Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C1([O:32][C:33]([NH:35][OH:36])=O)C=CC=CC=1.O>C1COCC1>[OH:36][NH:35][C:33]([N:3]1[CH2:4][CH:5]2[CH:8]([N:9]([CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:32]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CNC2
Reactant: O=C(NO)Oc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CN(C(=O)NO)C2
Yield: 74.5 %

Procedure:
A mixture of (3-aza-bicyclo[3.2.1]oct-8-yl)-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.064 g, 0.19 mmol) and hydroxylaminecarboxylic acid phenyl ester (PhOCONHOH) (0.058 g, 0.38 mmol) in dry THF (4 mL) was heated at reflux overnight. Water (10 mL) was then added, and the mixture was extracted with EtOAc (20 mL) and CH2Cl2 (2×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:4 CH2Cl2/MeOH/NH4OH), affording the product as a white solid (0.056 g, 75%). 1H NMR (CDCl3) δ 1.51-1.58 (m, 2H), 1.74-1.77 (m, 2H), 2.14 (s, 6H), 2.25 (s, br. 2H), 3.15 (t, 1H, J=4.2 Hz), 3.24-3.29 (m, 2H), 3.37-3.42 (m, 2H), 3.96 (s, 4H), 6.93 (s, br. 1H), 6.98 (dd, 2H, J=4.8, 7.5 Hz), 7.25 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 18.93, 26.08, 35.82, 44.58, 57.64, 67.11, 122.19, 132.69, 137.86, 146.39, 157.51, 163.07. ES-MS m/z 396 (M+H). Anal. Calcd. for C22H29N5O2.0.4CH2Cl2: C, 62.65; H, 6.99; N, 16.31. Found: C, 62.50; H, 7.35; N, 16.10.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:41][N:42]1[C:46]([CH3:47])=[C:45]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[N:43]1>O1CCCC1.O>[CH3:41][N:42]1[C:46]([CH3:47])=[C:45]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:44]=[N:43]1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1c(S(=O)(=O)Cl)cnn1C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cnn1C
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg) at room temperature, and the mixture was stirred for 5 min. 15-Crown-5 (273 mg) was added. Then 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 290 mg, 97%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCc1cccc(CC=C)c1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1cccc(CC=C)c1OCc1ccccc1

Procedure:
2,6-Diallylphenol (3.48 gm, 0.025 mol) was diluted with methanol (50 ml) and sodium hydroxide (0.8 gm 0.02 mol) was added to the solution followed by the benzyl chloride (3.60 gm, 0.2 mol.). The solution was refluxed for 2 hr, cooled, poured onto water and extracted with hexane. After washing with water and dilute sodium hydroxide, the organic layer was dried over MgSO4, filtered and evaporated to give 2,6-diallylphenyl benzyl ether. MS m/z 264 (M+ calcd for C19H20O=264). H NMR (300 MHz, CDCL3) d 3.45–3.55 (d, 4, CH2 allyl), 4.85 (s, 2, CH2 benzyl), 5.05–5.20 (m, 4, CH2 vinyl), 5.96–6.15 (m, 2, CH vinyl), 7.10–7.25 (m, 3, aromatic), 7.35–7.70 (m, 5, aromatic). Oxidation of the product as described in Example 1 gave 2,6-di(2,3-epoxyypropyl) phenyl benzyl ether as an oil. MS m/z 296 (M+ calcd for C+H20O3=296). H NMR (300 MHz, CDCl3) d 2.60–2.70 (m, 2, CH2 epoxypropyl), 2.75–3.10 (m, 6, CH2 epoxypropyl), 2.31–2.46 (m, 2, CH2 epoxypropyl), 4.75 (s, 2, CH2O), 7.10–7.25 (m, 1, aromatic) 7.45–7.60 (m, 2, aromatic), 7.60–8.15 (m, 5, aromatic).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1
Yield: 94 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(3-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 2 & 3, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 94% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)n2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1

Procedure:
The N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide was prepared from 2-chloro-4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.97) (0.350 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.400 g, 76%). MS (ISP) 527.2 [(M+H)+]; mp 218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(Cl)Cl.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32])(=[O:27])=[O:26]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:14])(=[O:26])=[O:27]
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(CNC(=O)c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
To a round bottom flask was added 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (160 mg, 0.520 mmol) in a solution of anhydrous CHCl3 (10 mL). To the reaction solution was added 3-methylsulfonyl benzylamine (122 mg, 0.661 mmol), TEA (150 μL, 1.10 mmol), and DMAP (67 mg, 0.549 mmol). The reaction solution was allowed to stir at 60° C. for 5 hrs. The reaction solution was diluted with EtOAc (150 mL), poured into a separatory funnel and washed with aq. NH4Cl. The partitioned organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure on the rotavapor. The crude material was chromatographed through a silica gel column using a solvent gradient of 100% hexane to 30% EtOAc to afford 50 mg of title compound (20%). 1H NMR (CDCl3): δ 7.83 (m, 1H), 7.79 (s, 1H), 7.48-7.58 (m, 4H), 7.42-7.46 (m, 2H), 7.05 (s, 1H), 6.66 (t, J=6 Hz, 1H), 4.58 (d, J=6 Hz, 2H), 3.03 (s, 3H); MS (ES): 458.1 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([CH2:68][C:69](O)=[O:70])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([C:69](=[O:70])[CH2:68][CH:65]5[CH2:66][CH2:67][N:62]([C:60]([O:59][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:61])[CH2:63][CH2:64]5)[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-((2-(Piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (225 mg, 0.688 mmol) (Intermediate 15) dissolved in DMF (10 mL) was added triethylamine (4 eq.) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (2 eq.). The solution was stirred for 5 minutes and 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1.5 eq.) was added and was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to afford the desired product. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.40 (1H, d), 8.00 (1H, d), 7.93 (1H, s), 7.86 (1H, dd), 5.34 (2H, s), 4.78 (1H, m), 4.35 (1H, m), 3.85-3.94 (3H, m), 3.21 (1H, m), 2.64-2.82 (3H, m), 2.27 (2H, d), 2.10 (2H, m), 1.86 (3H, m), 1.60 (2H, d), 1.35 (9H, s), 1.99 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:35]([CH2:34][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)#[N:36]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)NC(=O)CO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC#N)C(=O)CO3)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
A mixture of tert-butyl 4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (70 mg, 0.162 mmol), 2-bromoacetonitrile (58.4 mg, 0.487 mmol) and potassium carbonate (67.3 mg, 0.487 mmol) in DMF (2 ml) was stirred at 40° C. for 16 h. The reaction mixture was cooled and diluted with water (10 ml) and extracted with DCM (8 mlX3). The combined organic phase was concentrated and the residue was purified by column (biotage, 10 g) eluted with Ethyl acetate/cyclohexane 0-30% to give product 12 mg. 1H NMR (500 MHz, CDCl3) 7.29 (s, 1H), 7.19-7.26 (m, 5H), 7.13 (m, 2H), 7.05 (d, 2H), 4.88 (s, 2H), 4.81 (s, 2H), 4.73 (br, 1H), 4.21 (d, 2H), 1.38 (br, 9H). LCMS (Method D): RT=1.35 min, M+H+=472.2.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:34])[CH:6]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][N:19]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]1=[O:33])[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C(OC(=O)C(CCN1C(=O)C2=CC=CC=C2C1=O)NC(OC(C)(C)C)=O)C=C.[CH3:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([S:71](Cl)(=[O:73])=[O:72])=[CH:67][CH:66]=1>>[CH2:1]([O:4][C:5](=[O:34])[CH:6]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][N:19]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]1=[O:33])[NH:7][S:71]([C:68]1[CH:67]=[CH:66][C:65]([O:64][CH3:63])=[CH:70][CH:69]=1)(=[O:73])=[O:72])[CH:2]=[CH2:3]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCOC(=O)C(CCn1c(=O)ccn(COCc2ccccc2)c1=O)NC(=O)OC(C)(C)C
Agent: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Product: C=CCOC(=O)C(CCn1c(=O)ccn(COCc2ccccc2)c1=O)NS(=O)(=O)c1ccc(OC)cc1
Yield: 93 %

Procedure:
In a similar manner to the procedures described in Example 1(2)-a and b, reactions were carried out using (±)-2-[2-(1-benzyloxymethylpyrimidin-2,4-dione-3-yl)ethyl]-N-(tert-butoxycarbonyl)glycine allyl ester, the product of (1) above, instead of (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine allyl ester and using 4-methoxybenzenesulfonyl chloride instead of 4-phenoxybenzenesulfonyl chloride to afford the desired compound (yield 93%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH:39]=O)=[N:9]1)[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH2:39][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9]1)[CH3:7]
Reactant: C1CCNC1
Reactant: CCn1nc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1nc(CN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
A solution of pyrrolidine (0.167 mL, 2.017 mmol) and 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (0.87 g, 1.833 mmol) in 1,2-dichloroethane (DCE) (19 mL) and 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.583 g, 2.75 mmol). The reaction mixture was stirred for 1.5 h and then concentrated. The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichloromethane (0-60%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)cinnolin-4(1H)-one (750 mg, 1.416 mmol, 77% yield) as a light yellow gummy solid. LCMS: (M+H)+: 530.3
Reaction SMILES: [OH-].[NH4+:2].C(O)C.[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>O>[NH2:2][CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: [NH4+]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN
Temperature: 50 °C

Procedure:
Aqueous ammonium hydroxide (25%; 10 g, 150 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol and water were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.Cl>O.CN(C=O)C>[CH3:3][O:4][C:5](=[O:10])[C:6]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20])=[C:7]([OH:8])[CH3:9]
Reactant: COC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=C(C)O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 106.7 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.60 g, 65.0 mmol) and DMF (52 mL) is stirred in an ice bath and methylacetoacetate (6.46 mL, 59.9 mmol) is added via a syringe over 10 minutes. The mixture is stirred for an additional 10 minutes and the ice bath is removed. The solution is stirred at ambient temperature for 30 minutes and transferred via cannula into a flask containing 4-chloro-1-fluoro-2-nitrobenzene (5.00 g, 28.5 mmol) cooled to 0° C. via an ice bath. The reaction is allowed to warm slowly and is stirred for two days at room temperature. The black mixture is acidified with 2 N HCl, turning it yellow. The resulting solution is diluted with water and extracted with ether. The combined ether layers are washed with water and brine and dried over MgSO4 to give the crude title compound (8.26 g), which contains a small amount of mineral oil. The material is used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:21][C@@:19]1([CH2:22][OH:23])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([C:39]5[CH:40]=[N:41][NH:42][CH:43]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[N:12][N:13]=[C:14]2[CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5cn[nH]c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of the compound (500 mg, 0.98 mmol) obtained in Example 52-1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg, 1.08 mmol), tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.10 mmol), and potassium carbonate (272 mg, 1.97 mmol) in 1,2-dimethoxyethane (6 mL) and water (3 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate:methanol=40:60). A solution of the residue and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 N aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate/methanol=40:60). The residue was dissolved in a solution (8 mL) of ethyl acetate/methanol=3:1, and diisopropyl ether (20 mL) was gradually added to the mixture with stirring at room temperature to prepare a suspension. The suspension was stirred at 60° C. for 1 h and stirred for 1 h with cooling to room temperature. The colorless precipitate was collected by filtration and washed with diisopropyl ether. The solid was dried under reduced pressure to obtain the title compound (46 mg, 12%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[NH:9]1[CH2:10][CH:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCOCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C1CN(C2CNC2)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 3-morpholinoazetidine-1-carboxylate (31 mg) was treated with 4N HCl in dioxane (5 eq) in 1 mL of DCM. The reaction mixture was stirred for 3 hours at room temperature and then concentrated to dryness to yield 4-(azetidin-3-yl)morpholine in quantitative yield. 4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.413 g) was reacted with 4-(azetidin-3-yl)morpholine via General Procedure B to afford 0.4 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.O>[NH2:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
To tert-butyl 2-[3-{[(benzyloxy)carbonyl]amino}-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (6.19 g, 16.6 mmol) in the reactor a mixture of 4:1 ethanol/water (77 mL) was added and degassed with argon for several minutes. During degassing Pd(OH)2 (0.613 g) was added and subjected to catalytic hydrogenation in the reactor containing a hydrogenating agent under the conditions: p(H2)=100 psi, t=2 h. The reaction mixture was filtered through Celite and the solvent evaporated under reduced pressure. To obtain a solid ethanol was added to the resulting material several times and the azeotropic mixture with water was distilled under reduced pressure to give 3.18 g (13.4 mmol) of a grey compound.
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=O)[NH:14][C:15]=1[CH3:16].N1CCCCC1>C(O)C>[CH:1]1([C:4]2[C:8](=[CH:17][C:13]3[NH:14][C:15]([CH3:16])=[C:11]([CH3:10])[CH:12]=3)[C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C=O)[nH]c1C
Reactant: O=C1CC(C2CC2)=NN1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)NN=C2C2CC2)[nH]c1C

Procedure:
A reaction mixture of 3-cyclopropyl-2-pyrazolin-5-one (790 mg, 6.3 mmol), 4,5-dimethylpyrrole-2-carboxaldehyde (800 mg, 6.5 mmol), and piperidine 100 mg, in ethanol 50 mL was stirred at 90° C. for 3.5 h. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography using (3:7) ethyl acetate:hexane as the mobile phase, then further purified by recrystallization from toluene.