Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([CH3:11])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:34]([O:38][C:39]([C:41]1[C:49]2[CH2:48][CH2:47][O:46][CH:45]([CH2:50][NH2:51])[C:44]=2[S:43][C:42]=1[NH2:52])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[C:34]([O:38][C:39]([C:41]1[C:49]2[CH2:48][CH2:47][O:46][CH:45]([CH2:50][NH:51][C:6](=[O:8])[C@H:2]([NH:1][C:9](=[O:10])[CH3:11])[CH:3]([CH3:4])[CH3:5])[C:44]=2[S:43][C:42]=1[NH2:52])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of Ac-D-Val-OH (0.17 g, 1.09 mmol) dissolved in dichloromethane (15 ml) was added N,N-dimethylformamide (1 ml), 1-hydroxybenzotriazole (0.15 g, 1.09 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.21 g, 1.09 mmol). The reaction mixture was stirred for 15 min. at room temperature at which time a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.31 g, 1.09 mmol) in dichloromethane (10 ml) was added followed by N,N-diisopropylethylamine (0.186 ml, 1.09 mmol). The resulting mixture was stirred over night at room temperature diluted with dichloromethane (10 ml) washed with 10% aqueous citric acid (20 ml), sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent was evaporated in vacuo affording 415 mg (90%) of 7-((2-(R)-acetylamino-3-methyl-butyrylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:4]1[CH:3]=[CH:2][CH:6]=[N:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cccn2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-iodopyrazole (400 mg, 2 mmol) in DMF(4 mL) at 0 C was added sodiumhydride (80 mg, 60% dispersion in mineral oil, 2 mmol) followed by benzyl bromide (342 mg, 2 mmol) and reaction mixture was allowed to stir for 2 h. Reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give N-benzylpyrazole in almost quantitative yield. 1H NMR 5.29 (s, 2H), 7.18–7.28 (m,2H), 7.28–7.40 (m, 4H), 7.53 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9](C(O)=O)([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:24])([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(Cn1cncn1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred suspension of 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.13 g, 0.52 mmol) obtained in step III, in CHCl3 (2.6 mL) was added conc. H2SO4 (0.25 mL, 5.2 mmol). To this homogenous solution NaN3 (0.1 g, 1.56 mmol) was added in portions over a period of 30 minutes, while keeping the temperature of the reaction below 40° C. After stirring the reaction mixture for 2 h at r.t., the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% aq. NaOH solution and extraction with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonan-3-amine (0.08 g) as a viscous liquid in 70% yield. m/z (M+1) 219; 1H NMR (CDCl3) 300 MHz δ 7.98 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 2.38-2.30 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.55-1.36 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CO[C:12]1[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1>CO>[O:19]=[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:12]1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCN1CCNCC1
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(CCO)CC1
Yield: 51.1 %

Procedure:
A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (10.9 g) in methanol (50 ml) was refluxed for 24 hr and evaporated. The residue was chromatographed on silica gel (100 g) using methanol-ethyl acetate (1:4). The eluates were evaporated and crystallized from ethyl acetate-hexane to give 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (9.2 g): mp 85°-86° C.; ir(CHCl3) 3440, 1616 and 1555 cm-1 ; nmr(CDCl3) δ2.55 (t, 2H), 2.63 (m, 4H), 3.30 (m, 4H), 3.60 (t, 2H) and 6.40-7.65 (m, 5H); and Anal. Calcd for C13H18N2O2 : C, 66.64% H, 7.74% N, 11.96% and Found: C, 66.12% H, 7.83% N, 11.99%.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[Cl:1][C:2]1[C:11](/[CH:12]=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: Cc1c(F)ccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Yield: 86.1 %

Procedure:
Following the procedure described for Intermediate 1, 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (6.6 g, 29.5 mmol), titanium(IV) isopropoxide (17.0 g, 60 mmol), (R)-2-methyl-2-propanesulfinamide (3.6 g, 29.5 mmol) and THF (200 mL) gave the title compound (8.3 g, 86%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.73 (1H, s), 7.71 (1H, dd, J 6.0 Hz), 7.40 (1H, t, J 8.2 Hz), 2.69 (3H, s), 1.32 (9H, s).
Reaction SMILES: [CH2:1]([N:4]1[C:28](=[O:29])[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][CH:18]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1)[CH:2]=C.C[N+]1([O-])CC[O:34]CC1.[C:38](=[O:41])(O)[O-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[OH:34][CH:2]([CH2:38][OH:41])[CH2:1][N:4]1[C:28](=[O:29])[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:21][CH:22]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1CC(O)CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Allyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 10), 600 mg, 1.57 mmol] was dissolved in tetrahydrofuran (65 mL) and water (65 mL), treated with 4-methylmorpholine 4-oxide (221 mg, 1.88 mmol, 1.2 equiv) and osmium tetroxide (50.0 μL, 0.160 mmol, 0.1 equiv). The mixture was stirred for 72 hours at ambient temperature, poured into sodium bicarbonate (200 mL, saturated aqueous) and extracted with ethyl acetate (2×150 mL) and chloroform (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The sodium sulfate was washed with a 1:1 mixture of methanol:chloroform (6×30 mL) and the filtrate was concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 85:15; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.30-8.26 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.72-7.67 (3H, m), 7.62-7.54 (3H, m), 7.39 (2H, d, J=8.4 Hz), 6.47-6.45 (1H, m), 5.88 (2H, s), 4.31 (2H, dd, J=5.3, 2.0 Hz), 4.18-4.13 (1H, m), 3.69-3.65 (2H, m), 3.49 (1H, d, J=5.8 Hz), 3.02 (1H, m); high resolution mass spectrometry (ES+) m/z 417.1684 [(M+H)+; calculated for C22H21N6O3: 417.1670].
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[CH:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of (2R)-2-amino-N-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]butanamide (Intermediate 160, 40 mg, 0.11 mmol) in dry DCM (5 ml) TEA (0.042 ml, 0.3 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (23.7 mg, 0.08 mmol) in dry DCM (3 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (22 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[C:15](=[O:22])[NH:14][C:11]2=[CH:12][CH:13]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:17][CH2:18][S:19][CH2:20][CH2:21]3)[C:15](=[O:22])[N:14]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CCSCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Reaction time: 16 h

Procedure:
Cesium carbonate (610 mg, 1.87 mmol) was added to a solution of 5-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one from Step C (372 mg, 1.25 mmol) and ethyl bromoacetate (0.166 mL, 1.50 mmol) in DMF (2 mL). After 16 h, H2O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the title compound. MS: m/z=386 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26](=O)[CH3:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH3:27])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 (45 mg, 0.11 mmol) in MeOH (4 mL) was added cyclohexylarnine (31 mg, 0.22 mmol) and sodium cyanoborohydride (34 mg, 0.69 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The resultant solid was purified by reverse phase HPLC providing the title compound (G-30). 1H NMR (300 MHz, MeOD) δ 8.84 (m, 1H), 8.42 (s, br, 1H), 8.35 (m, 2H), 7.82 (m, 3H), 5.55 (d, 1H), 4.02 (q, 2H), 3.80 (d, 2H), 3.22(m, 1H), 3.00 (m, 1H), 2.77(s, br, 2H), 2.19 (d, 1H), 2.05 (d, 1H), 1.78 (m, 4H), 1.50 (m, 5H), 1.24 (m, 9H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][C@@H:43]([C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1)[CH3:44]>ClCCl>[CH3:57][C:55]([CH3:56])([CH3:58])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([C@H:43]([CH3:44])[CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: O=C(O)c1ccon1
Reactant: C[C@@H](CCN)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CCNC(=O)c1ccon1)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-Isoxazolecarboxylic acid (0.015 g, 0.13 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.05 g, 0.13 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 36-4 (0.03 g, 0.10 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 0-60% ethyl acetate/hexane gradient, followed by 10-90% reverse phase gradient gave 36-5. (0.017 g, 43%). HRMS (M+H)+: observed=386.2189, calculated=386.2187
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(CCC2C=CC=CC=2)C=CC=CC=1.C1(CCC2C=CC(S(Cl)(=O)=O)=CC=2)C=CC(S(Cl)(=O)=[O:40])=CC=1.ClS(O)(=O)=O>>[C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7]([OH:40])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: O=S(=O)(O)Cl
Solvent: c1ccc(CCc2ccccc2)cc1
Product: O=S(=O)(O)c1ccc(CCc2ccccc2)cc1

Procedure:
Polybibenzyl sulfone homopolymers are prepared by heating bibenzyl-4-sulfonyl chloride in the presence of a catalytic amount of an anhydrous Lewis acid, or by using a stoichiometric mixture of bibenzyl and bibenzyl-4,4'-disulfonyl chloride is hereinafter described. The preparation of the homopolymer first necessitates the synthesis of either the mono or di sulfonyl chloride derivative of bibenzyl. Bibenzyl-4-sulfonyl chloride may be prepared by a three step procedure by treating bibenzyl in solution with approximately equi molar quantities of chlorosulfonic acid to form bibenzyl-4-sulfonic acid followed by neutralization in an aqueous medium using sodium or barium hydroxide to yield the sodium or barium salt which is in turn treated in a solvent with an acid halide such as thionyl chloride to yield bibenzyl-4-sulfonyl chloride. Another suitable technique for the preparation of the monosulfonyl chloride derivative involves the treatment of the free sulfonic acid derivative of bibenzyl in a solvent with a complex of phosgene and a tertiary organic amide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([CH3:22])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([Cl:42])[CH:33]=1>C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:2]2[N:7]=[C:6]([N:8]3[CH2:9][C@H:10]([CH3:22])[N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@H:12]([CH3:14])[CH2:13]3)[CH:5]=[CH:4][C:3]=2[O:23][CH3:24])(=[O:39])=[O:40])=[C:34]([Cl:42])[CH:33]=1
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-amino-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D12)(1.0 g, 2.97 mmol) was dissolved in DCM (10 mL) and pyridine (10 mL) and then cooled to 0° C. 4-Bromo-2-chlorobenzenesulfonyl chloride (0.946 g, 3.27 mmol), dissolved in DCM (5 mL) was then added dropwise and the reaction then allowed to warm to rt overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (50 mL). Aqueous layer was extracted with DCM (2×50 mL) and combined organic extracts washed with brine (100 mL). The organic layer was dried (MgSO4) and evaporated to give a dark oil which was purified by chromatography [silica gel, eluting with 0 to 50% Ethyl acetate/pentane]. Product fractions evaporated to give a yellow crunchy foam (D13) (1.29 g), MS (ES+) m/e 589/591 [M+H]+.
Reaction SMILES: COC(=O)C[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7].C[O-].[Na+].CO.IC[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CS(C)=O.O>[CH2:46]([O:45][C:43](=[O:44])[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])[CH3:47]
Reactant: CCOC(=O)CI
Reactant: COC(=O)CCS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 0.25 h

Procedure:
A solution of 3-[4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (200 mg, 0.4 mmol) in DMSO (5 mL) was treated a 15% solution of sodium methoxide in methanol (150 μL, 0.42 mmol). After 15 minutes, the mixture was cooled (water bath) and ethyl iodoacetate (50 μL, 0.42 mmol) was added followed by removal of the water bath. After 18 hours, the mixture was diluted with EtOAc (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-6% methanol in dichloromethane. The material from the column was twice triturated with ether, filtered and dried under vacuum to afford the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(N)nc2c1nnn2Cc1ccccc1F
Reaction time: 2 h

Procedure:
2.8 g (10 mmol) of 5-amino-7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine are dissolved in 150 ml of ethanol while heating at 40°-50°, and 10 ml of an aqueous solution of dimethylamine (40%) is added to the resulting solution. The reaction mixture is left to stand at room temperature for 2 hours. The precipitated product is then filtered off with suction and washed with water. Recrystallisation from ethanol yields 5-amino-7-(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 165°-167°.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[S:20](Cl)([C:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:28]([N:29]([CH3:31])[CH3:30])[C:27]=2[CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21].Cl>[OH-].[Na+].O1CCCC1>[CH3:30][N:29]([CH3:31])[C:28]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:27]=1[CH:26]=[CH:25][CH:24]=[C:23]2[S:20]([NH:16][CH:15]([CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C:17]([OH:19])=[O:18])(=[O:22])=[O:21]
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)c1cccc2c(S(=O)(=O)NC(CCCNC(=O)OCc3ccccc3)C(=O)O)cccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nδ -Carbobenzyloxy-L-ornithine (39.6 g, 0.149 mol) was dissolved in a solution of 2N NaOH (90 mL) and tetrahydrofuran (200 mL) under nitrogen. After about 15 minutes at ambient temperature, the mixture was cooled to about 0° C. and subsequently treated with additional 2N NaOH (85 mL) and dansyl chloride (45.0 g, 0.167 mol) in 5 g portions over 15 minutes. The mixture was stirred at about 0° C. for about 1 hour and at room temperature for about 2 hours before it was neutralized to pH 7 with 1N HCl. The precipitate was suction-filtered and the filtrate was diluted with ethyl acetate. The organic phase was then separated, washed with brine, dried over Na2SO4 and concentrated to give a combined yield of 103.17 g (70.4%, two runs) of 2d as a yellow foam which was used directly.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>C1C=CC=CC=1>[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 18 h

Procedure:
α-(3-(1-Phenylethenyl)phenyl)propionic acid (35 g) obtained in Example 2 was dissolved in 250 ml of benzene and 250 ml of water was further added thereto with vigorous stirring to prepare a suspension. Then, 2 liter of 2% aqueous solution of potassium permanganate was dropped little by little over 1.5 hours. After the dropping, stirring was continued for 18 hours at room temperature. After the reaction, it was acidified by adding concentrated sulfuric acidand was treated by adding 35 g of sodium sulfite. After that, 500 ml of water was added and extraction was carried out three times with 150 ml of ether. The ether solution was washed with water and it was extracted three times with 200 ml of 5% aqueous solution of sodium hydroxide. The aqueous layer was then acidified by adding hydrochloric acid and extracted again three times with 150 ml of ether, which was followed by washing with water, drying with anhydrous magnesium sulfate, and filtration. The ether was then removed by reduced-pressure evaporation. Finally, 20 g of α-(3-benzoylphenyl)propionic acid (ketoprofen) was obtained by re-crystallization from benzene/petroleum ether mixture. The melting point and spectrum were the same as those of an authentic sample.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.Cl.[O:34]([NH2:36])[CH3:35]>CO.N1C=CC=CC=1>[CH3:35][O:34][N:36]=[C:25]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(c1ccccc1)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol) in MeOH (4.0 mL) was added methoxylamine hydrochloride, 98% (0.089 g, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, as determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone O-methyl oxime as a off-white solid. MS (ESI, pos. ion) m/z: 453 (M+1).