Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:15]=[C:14]([CH:16]=[C:17]([CH3:19])[CH3:18])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)C.[OH-].[Na+].ON1C2C=CC=CC=2N=N1.[CH3:33][NH:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C.[OH-].[Li+].Cl>CC(C)=O.CO.CN(C=O)C.C(OCC)(=O)C>[CH3:33][N:34]([CH2:35][CH2:36][CH3:37])[C:4](=[O:20])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([CH:16]=[C:17]([CH3:18])[CH3:19])[CH:15]=1)[C:8]([OH:10])=[O:9]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(C=C(C)C)cc(C(=O)OCC)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(C=C(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
Dissolve 5-(2-methylpropenyl)-isophthalic acid diethyl ester (535 mg, 1.94 mmol) in acetone (10 mL) and add a solution of NaOH (77 mg, 1.94 mmol) in methanol (2 mL). Stir at room temperature 2 days and concentrate. Dissolve in water and wash with diethyl ether. Acidify the water layer to about pH=1 with 1 N HCl and extract with dichloromethane. Dry the dichloromethane layer over magnesium sulfate, filter and concentrate. Dissolve the residue in DMF (10 mL) and add 1-(3-dimnethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (409 mg, 2.13 mmol) and 1-hydroxybenzotriazole (288 mg, 2.13 mmol). After 30 min, add methyl-propyl-amine (283 mg, 3.87 mmol) and triethylamine (665 mg, 6.58 mmol) in DMF (2 mL). Stir at room temperature 1 h and dilute with ethyl acetate. Wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride and concentrate. Dissolve the residue in THF (20 mL) and add 1 N lithium hydroxide (10 mL, 10 mmol). Stir at room temperature for 4 h and acidify to about pH=1 with 1 N HCl. Extract with dichloromethane, dry (magnesium sulfate), filter and concentrate to give the title compound as a solid (220 mg, 41%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:21]([C:18]2[CH:19]=[N:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of benzylpiperazine (0.45 mL, 2.59 mmol) in methylene chloride (15 mL), cooled on an ice-bath, was 6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) added slowly. The reaction was stirred for 30 min and the formed white precipitation was filtered and washed with methylene chloride and water affording, after drying, 0.68 g (82% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.70 (d, J=3 Hz, 1 H), 8.14 (dd, J=8, 3 Hz, 1 H), 7.76 (d, J=8 Hz, 1 H), 7.50-7.43 (m, 2 H), 7.38-7.30 (m, 3 H), 4.23 (br s, 2 H), 3.79-3.63 (m, 2 H), 3.45-3.18 (m, 2 H), 3.11-2.96 (m, 2 H), 2.96-2.81 (m, 2 H); MS (ES) m/z 352 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[OH2:22]>Cl>[OH:15][CH2:14][CH:13]([CH2:18][OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: O
Agent: Cl
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 49 %

Procedure:
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.59 g, 1.9 mmol) in hydrochloric acid (1.0M, 4 ml) was stirred at 60° C. for 24 hours. The solution was diluted with water and neutralised with Amberlite IR 45 (OH− form). The mixture was filtered, the resin washed with water and the solvent evaporated under reduced pressure. The residue was recrystallised from water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (238 mg, 49%), m.p. 275-277° C.; λmax (H2O) 253 (ε 11,500) and 270 (shoulder, ε 8,630) nm; νmax (KBr) 3420, 3140, 1690, 1645, and 1605 cm−1; δH [(CD3)2SO] 1.3-1.5 (3H, m, CHCH2CH2), 3.42 (4H, d, J 5 Hz, 2×CH2O), 3.99 (2H, t, J 7 Hz, CH2N), 4.41 (2H, br, D2O exchangeable, 2×OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 7.71 (1H, s, 8-H), and 10.55 (1H, br, D2O exchangeable, 1-H); (M+ found 253.1176. C10H15N5O3 requires M+ 253.1175).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CCN(CC)CC>C(Cl)Cl>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([C@H:11]2[CH2:12][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]2([CH3:17])[CH3:16])=[O:15])[CH2:32][CH2:31]1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (2 g, 8.23 mmol) in DCM (50 ml) EDCI (946 mg, 9.876 mmol) and HOBt (756 mg, 9.876 mmol) were added at 0° C., after 10 minutes N-Ethyl piperazine (939 mg, 16.46 mmol) and Et3N (3 mL, 41.15 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude residue was stirred in hexane and obtained solid was filtered. Wt: 1.6 g; Yield: 70%. 1H NMR (300 MHz, CDCl3): δ 4.77 (d, 1H, J=8.4 Hz), 3.89-3.78 (m, 1H), 3.6-3.46 (m, 3H), 2.80 (m, 1H), 2.60-2.40 (m, 8H), 1.80 (m, 1H), 1.43 (s, 9H), 1.12 (s, 3H), 1.2 (t, 3H), 0.87 (s, 3H); Mass: [M+1]+ 340 (25%), [M+Na]+ 362 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C=Cc2ccc(OC(F)F)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1ccc(CCc2ccc(OC(F)F)cc2)cc1

Procedure:
19.7 g of 1-(4-ethoxyphenyl)-2-(4'-difluoromethoxyphenyl)-ethene are hydrogenated in 150 ml of THF analogously to Example 6ab), using 6 g of Pd/C (5% Pd) as catalyst. m.p.: 37° C., Δn=0.103, viscosity: 8
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].O.[NH2:12][NH2:13]>C(O)C.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:12][NH2:13])[NH2:7]
Reactant: NN
Reactant: N#Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NN=C(N)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1H-pyrrole-2-carbonitrile 10 g (108 mM) and sodium methoxide (1 eq) in ethanol (20 ml) and stirred for 10 min. Hydrazine hydrate (3 eq.) is then added and resulting reaction mixture is stirred at room temperature for 18 hrs. Reaction mass is then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuum to yield desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=O)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:17])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
75.6 g (264 mmol) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamide were suspended in 340 ml of dioxan and 45 ml of pyridine and treated dropwise at about 7° with (323 mmol) of trifluoroacetic anhydride. The reaction mixture was stirred at room temperature overnight and poured into 2 l of water. By suction filtration of the resulting suspension and drying the crystals there were obtained 45.65 g (64%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carbonitrile, which was used in the next step without further purification.
Reaction SMILES: [Na+:1].[CH3:2][C:3]1[C:11]([CH3:19])([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24].[C:27]1([NH:33][CH:34]=NC2C=CC=CC=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[Na+:1].[CH3:19][C:11]1([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]([CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:24])=[O:25])=[C:3]1/[CH:2]=[CH:34]/[NH:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1=[N+](CCCS(=O)(=O)O)c2ccccc2C1(C)CCCS(=O)(=O)O
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.822 g (2 mmol) 2,3-dimethyl-1,3-bis-(3-sulfo-propyl)-3H-indolium sodium salt 7 and 0.49 g (2.5 mmol) N,N′-diphenyl-formamidine are dissolved in 20 ml methanol and stirred for about four hours under reflux. The solvent is removed in vacuum after cooling to room temperature. The residue is washed carefully with ethyl acetate. A dark yellow solid is obtained which is processed without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][S:8](=[S:11])([O-:10])=[O:9].[Na+].C(OCC)(=O)C.CO>CN(C=O)C.O>[CH3:7][S:8](=[S:11])([O:10][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:9]
Reactant: CS(=O)([O-])=S
Reactant: O=C(O)CCBr
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=S)OCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 3-bromopropionic acid 22 (571 mg, 3.73 mmol) and sodium methanethiosulfonate 21 (511 mg, 3.81 mmol) in DMF (5 mL) was stirred under argon at 70° C. After 2 h, t.1.c. (ethyl acetate:methanol, 4:1) indicated the formation of two products (Rf 0.3, 0.6) and the absence of any starting material (Rf 0.2). The reaction mixture was cooled to room temperature, water (10 mL) was added and the resulting mixture extracted with ether (3×20 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:ether, 3:1 (acetic acid, 0.6%)) to yield 2-carboxyethyl methanethiosulfonate 16 (438 mg, 64%) as a white crystalline solid; m.p. 44-46° C. (ethyl acetate/petrol) [Lit. 44-48° C. m.p., value obtained from Toronto Research Chemicals Inc. website (www.trc-canada.com), nmr spectra assigned using Chemical Concepts SpecInfo]; νmax (thin film) 1716 (st, C═O), 1312, 1130 (S—SO2)cm−1, δH (400 MHz, CDCl3) 2.94 (2H, t, J1,2 6.7Hz, 2 x H-2), 3.36 (3H, s, CH3), 3.38 (2H, t, 2 x H-1); δC (100.6 MHz, CDCl3) δ0.6 (t, C-1), 34.4 (t, C-2), 50.6 (q, CH3), 176.7 (s, C═O); m/z (ES−) 183 (M-H+, 100%). HRMS (ES−) Calcd. For C4H7O4S2 (M-H−) 182.9786.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:18]=[CH:19][N:20]=3)[C:14]([Br:17])=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[Br:17][C:14]1[N:13]2[CH:18]=[CH:19][N:20]=[C:12]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=2)=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1

Procedure:
A solution of 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid methyl ester (6.02 g, 17.3 mmol) and LiOH (7.3 g, 174 mmol) in THF (200 mL) and water (200 mL) is stirred at 25° C. for 18 hours. The majority of the solvents are removed in vacuo, then to the remaining aqueous solution is added EtOAc. The aqueous layer is separated, then washed once more EtOAc. The aqueous phase is separated, acidified to pH 5 using concentrated hydrochloric acid and the resultant solid filtered and dried in the vacuum oven. The solid is identified as the desired title acid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10](Cl)=[O:11])(=[O:3])[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31].O>ClCCl.N1C=CC=CC=1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[C:10](=[O:11])/[CH:9]=[CH:8]/[C:7]2[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:19])[CH3:18])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: CNc1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(/C=C/C(=O)N(C)c2ccc(S(=O)(=O)NC3Cc4ccccc4C3)cc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of 3,4-diacetoxycinnamoyl chloride (5.61 g, 19.9 mmol) in dichloromethane (50 ml) was dropped into a solution of the N-(2-indanyl)-4-(methylamino)benzenesulfonamide (5.00 g, 16.6 mmol) prepared in Preparative Example 14 in pyridine (50 ml) at 0° C. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. This residue was recrystallized from ethyl acetate/ether/isopropyl ether to give the title compound as a white crystal (8.90 g, 100%). m.p. (°C.): 152~153 (iso-Pr2O)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,4-dihydroxybenzoic acid (5 g), anhydrous K2CO3 (40 g) and benzyl bromide (16 mL) in acetone (100 mL) was refluxed for 4 hours. After filtration of solid, the filtrate was concentrated. The residue was stirred at room temperature with KOH (6 g), and methanol (20 mL) for 4 hours, and neutralized with dilute HCl (pH 2). The solid thus formed was filtered and recrystallized from a methanol-chloroform mixture (3:1) to get 3.5 g of the product. Concentration of mother liquor gave an additional 1 g of the product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:29][C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:28]>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([N:33]1[CH2:34][CH2:35][C:30]([O:29][CH2:27][CH3:28])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:31][CH2:32]1)=[O:14]
Reactant: O=C(O)CC1COc2ccccc2O1
Reactant: CCOC1(c2ccccc2)CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC1(c2ccccc2)CCN(C(=O)CC2COc3ccccc3O2)CC1

Procedure:
The starting material is prepared as follows: To the solution of 3.3 g of 1,4-benzodioxan-2-yl-acetic acid in 30 ml of tetrahydrofuran, 3.1 g of 1,1'-carbonyldiimidazole are added while stirring followed, after 30 minutes, by 3.5 g of 4-ethoxy-4-phenylpiperidine in 30 ml of tetrahydrofuran. The mixture is stirred for 18 hours at room temperature, evaporated and the residue taken up in ethyl acetate. The solution is washed with water, N hydrochloric acid and saturated aqueous sodium chloride, dried and evaporated, to yield the 1-(1,4-benzodioxan-2-yl-acetyl)-4-ethoxy-4-phenylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[Br:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccccc3Br)nc2n1
Temperature: 120 °C
Yield: 36.9 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (19.7 g), 2-bromophenol (81.5 g) and potassium hydroxide pellets (15.15 g; 85% purity). After 10 hours' heating at 120° C. and treatment under the conditions described above in Example 4, the product produced (21.5 g; m.p. 160° C.) is purified by chromatography on a column 45 mm in diameter containing silica (300 g; 0.040-0.063 mm), eluting with a mixture (95:5 by volume) of methylene chloride and methanol and collecting 100-cc fractions. After concentration to dryness of the fractions 2 to 10 at 40° C. under reduced pressure (4 kPa), 2-amino-7-(2-bromophenoxy)-1,8-naphthyridine (12.8 g) is produced, m.p. 206° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH:3]1[CH2:35][C:36]1[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[N:38](CC2C=CC=CC=2)[N:37]=1.C(O)=O>C(O)C.[Pd]>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:22])[CH3:23])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:35][C:36]1[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[NH:38][N:37]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a stirring solution of 150 mg (0.22 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(4,5,6,7-tetrahydro-1-benzyl-1H-indazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 52, in 10 mL of a 10% solution of formic acid in absolute ethanol is added 150 mg of 10% palladium on carbon. The resulting black suspension is refluxed for 3 h, then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue via silica gel MPLC using an Si60 column and hexane/EtOAc 1/5 as eluent afforded 105 mg of the title compound as a white solid: mp 170°-173° C.; 1H NMR (CDCl3, 400 MHz) δ7.38-6.88 (m, 13H), 5.03 (m, 1H), 4.34 (d, 1H, J=16.8), 4.14 (d, 1H, J=16.8), 3.84(s, 3H), 3.58 (dd, 1H, J=6.8, 6.8), 3.46 (dd, 1H, J=7.0, 14.0), 3.30 (dd, 1H, J=7.5, 15.2), 2.60 (m, 2H), 2.36 (m, 2H), 1.70 (m, 4H), 1.08 (2×d, 6H, J=6.6); low resolution MS (FAB)m/e 592 (MH+), 591 (M+), 427; Anal. (C35H37N5O4) Calcd. C, 71.05; H, 6.30; N, 11.84; Found C, 70.20; H, 6.47; N, 11.66.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OCc1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nccs1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a room temperature solution of thiazol-2-ylmethanol (1.00 g, 8.684 mmol) in CH2Cl2 was added imidazole (1.18 g, 17.4 mmol) followed by tert-butyldimethylsilyl chloride (1.70 g, 11.3 mmol). After 30 minutes, the mixture was quenched with 2 mL of MeOH and passed through a pad of silica gel eluting with CH2Cl2 (700 mL) and concentrated in vacuo to afford 2.01 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[C:28](Cl)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=3[CH2:17][CH2:18][CH3:19])[CH:3]=2)[CH:27]=1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(Nc3cc(C(=O)OC)ccn3)c2)ccc(C(C)=O)c1O
Temperature: 110 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 2-chloro-isonicotinic acid methyl ester (287 mg, 1.67 mmol) and cesium carbonate (762 mg, 2.34 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add 2-(bicyclohexylphosphino)biphenyl (234 mg, 0.668 mmol), and tris(dibenzylideneacetone)dipalladium (153 mg, 0.167 mmol). Purge reaction vessel with argon. Heat to 110° C. After 18 hours, cool to ambient temperature. Add diethyl ether (25 mL) and filter. Concentrate filtrate under reduced pressure to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate:hexanes to yield the title compound as a yellow solid (282 mg, 39%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.52 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 3.88 (s, 3H), 5.25 (bs, 2H), 6.72 (d, 1H), 6.99 (d, 1H), 7.14 (d, 1H), 7.31 (t, 1H), 7.39 (s, 1H), 7.58 (d, 1H), 7.80 (d, 1H), 7.91 (s, 1H), 8.29 (d, 1H), 9.43 (s, 1H), 12.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:19]=1)=[O:17].CC([O-])=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)CCc1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1
Yield: 80 %

Procedure:
Compound 19 was synthesized from 16b (4.37 mmol), p-tolylsulfonyl hydrazide (13.1 mmol) and NaOAc (39.3 mmol) using the procedure according to Method F described above.