Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccco1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3ccco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using furan-2-yl-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil. LC/MS (Method B) 2.77 min, [M+1]+ 461. Potency class B.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:11][C:12]1[C:21]([N+:22]([O-])=O)=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(O)C.C(#N)C.O>[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: C#CCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: C#CCCCNc1c(N)c(Cl)nc2ccccc12
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
An aqueous solution (125 mL) of sodium dithionate (38.0 g, 218 mmol) was added to a solution of 2-chloro-3-nitro-N-pent-4-ynylquinolin-4-amine (12.64 g, 43.63 mmol) in ethanol (15 mL) and acetonitrile (130 mL). A fine white precipitate formed within seconds. After 2.5 hours, the volatiles were removed under reduced pressure leaving a yellow aqueous mixture that was diluted with water (1 L) and washed with dichloromethane (250 mL×3). The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to yield 2-chloro-N4-pent-4-ynylquinoline-3,4-diamine as an amber oil (8.10 g) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[C:14]([CH3:27])=[CH:13][C:12]=2[N+:28]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([NH2:28])=[CH:13][C:14]([CH3:27])=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)c(C)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COc1ncc(Cl)cc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)c(C)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Raney®-Nickel (0.7 g) was added to a solution of N6-(5-chloro-2-methoxypyridin-3-yl)-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3-methyl-5-nitropyridine-2,6-diamine (Preparation 25b, 0.67 g, 1.56 mmol) in ethanol (15 mL) and the resulting mixture was stirred at ambient temperature for 2 hours under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol (30 mL). The combined filtrate and washings containing the title compound as a methanolic solution were concentrated under reduced pressure to half of their volume and were used in the next synthetic step without further purification.
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1OCC1CCNCC1)[N:10]=[CH:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2=[O:30].[OH-].[Na+]>O>[C:24]([O:23][CH2:22][N:8]1[C:7](=[O:30])[C:6]2[C:11](=[CH:12][CH:13]=[CH:4][CH:5]=2)[N:10]=[CH:9]1)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)OCn1cnc2ccccc2c1=O
Temperature: 0 °C
Yield: 132.6 %

Procedure:
To a suspension of 6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (34 g, 84 mmol), (prepared as described for the starting material in Example 12), in water cooled at 0° C. was added 1N sodium hydroxide until the mixture was at pH8. The solution was extracted with trichloromethane and the organic layer was dried (MgSO4), filtered and evaporated to give 6-methoxy-7-piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (29 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH:3]1[CH3:25].[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[C:27]([O:1][CH:2]1[CH:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:28])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1O
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)CC(c2ccncc2[N+](=O)[O-])=CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of (+/−)-tert-butyl 6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in pyridine (0.1M) was added Ac2O (2.0 equiv.) and the reaction was stirred at room temperature overnight. Upon completion, the reaction was concentrated to dryness, then worked-up with ethyl acetate and water. The organic phase was dried with brine, then sodium sulfate, filtered, and concentrated to give (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl acetate in 94% yield. LC/MS=392.2 (M+H), Rt=0.94 min.
Reaction SMILES: C(C1C=CC(S[C:12]2[C:49]3[C:16](=[CH:17][C:18]4[C:19](C5C(C)=CC=CC=5C)(O)[C:20]5[C:45]([C:46](C6C(C)=CC=CC=6C)(O)[C:47]=4[CH:48]=3)=[CH:44][C:43]3[C:22](=[C:23](SC4C=CC(C(C)(C)C)=CC=4)[C:24]4[C:41]([C:42]=3SC3C=CC(C(C)(C)C)=CC=3)=[CH:40][C:39]3[C:38](C6C(C)=CC=CC=6C)(O)[C:37]6[C:28](=[CH:29][C:30]7[C:35]([CH:36]=6)=[C:34](SC6C=CC(C(C)(C)C)=CC=6)[C:33](SC6C=CC(C(C)(C)C)=CC=6)=[C:32](SC6C=CC(C(C)(C)C)=CC=6)[C:31]=7SC6C=CC(C(C)(C)C)=CC=6)[C:27](C6C(C)=CC=CC=6C)(O)[C:26]=3[CH:25]=4)[CH:21]=5)[C:15](SC3C=CC(C(C)(C)C)=CC=3)=[C:14](SC3C=CC(C(C)(C)C)=CC=3)[C:13]=2SC2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.Cl[Sn]Cl.Cl>O1CCOCC1>[CH:15]1[C:16]2[C:49](=[CH:48][C:47]3[C:18]([CH:17]=2)=[CH:19][C:20]2[C:45](=[CH:44][C:43]4[C:22]([CH:21]=2)=[CH:23][C:24]2[C:41](=[CH:40][C:39]5[C:26]([CH:25]=2)=[CH:27][C:28]2[C:37](=[CH:36][C:35]6[C:30]([CH:29]=2)=[CH:31][CH:32]=[CH:33][CH:34]=6)[CH:38]=5)[CH:42]=4)[CH:46]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(C)c1C1(O)c2cc3c(Sc4ccc(C(C)(C)C)cc4)c(Sc4ccc(C(C)(C)C)cc4)c(Sc4ccc(C(C)(C)C)cc4)c(Sc4ccc(C(C)(C)C)cc4)c3cc2C(O)(c2c(C)cccc2C)c2cc3c(Sc4ccc(C(C)(C)C)cc4)c4cc5c(cc4c(Sc4ccc(C(C)(C)C)cc4)c3cc21)C(O)(c1c(C)cccc1C)c1cc2c(Sc3ccc(C(C)(C)C)cc3)c(Sc3ccc(C(C)(C)C)cc3)c(Sc3ccc(C(C)(C)C)cc3)c(Sc3ccc(C(C)(C)C)cc3)c2cc1C5(O)c1c(C)cccc1C
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Product: c1ccc2cc3cc4cc5cc6cc7cc8cc9ccccc9cc8cc7cc6cc5cc4cc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1,2,3,4,8,12,13,14,15,19-deca(4′-t-butylphenylthio)-6,10,17,21-tetrahydro-6,10,17,21-tetra(2′,6′-dimethylphenyl)nonacene-6,10,17,21-tetraol (0.04 g, 0.015 mmol) in 1,4-dioxane (10 mL) was added anhydrous SnCl2 (0.1 g, 0.52 mmol). To this suspension was added 10% HCl (1 mL) in complete darkness and the resulting mixture was stirred at room temperature for 0.5 h under Ar. Upon completion of the reaction, black precipitates were filtered in the dark light under N2. The solids were washed with water (50 mL) followed by methanol to yield persistent nonacene derivative 1,2,3,4,8,12,13,14,15,19-deca(4′-t-butylphenylthio)-6,10,17,21-tetra(2′,6′-dimethylphenyl)nonacene as a black solid. 1H NMR (500 MHz, CDCl3): δ 8.83 (s, 4H), 8.74 (s, 4H), 7.14 (m, 20H), 7.08 (m, 10H), 7.00 (m, 10H), 6.72 (m, 8H), 6.66 (m, 4H), 1.96 (s, 24H), 1.23 (bs, 90H). 13C NMR (125.68 MHz, CDCl3): δ 148.9, 148.7, 148.5, 148.4, 143.5, 143.4, 142.9, 137.7, 137.1, 136.0, 134.2, 133.7, 131.4, 131.3, 130.9, 128.7, 128.4, 128.2, 128.0, 127.9, 127.5, 127.2, 126.1, 126.1, 126.0, 126.0, 34.50, 34.48, 31.51, 31.45, 31.4, 19.9. LDI-MS m/z: 2536 [M+], UV-vis λmax (nm): 550, 600, 655, 716, 846, 921, 1033. The 1H NMR spectrum of 1,2,3,4,8,12,13,14,15,19-deca(4′-t-butylphenylthio)-6,10,17,21-tetra(2′,6′-dimethylphenyl)nonacene and the compound structure are shown in FIGS. 17A & B.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]\[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1.[N+](C1C=C(C(C2C=CC=C([N+]([O-])=O)C=2)=C/C=C/C(NCCCCC2C=NC=CC=2)=O)C=CC=1)([O-])=O>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: NCCCCc1cccnc1
Agent: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C\C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 39 %

Procedure:
As in Example 134, a solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.2 g) and 3-pyridinebutanamine (0.42 g) in tetrahydrofuran (7 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was contaminated with a minor amount of the (E)-isomer. The mixture was separated by HPLC (ethyl acetate) and the desired product was crystallized from ether (2x) to yield 0.48 g of (Z)-5,5-bis(3-methoxyphenyl)- N-[4-(3-pyridinyl)-butyl]-2,4-pentadienamide mp 69°-73° C. Anal. Calculated for C28H30N2O3 : C, 75.99; H, 6.83; N, 6.33 Found: C, 75.79; H, 6.70; N, 6.39.
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4]>>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:4])=[O:1])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: [OH-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]

Procedure:
From N-Boc-D-cHyp(Tosyloxy)-OMe (5.27 mmol, 2.50 g), powdered KOH (13.2 mmol, 0.74 g), and 2-nitrophenol (13.2 mmol, 1.83 g), held at reflux for 6 days, the 2-nitrophenyl ether of D-trans-hydroxyproline methyl ester (0.29 g, 14%) was obtained. Purification by column chromatography (silica ge, ethyl acetate/hexane mixtures) yielded no pure fractions. All fractions bearing product were combined and purified in three equal portions using the chromatotron (4 mm silica gel plates) and a mixture of ethyl acetate/CH2Cl2/hexane (2:9:9:) which was found to effect separation on TLC plates. The mixture of ethyl acetate/CH2Cl2 (2:9) will be referred to as mixture A or simply A.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-].C1COCC1.Cl>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
The mixture of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (130 mg), LiOH (67 mg), THF (9 mL) and water (3 mL) was stirred at room temperature overnight. It was acidified with HCl to pH˜3. It was extracted with EtOAc and the extracts were combined and dried over Na2SO4. Removing the solvent provided the desired product (137 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[O:11]1CCOCC1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCO1
Reactant: Cc1ccc([N+](=O)[O-])cn1
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirred solution of compound 2-methyl-5-nitropyridine (30) (10 g, 72.5 mmol) in 1,4-dioxane (150 mL) was added SeO2 (9.5 g, 87.0 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was evaporated, the residue was diluted with water (100 mL), the resulting precipitate was separated by filtration and the filtrate was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), the organic layer was dried over Na2SO4 and concentrated to give 31 (6.4 g, 58%) as a brown solid. Rf: 0.7 (30% EtOAc/pet-ether); 1H NMR (400 MHz, CDCl3): δ 10.18 (1H, s), 9.59 (1H, d, J=2.0 Hz), 8.68-8.65 (1H, m), 8.16 (1H, d, J=8.4 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 6-chloro-2-pyridinecarboxylic acid (10 g, 63.5 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled, and monoethyl malonate magnesium salt (10 g, 34.9 mmol) was added. The mixture was stirred at room temperature for 30 min. To the reaction solution was added water (200 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl-acetate=4:1) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.96 g, 55%) as a brown oil. IR ν maxKBrcm−1: 1738, 1713, 1651, 1645. Anal. Calcd for C10H10NO3Cl: C, 52.76; H, 4.43; N, 6.15. Found: C, 52.63; H, 4.55; N, 6.02. 1H-NMR (CDCl3)δ: 1.20-1.40 (3H, m), 4.15 (2H×2/3, s), 4.14-4.32 (2H, m), 6.35 (1H×1/3, s), 7.37 (1H×1/3, d, J=6.6 Hz), 7.53 (1H×2/3, d, J=7.0 Hz), 7.70-8.02 (2H, m), 12.31 (1H×1/3, s).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:24]=[CH:25][C:18]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]2[CH:25]=[N:24]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Sodium hydride (94 mg, 2.34 mmol) was added to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (300 mg, 1.56 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (538 mg, 2.03 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was neutralized with 1M citric acid, diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (358 mg, 54.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[C:23](C)[CH:24]=1)=[CH:16][CH:15]=3.Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:21]=1)=[CH:16][CH:15]=3
Reactant: BrCCOC1CCCCO1
Reactant: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOC5CCCCO5)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(5-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one described in Example 39 and 2-(2-bromoethoxy)tetrahydropyran (Collect. Czech. Chem. Commun.; EN; 69; 10; 2004; 1843-1876).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:38]=[O:39])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>ClCCCl.O>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:39][CH3:38])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: ClCCCl
Solvent: c1ccccc1
Solvent: O
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Reaction time: 0.5 h

Procedure:
A solution of 1.91 g. (4 mmol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.94 g. (4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 150 ml. of dry benzene is refluxed for ca. 4 hours under a Dean-Stark trap until no more water separates. The solution is evoporated under reduced pressure to give a residue which is dissolved in 150 ml. of 1,2-dichloroethane and cooled to 0°-5° in an ice bath. Freshly prepared lead dioxide (5 g.) is added in 1 g. portions over 30 minutes and the reaction is stirred in the cold until complete consumption of the starting material is indicated by thin layer chromatography. The mixture is then filtered through Celite and the filter cake is washed with two 30 ml. portions of cold 1,2-dichloroethane. The filtrate is treated with 30 ml. of dry methanol (distilled from magnesium) and the reaction is stirred at ambient temperature for 3 hours until complete consumption of the intermediate and formation of a new product is shown by thin layer chromatography. The reaction mixture is evaporated to dryness and the residue is taken up in 50 ml. of methanol and treated with 4.0 g. of Girard reagent T (trimethylaminoacetohydrazide chloride). This solution is stirred at ambient temperature for 3 hours and evaporated under vacuum to give a solid residue which is partitioned between 150 ml. of ethyl acetate and 100 ml. of 20% aqueous sodium chloride solution. The organic phase is washed with three 100 ml. portions of 10% aqueous sodium chloride, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:42])[CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 1.6 mmol) in pyridine (11 mL) at 0° C. was treated with hydrocinnamoyl chloride (0.324 g, 1.92 mmol). The reaction mixture was stirred at 0° C. for 20 min and the ice bath was removed to stir at room temperature. The reaction was complete after 5.5 hours. Sodium hydroxide solution (1 N, 20 mL) was added and stirred for 30 minutes. The organic layer was removed under reduced pressure. Dichloromethane (20 mL) was added, and the layers were partitioned. The aqueous layer was extracted with dichloromethane (80 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 35 g ISCO silica gel column to give 0.569 g (63%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.569 g, 1 mmol) in warmed ethyl acetate was treated with a warmed solution of maleic acid (0.384 g, 3 mmol) in ethyl acetate. The formed precipitate was filtered under a nitrogen atmosphere and dried under high vacuum to give the tri maleate salt. 1H NMR (d6-DMSO) δ 9.238 (s, 1H), 8.2216 (s, 1H), 8.1991-8.1786 (d, 1H, J=8.2 Hz), 7.3147-7.2664 (m, 4H), 7.2366-7.2330 (m, 1H), 7.2026-7.1732 (dd, 2H), 6.171 (s, 6H), 4.6649-4.6083 (m, 1H), 4.0948-4.0697 (m, 1H), 3.8916 (s, 3H), 3.1750-3.1632 (d, 2H, J=4.72 Hz), 2.9364-2.8984 (m, 2H), 2.7885-2.7506 (m, 2H), 2.5290 (s, 2H), 2.3905-2.3231 (m, 4H), 2.1489 (s, 3H), 2.0549-1.9243 (m, 6H), 1.4821-1.4457 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 1.75 min (100%), MH+ 569.4.