Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([C:35](C)=O)[CH3:34].C(Br)C=C>O>[CH2:35]([O:4][C:3]1[CH:5]=[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([OH:9])=[CH:8][C:2]=1[CH3:1])[CH:33]=[CH2:34]
Reactant: CCC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOc1cc(C(=O)CCCCCCCCCCCCCCC)c(O)cc1C

Procedure:
Under nitrogen atmosphere a mixture of 17.5 g of the keto-compound of step 1, 10.2 g of potassium carbonate and 200 ml of methyl ethyl ketone was refluxed with stirring together with 6.9 g of allyl bromide for 1 hour. After a total refluxing time of 9 h the reaction mixture was mixed with 100 ml of water. The methyl ethyl ketone layer is separated, shaken twice with a 20% by weight sodium chloride solution and dried with sodium sulphate. The residue left after evaporation of the solvent was stirred with methanol, whereupon the precipitate formed was filtered with suction and recrystallized from methanol.
Reaction SMILES: [F:1][CH2:2][CH2:3][C@@H:4]1[C@@H:12]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:18])[O:10][C:9](=[O:19])[C@@H:8]([NH:20][C:21](=[O:31])[C:22]2[C:27]([OH:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=2)[CH2:7][CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39]>CC(C)=O>[C:38]([O:41][CH2:42][O:28][C:27]1[C:22]([C:21](=[O:31])[NH:20][C@H:8]2[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:3][CH2:2][F:1])[C@@H:12]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:18])[O:10][C:9]2=[O:19])=[N:23][CH:24]=[CH:25][C:26]=1[O:29][CH3:30])(=[O:40])[CH3:39]
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CCF)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CCF)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of N-((3S,7R,8R,9S)-7-(2-fluoroethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (97 mg, 0.220 mmol) in anhydrous acetone (2.2 mL) were added powdered K2CO3 (60.9 mg, 0.440 mmol) and bromomethyl acetate (32.4 μl, 0.330 mmol). The resulting mixture was heated to 50° C. and stirred vigorously for 16 h, then filtered through a plug of Celite®, concentrated, and purified by column chromatography on SiO2 (5→50% acetone/hexanes) to provide the title compound as a sticky solid (87 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 5.74 (s, 2H), 4.90 (dq, J=9.1, 6.4 Hz, 1H), 4.58 (ddt, J=9.4, 5.9, 4.6 Hz, 2H), 4.50-4.39 (m, 1H), 3.91 (s, 3H), 3.45 (dd, J=8.4, 6.6 Hz, 1H), 3.26 (dd, J=8.4, 6.4 Hz, 1H), 3.14-3.02 (m, 1H), 2.36 (dt, J=12.9, 6.7 Hz, 1H), 2.07 (s, 3H), 2.06-1.98 (m, 1H), 1.84 (dp, J=13.4, 6.7 Hz, 1H), 1.78-1.60 (m, 4H), 1.57 (s, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.39-1.29 (m, 1H), 1.10 (dd, J=14.3, 5.7 Hz, 1H), 0.92 (d, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.35, 167.84, 160.52, 157.81, 143.31, 141.51, 140.02, 107.14, 87.11, 81.42, 81.36, 79.73, 77.78, 72.81, 53.74, 49.43, 37.34, 37.30, 31.13, 29.17, 28.98, 26.73, 26.26, 18.44, 17.02, 16.98, 16.74, 15.69; HRMS-ESI (m/z) ([M+Na]+) calcd for C25H37FN2O8Na, 535.2426, found 535.2423.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17])([O-])=O.[CH3:26]O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:17]
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Product: CN1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.045 g, 0.12 mmol, 1.0 equiv.) in methanol was added Pd/C (0.02 g, 0.02 mmol, 0.16 equiv.). The reaction mixture was stirred at room temperature under H2 balloon pressure for 1h. The reaction was filtered through celite and concentrated under reduced pressure. The crude solid was washed with ether to obtain of pure 1-(2-Amino-5-(thiophen-2-yl)phenyl)-3-((1-methylpiperidin-4-yl)methyl)urea (0.03 g, 67% yield). ESI+ MS: m/z 345 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ 7.66 (d, J=1.5 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.10 (dd, J=3.5 Hz, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.27 (t, J=5.5 Hz, 1H), 4.88 (bs, 2H), 2.98 (t, J=5.5 Hz, 2H), 2.77 (d, J=11.0 Hz, 2H), 2.16 (s, 3H), 1.85 (m, 2H), 1.63 (d, J=4.5 Hz, 2H), 1.36-1.33 (m, 1H), 1.20-1.13 (m, 3H).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C#N)c1ccc(OCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cnc2nc(C=O)nn2c1
Solvent: CO
Product: Cc1cnc2nc(CC3=C(O)CC(COc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Reaction time: 5 h
Yield: 32.4 %

Procedure:
A solution of 2-[4-(2-Cyclopentyl-4,6-dioxo-tetra hydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile (200 mg, 0.54 mmol) in anhydrous MeOH (4.0 mL) was treated with 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (140 mg, 0.86 mmol), followed by borane-dimethylamine complex (47 mg, 0.8 mmol) at room temperature. The reaction was stirred for 5 hours before it was quenched by the addition of 0.5N HCl (25 mL). The mixture was extracted with 10% MeOH in CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by crystallization from EtOAc/Hexanes to give the product as a white solid (91 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6) δ: 1.67 (m, 8H), 1.70 (s, 6H), 2.38 (s, 3H), 2.55 (m, 1H), 2.77 (m, 2H), 3.77 (m, 2H), 4.12 (m, 1H), 4.44 (m, 1H), 6.97 (m 2H), 7.35 (m, 1H), 8.69 (s, 1H), 9.03 (s, 1H), 10.98 (brs, 1H).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][C:25]([CH3:41])([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[CH3:26])(=O)=O)=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([S:8][CH2:22][CH2:23][CH2:24][C:25]([CH3:41])([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29])[CH3:26])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(C)(C)NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: OC(=S)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CCCSC(=O)c1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
A mixture of thiobenzoic acid (890 mg) and sodium hydride (50%) (220 mg) in dimethylformamide (8 ml) was stirred for 10 minutes with ice-cooling. 5-p-Toluenesulfonyloxy-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane (1.64 g) in dimethylformamide (8 ml) was added thereto, followed by stirring for 25 minutes. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and then water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 5-benzoylthio-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane.
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH:23]1[CH2:29][CH2:28][C:26](=O)[CH2:25][CH2:24]1)=[O:22]>>[C:2]([N:10]1[C:26]2[CH2:28][CH2:29][CH:23]([C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:24][C:25]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Product: CCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1

Procedure:
Following a procedure similar to that of Example 31 and using 11 g. of 1-benzoyl-1-phenylhydrazine hydrochloride and 7.62 g. of ethyl cyclohexanone-4-carboxylate (prepared in situ from the corresponding ethylene ketal) there was obtained 6.2 g. of the title compound; m.p. 67°-69°C. (ether-pentane).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]2([C:20]3[C:15](=[N:16][CH:17]=[C:18]([OH:21])[CH:19]=3)[O:14][C:13]3[C:8]2=[CH:9][C:10]([C:22]2[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][CH:12]=3)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.CC1OCCC1>[F:28][C:23]1[C:22]([C:10]2[CH:9]=[C:8]3[C@:4]4([N:3]=[C:2]([NH2:1])[CH2:7][O:6][CH2:5]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:19]=4)[O:14][C:13]3=[CH:12][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Yield: 15.9 %

Procedure:
A vial charged with a solution of (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.880 g, 1.864 mmol), 2-fluoropyridin-3-ylboronic acid (0.276 g, 1.957 mmol), PdCl2(dppf)-CH2Cl2-adduct (0.038 g, 0.047 mmol), and potassium carbonate (1.031 g, 7.46 mmol). Dioxane (10 mL) and water (5 mL) were added, and the vial was flushed with argon and heated to 100° C. for 90 minutes. Pd2(dba)3 (0.171 g, 0.186 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.224 g, 0.466 mmol), and potassium hydroxide (1.046 g, 18.64 mmol) were added to the reaction mixture. The vial was sealed and heated to 120° C. for an additional 3 hours. The reaction mixture was then neutralized to pH 7 with 1N HCl, and was diluted with 2-MeTHF. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-5′-amino-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-3-ol (0.133 g, 0.352 mmol). Step 2: A solution of (S)-5′-amino-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-3-ol (0.133 g, 0.352 mmol), potassium carbonate (0.194 g, 1.406 mmol), and neopentyl iodide (0.093 mL, 0.703 mmol) in 1.5 mL DMF was heated to 115° C. overnight. The reaction mixture was then diluted with 2-MeTHF and washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 EtOAc/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.025 g, 0.056 mmol, 15.86% yield). MS m/z=449.20 [M+H]+. Calculated for C25H25FN4O3: 448.49.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ccc2c(Br)cccc21
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 51 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of n-butyllithium in pentane (28.8 ml) over 30 minutes and stirred for 30 minutes. The mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) added with ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was acidified with 5 N aqueous hydrochloric acid under ice cooling and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 52, 3.17 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([OH:40])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([O:40][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](O)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Yield: 84.8 %

Procedure:
A solution of p-toluenesulphonyl chloride (650 mg, 3.4 mmol) in pyridine (10 ml) was added dropwise to a mixture of the 20,20-Ethylenedioxypregna-5,14-diene-3β,12β-diol 12-acetate (22) (1.3 g, 3.1 mmol) in pyridine (15 ml) at 0° C. The reaction mixture was left stirring at room temperature for 24 hours after which water was added to the reaction mixture. The solution was extracted with ethyl acetate (2×50 ml), the ethyl acetate layer was washed citric acid (5×50 ml), saturated sodium bicarbonate solution (100 ml), saturated sodium chloride solution (100 ml) and water (100 ml) The ethyl acetate was dried (MgSO4), filtered, and evaporated and purified by flash column chromatography using hexane-ethyl acetate (8:2 v/v) as the eluant to give the β-O-tosyl steroid (26), (1.5 g, 84%), as a yellow oil, (Found M 570.271, C32H42O7S requires: M 570.273).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:20])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:10][C:9]([Br:21])=[CH:8][CH:7]=2)[CH3:3].C(N(CC)C(C)C)(C)C.Br[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2>C(O)(C)(C)C>[N:40]1[C:32]([NH:1][C@H:2]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]([Br:21])=[CH:8][CH:7]=3)[CH3:3])=[C:33]2[C:37]([NH:36][CH:35]=[N:34]2)=[N:38][CH:39]=1
Reactant: Brc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1

Procedure:
This example is also described in Example 24 of WO 2011/055215. To a solution of (S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one (0.20 g, 0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine (0.2 ml, 1.162 mmoles) and 6-bromopurine (0.087 g, 0.435 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid. MP: 151-154° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d, J=6.4 Hz, 3H). Mass: 463.99 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[C:36](O)=[O:37]>O>[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[C:36]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:15]1[S:14][C:11]2[C:10]([N:16]=1)=[CH:9][C:8]([CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH:13][N:12]=2)=[O:37]
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C28H25N5O3S: 511.17. Found (M+H)+ m/z=512.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]([CH3:20])[S:10]2(=[O:22])=[O:21])C=CC=CC=1.C(Cl)[Cl:24]>>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]([CH3:20])[S:10]1(=[O:22])=[O:21]
Reactant: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Reactant: ClCCl
Product: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of 2-phenylthiomethyl-4- (3-methylbutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.15 g, 24.66 mmol) in 200 ml of methylene chloride was added in one portion under nitrogen sulfuryl chloride (2.36 ml, 29.6 mmol) and the mixture was stirred for 3.5 hours at room temperature. The mixture was concentrated in vacuo and the residue was triturated in hexane to afford 4.64 g (70%) of 2-chloromethyl-4- (3methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3 ; X'=Cl) as a solid, m.p. 59°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.[BH4-].[Na+]>CCCCCC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[O:13][CH:14]1[CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1cc(C=O)cc(C)c1OC1CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)c1cc(CO)cc(C)c1OC1CCC1
Temperature: 40 °C
Yield: 83.8 %

Procedure:
A mixture of 2-cyclobutoxy-5-formyl-3-methyl-benzoic acid methyl ester (676 mg, 2.7 mmol), silica gel (5.15 g) and NaBH4 (103 mg, 2.7 mmol) in hexane (30 mL) is heated at 40° C. overnight. The mixture is cooled to RT and filtered, washing the solids with EtOAc (15 mL) and diethyl ether (15 mL). The filtrate is concentrated in vacuo to give product (283) as viscous yellow oil (566 mg, 84%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH3:32])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18FN5O2, 391.1
Reaction SMILES: [CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][OH:12])[C:4]1=[O:13])[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][OH:12])[C:4]1=[O:13])[CH3:2]
Reactant: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCO)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC1(c2cccc(O)c2)CCCCN(CCO)C1=O

Procedure:
To a solution of 3-ethyl-1-(2-hydroxy-ethyl)-3-(3-benzyloxy-phenyl)-azepan-2-one, as described above in Step C, (0.270 g, 0.735 mmol) in MeOH (15 mL) was added 10% Pd on C (0.06 g), and the mixture was hydrogenated under a H2 balloon at ambient temperature for 16 h. The reaction mixture was filtered, and the filtrate concentrated to dryness to give the title compound.
Reaction SMILES: N1CCCC1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>CO>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[CH:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Yield: 71 %

Procedure:
2.5 mL (30.1 mmol) of pyrrolidine were added to a room temperature (about 25° C.) solution of 5.30 g (30.1 mmol) of 7-methoxy-1-tetraione and 4.55 g (30.1 mmol) of 3-nitrobenzaldehyde in 25 mL methanol. The reaction flask was fitted with a soxhlet extractor containing a thimble filled with 3 Å molecular sieves and a reflux condenser was placed on top of the soxhlet extractor. The reaction mixture was heated to reflux under N2 for 18 hours, cooled to room temperature and filtered. The precipitate was washed twice with CH3OH, and then dried on the funnel for 24 hours to yield 6.62 g of light tan powder. (71% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].Br[CH2:32][C:33]#[N:34]>>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:32][C:33]#[N:34])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: N#CCBr
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2O)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OCC#N)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared in a similar manner as described for Example 32 starting from N-(2,6-dichlorobenzoyl)-4-(2-hydroxyphenyl)-L-phenylalanine methyl ester and bromoacetonitrile. ESMS: m/z 483 (MH+)
Reaction SMILES: OCCC[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[NH+]1C=CC=CC=1.[C:16]([CH2:18][CH2:19][O:20][P:21](=[O:24])([OH:23])[OH:22])#N>>[NH:7]1[CH:8]=[CH:9][N:5]=[C:6]1[CH2:16][CH2:18][CH2:19][O:20][P:21](=[O:22])([OH:24])[OH:23]
Reactant: OCCCn1ccnc1
Reactant: N#CCCOP(=O)(O)O
Agent: c1cc[nH+]cc1
Product: O=P(O)(O)OCCCc1ncc[nH]1

Procedure:
Using 0.13 g of the purified 1-(3-hydroxypropyl)imidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium solution (1 mmol/ml), and subsequently following the same processes as in Example 1, 0.2 g of crude 3-imidazolylpropylphosphoric acid was obtained.