (20 ml) and the mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound (0.25 g, 85%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:24](=[O:25])[N:23]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:31].C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC>C1(C)C=CC=CC=1.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>[CH:26]1([N:23]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:31])=[C:2]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[C:24]2=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cn3)ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 38.7 %

Procedure:
6-Bromo-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.290 g, 0.597 mmol), tetrakis(triphenylphosphine)palladium (0.083 g, 0.072 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.336 g, 0.932 mmol) were dissolved in toluene (4 mL) and slowly brought to reflux for 3 hours. The reaction mixture was purified by silica gel chromatography to give 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.110 g, 38.6%). 1H NMR δ (400 MHz, DMSO-d6) 8.95 (s, 1H), 8.83 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.44 (dd, J=3.2, 9.3 Hz, 1H), 5.79 (m, 1H), 4.42 (d, J=2.0 Hz, 1H), 4.01 (d, J=2.0 Hz, 1H), 3.79 (q, J=6.8 Hz, 2H), 3.72 (m, 4H), 3.09 (m, 4H), 2.34 (s, 3H), 2.17 (m, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 2H), 1.21 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[C:5]([OH:16])[NH:4][N:3]=1.[C:17]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[O:18]1>C(O)(=O)C>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[C:5]([OH:16])=[N:4][NH:3][C:2]=1[N:1]1[C:17](=[O:18])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:26]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1[nH]nc(O)c1Cc1cccc(Cl)c1Cl
Yield: 47.8 %

Procedure:
A mixture of 3-amino-4-(2,3-dichlorobenzyl)-1H-pyrazol-5-ol (18 g, 70 mmol) and isobenzofuran-1,3-dione (20 g, 140 mmol) in acetic acid (100 mL), was stirred under reflux for 16 h. The reaction mixture was cooled and filtered to provide the titled compound (13 g, 50%); LC/MS: MS (ES+) m/e 388 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.66 (s, 2H), 7.20-7.31 (m, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.99-8.02 (m, 2H), 8.11 (s, 2H), 8.25-8.28 (m, 2H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])C=C.C1(=O)OC(=O)CC1=C.C(C1CC(=O)OC1=O)C=C>>[C:5]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[C:4]([CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH2:1]
Reactant: C=CCOC(=O)CC(CC=C)C(=O)OCC=C
Agent: C=C1CC(=O)OC1=O
Agent: C=CCC1CC(=O)OC1=O
Product: C=CCOC(=O)CC(=C)C(=O)OCC=C

Procedure:
The procedure described in (a) above is repeated, except that 140 g (1.25 mol) of itaconic anhydride are substituted for the 175 g of allylsuccinic anhydride. About 190 g of diallyl itaconate having a boiling point of 95° C. at 2 hPa (abs.) are recovered.
Reaction SMILES: CC(S[C@@H]1[O:10][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO>>[NH:16]1[CH2:23][C@H:22]([OH:10])[CH2:21][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 37 °C
Reaction time: 13 h

Procedure:
A plasmid (pHuCol-Fl, FIG. 6) encoding the gene sequence of the first 80 amino acids of human Type 1 (α1) collagen (FIG. 5) (SEQ. ID. NO. 2) placed behind the isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible tac promotor and also encoding β-lactamase is transformed into Escherichia coli proline auxotrophic strain NM519 (pro−) by standard heat shock transformation. Transformation cultures are plated on Luria Broth (LB) containing 100 μg/mL ampicillin and after overnight growth a single ampicillin-resistant colony is used to inoculate 5 mL of LB containing 100 μg/mL ampicillin. After growth for 10-16 hours with shaking (225 rpm) at 37° C., this culture is used to inoculate 1 L of M9 minimal medium (M9 salts, 2% glucose, 0.01 mg/mL thiamine, 100 μg/mL ampicillin, supplemented with all amino acids at 20 μg/mL except proline which is supplemented at 12.5 mg/L) in a 1.5 L shaker flask. After growth at 37° C., 225 rpm, for 15-20 hours post-inoculation, the optical density at 600 nm is constant at approximately 0.5 OD/mL. The cells are harvested by centrifugation (5000 rpm, 5 minutes), the media decanted, and the cells resuspended in 1 L of M9 minimal media containing 100 μg/mL ampicillin, 0.08M L-hydroxyproline, and 0.5M NaCl. Following growth for 1 hour at 37° C., 225 rpm, IPTG is added to 1 mM and the cultures allowed to grow for an additional 5-15 hours. Cells are harvested by centrifugation (5000 rpm, 10 minutes) and lysed by mechanical disruption. The hydroxyproline-containing collagen fragment is purified by ammonium sulfate fractionation and column chromatography.
Reaction SMILES: B(Br)(Br)Br.Cl.C[O:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]1[CH:15]([C:21]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22]3)[NH:14][CH2:13][CH2:12][C:11]2=1.[Cl-].[NH4+]>ClCCl>[OH:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]1[CH:15]([C:21]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23][CH2:24]3)[NH:14][CH2:13][CH2:12][C:11]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(O)cc32)CCC1

Procedure:
12 ml of 1M boron tribromide in dicloromethane are added at −30° C., under an inert atmosphere, to a solution of 2 g of the compound obtained in Example 7 in 50 ml of dichloromethane. After reaction for two hours at ambient temperature, the reaction mixture is hydrolysed with 1 ml of a saturated ammonium chloride solution. The precipitate obtained is filtered off, washed with water and then dried, enabling the expected product to be isolated.
Reaction SMILES: C(P(O)(=O)O)[CH:2]([P:8]([OH:11])(=[O:10])[OH:9])[CH2:3][P:4]([OH:7])(=[O:6])[OH:5].C[P:17](=[O:20])([OH:19])[OH:18].C(P(=O)(O)O)C.C(P(=O)(O)O)CC.C(P(=O)(O)O)CCC.C1(P(=O)(O)O)C=CC=CC=1.CC(P(O)(O)=O)(P(O)(O)=O)O.P(C(C)C(O)=O)(O)(O)=O.P(CCC(O)=O)(O)(O)=O.P(C(CC)C(O)=O)(O)(O)=O.P(CCCC(O)=O)(O)(O)=O>>[CH:2]([P:8]([OH:9])(=[O:10])[OH:11])([P:17]([OH:20])(=[O:18])[OH:19])[CH2:3][P:4]([OH:5])(=[O:6])[OH:7]
Reactant: CP(=O)(O)O
Reactant: O=P(O)(O)CC(CP(=O)(O)O)P(=O)(O)O
Agent: CC(C(=O)O)P(=O)(O)O
Agent: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: CCC(C(=O)O)P(=O)(O)O
Product: O=P(O)(O)CC(P(=O)(O)O)P(=O)(O)O

Procedure:
ethane-2-hydroxy-1,1,2-triphosphonic acid; propane1,2,3-triphosphonic acid; methylphosphonic acid; ethylphosphonic acid; n-propylphosphonic acid, n-butylphosphonic acid; phenylphosphonic acid; ethane-1-amino-1,1-diphosphonic acid; ethane-1-hydroxy-1,1-diphosphonic acid; dodecane-1-hydroxy-1,1-diphosphonic acid; acid; 2-phosphonopropionic acid; 3-phosphonopropionic acid; 2-phosphonobutyric acid; 4-phosphonobutyric acid; amino tris (methylenephosphonic) acid; ethylenediamino-tetra (methylenephosphonic) acid; hexamethylenediamino-tetra (methylenephosphonic) acid; diethylenetriamino-penta(methylene phosphonic) acid; and so forth.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][C:12]2[S:13][C:14]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[CH:15][C:16]=2[CH2:17][CH2:18]O)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.C(#N)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][C:12]2[S:13][C:14]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[CH:15][C:16]=2[CH2:17][CH2:18][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: CSc1ncc(Cl)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(Cl)c(-c2cc(CCN3CCOCC3)c(Cc3ccc(F)cc3)s2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Methanesulfonyl chloride (59 mg, 0.52 mmol) was added to a mixture of 2-(2-(4-fluoro-benzyl)-5-(5-chloro-2-(methylthio)pyrimidin-4-yl)thiophen-3-yl)ethanol (170 mg, 0.43 mmol) and diisopropylethylamine (72 mg, 0.55 mmol) in dichloromethane (8 mL) at 0° C. After stirring at 0° C. for 1 h, the solvent was removed in vacuo. Acetonitrile (5 mL) and morpholine (112 mg, 1.29 mmol) were added to the residue and the mixture was heated to 70° C. overnight. After cooling to rt solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with methanol (1 M ammonia)/dichloromethane (1:20) to afford the title compound (148 mg, 74%). MS (M+H)+ 464/466.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CS[C:26]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:37]=1)=[CH:27][N+:28]([O-:30])=[O:29]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][NH:20][C:26]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:37]=2)=[CH:27][N+:28]([O-:30])=[O:29])[CH3:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(CN(CCN(C)CCN)c2ccccn2)cc1
Reactant: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1
Product: COc1ccc(CN(CCN(C)CCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN3CCCCC3)c2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 22, using 0.85 g (2.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitroethene as starting materials. Chromatographic working-up analogously to Example 22 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=632 ([M+H]+, 8), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/ether; m.p.: 102°-104° C. (isopropanol/ether).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(Cl)(Cl)Cl>[C:7]1([CH:6]2[S:5][CH2:1][CH2:2][CH2:3][S:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: SCCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
1,3-propanedithiol (11.22 g, 103.7 mmol) was added to a solution of benzaldehyde (10.0 g, 94.2 mmol) in 150 mL of CHCl3. The mixture was stirred at room temperature for 4 h. Concentrated HCl (2 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for additional 2 h. The mixture was washed with H2O and brine. The organic layer was dried over MgSO4 and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:dichloromethane=3:1 (v/v)) to give a colorless solid (15.29 g, 83%). 1H NMR (300 MHz, CDCl3, δ): 7.43-7.48 (m, 2H), 7.25-7.36 (m, 3H), 5.15 (s, 1H), 2.85-3.10 (m, 4H), 2.10-2.20 (m, 1H), 1.84-1.99 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 138.95, 128.59, 128.29, 127.61, 51.48, 32.13, 25.15.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Finely powdered potassium carbonate (5.8 g) was suspended in a solution of 2-(aminomethyl)pyridine (3.0 g) and ethyl bromoacetate (3.1 ml) in dimethylformamide (30 ml). The mixture was stirred at room temperature overnight, then poured into ice water. The mixture was extracted with ethyl acetate (50 ml×2) and the organic layer was washed with saturated sodium chloride solution (2 times), dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with a silica gel column chromatography (MeOH:CHCl3 =1:99 as an eluent) to give N-(ethoxycarbonylmethyl)-N-(pyridin-2-ylmethyl)amine (2.30 g).
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[CH2:37][CH:36](O)[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:39])[CH:34]=2)[O:29]1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:39])[CH:34]=2)[O:29]1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1C1CC(O)c2cc(O)ccc2O1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: O=[N+]([O-])c1ccccc1C1CCc2cc(O)ccc2O1

Procedure:
2-(2-Nitrophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 2-(2-nitrophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 8.00 (d, 1H, J 8.0 Hz), 7.79-7.80 (m, 2H), 7.59-7.63 (m, 1H), 6.59-6.62 (m, 1H), 6.50-6.53 (m, 2H), 5.36 (dd, 1H, J 10.2, 2.0 Hz), 2.89-2.93 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.31 (m, 1H), 1.90-1.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1
Reactant: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
In a round bottom flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (118 mg, 0.23 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (9 mg). The mixture was stirred at 25° C. for 16 h and then concentrated in vacuo, dissolved in ethyl acetate with a little methanol to solubilize the material and concentrated in vacuo with silica gel (1 g). Purification by Biotage flash chromatography (AnaLogix, 12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (80 mg, 74%) as a white foam: HR-ES-MS m/z calculated for C21H25N4O5ClS [M+H]+ 481.1307, observed 491.1307; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.96-2.19 (m, 2H), 2.09 (s, 3H), 2.29-2.48 (m, 2H), 3.21-3.33 (m, 2H), 3.69-3.81 (m, 1H), 3.86 (dd, J=13.5, 7.5 Hz, 1H), 4.09 (dd, J=13.5, 3.8 Hz, 1H), 4.27 (d, J=18.2 Hz, 1H), 4.56 (d, J=18.2 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.78-4.86 (m, 1H), 4.81 (s, 1H), 4.94 (d, J=5.4 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.37 (td, J=7.8, 1.8 Hz, 1H), 7.47 (td, J=7.8, 1.4 Hz, 1H), 7.50-7.55 (m, 2H), 7.66 (dd, J=7.8, 1.4 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([N:25]([CH2:38][CH2:39][C@H:40]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:41](O)=[O:42])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36])(=[O:28])=[O:27])[CH2:22][CH:23]=[CH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(#N)C.O.C(OCC)(=O)C>[CH2:21]([N:25]([CH2:38][CH2:39][C@H:40]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:41]([N:16]1[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:15]1[C:13]([NH:12][C@:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:14])=[O:42])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36])(=[O:28])=[O:27])[CH2:22][CH:23]=[CH2:24]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-ethyl-1-((2S,4R)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride salt (WO2005095403) (1.04 g, 3.32 mmol), (S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino)-butanoic acid (1.38 g, 3.02 mmol) and HATU (1.26 g, 3.32 mmol) in toluene (36 mL) and ACN (4 mL) was added DIEA (2.05 mL, 6.03 mmol) at 0° C. The reaction warmed to rt and stirred at rt for 1 hr. Ethyl acetate (50 mL) and water (20 mL) was added. The organic layer was separated and washed with brine, dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to give (1R,2S)-ethyl 1-((2S,4R)-1-((S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino)butanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate as white foam solid (1.63 g, 76%). MS: Calcd.: 707; Found: [M+H]+ 708.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]/[N:10]=[C:11]2\[NH:12][C@@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3Br)[CH2:14][C:15]3[N:16]=[C:17]([NH2:22])[N:18]=[C:19]([CH3:21])[C:20]\2=3)[CH2:3][CH2:2]1.B1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[N:46]=2)OCCN(C2C=CC=CC=2)CCO1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]/[N:10]=[C:11]2\[NH:12][C@@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[N:46]=3)[CH2:14][C:15]3[N:16]=[C:17]([NH2:22])[N:18]=[C:19]([CH3:21])[C:20]\2=3)[CH2:3][CH2:2]1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1nc(N)nc2c1/C(=N/OCCN1CCOCC1)N[C@@H](c1ccc(F)cc1Br)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCN3CCOCC3)N2)n1
Temperature: 85 °C
Yield: 61.9 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime (100 mg, 0.21 mmol) in DMA was added 6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester (250 mg, 0.84 mmol), Pd(dppf)2Cl2 (17 mg, 0.02 mmol), and 2N Na2CO3 (522 μL, 1.05 mmol). The resultant mixture was degassed with N2 for 5 min then heated in a sealed tube at 85° C. for 14 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite topped with anhydrous Na2SO4, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a brown residue which was purified by preparative HPLC eluting with TFA/ACN/H2O. The solvent was removed on a rotary evaporator and the sample was dried under high vacuum to yield (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime (67.4 mg, 0.13 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ 2.81 (s, 3H), 2.95 (td, J=11.87, 3.79 Hz, 2H), 3.12 (dd, J=17.18, 9.60 Hz, 1H), 3.34-3.56 (m, 3H), 3.70 (dd, J=11.75, 3.41 Hz, 2H), 3.84-4.06 (m, 7H), 4.39 (t, J=4.80 Hz, 2H), 4.94 (dd, J=9.60, 4.04 Hz, 1H), 6.81 (d, J=8.34 Hz, 1H), 7.06 (d, J=7.07 Hz, 1H), 7.08-7.21 (m, 2H), 7.50 (dd, J=8.59, 5.31 Hz, 1H), 7.68-7.81 (m, 1H). [M+H] calc'd for C26H30FN7O3, 508. found, 508.