Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.[K].[I-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:44]4[C:43](=[O:45])[C:42]5=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]5[C:40]4=[O:50])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCCl)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 114.2 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-chloropentyloxy)phenyl]benzamide (800 mg) in N,N-dimethylformamide (15 ml) was added Potassium phthalimide (821 mg) and sodium iodide (cat.) at ambient temperature. The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with water and brine. The organic solution was dried over magnesium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 50 g, 0.5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phthalimidopentyloxy)phenyl]benzamide (1.1 g).
Reaction SMILES: [CH3:1][NH2:2].O.Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>CC#N>[Cl:15][C:7]1[CH:6]=[C:5]([NH:2][CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: CN
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CC#N
Solvent: O
Product: CNc1cc(Cl)ncc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
40% Methylamine in water (0.847 mL, 9.78 mmol) was added slowly over 5 minutes at 0° C. to a solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in MeCN (6 mL). The solution was stirred at 0° C. for 30 minutes then at room temperature for 2 hours. The reaction mixture was concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-(methylamino)nicotinate (278 mg, 1.386 mmol, 71.4% yield) as a white solid.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][CH2:15][C:16](OC)=[O:17])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]([CH3:27])[C:8]2=[N:9][CH:10]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:57]1([CH2:63][C:64]2([OH:70])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CO.O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][CH2:15][C:16]([N:67]3[CH2:66][CH2:65][C:64]([CH2:63][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([OH:70])[CH2:69][CH2:68]3)=[O:17])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]([CH3:27])[C:8]2=[N:9][CH:10]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: COC(=O)CCc1c(-c2ccc(Cl)cc2)n(C)c2ncc(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCC(O)(Cc3ccccc3)CC2)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Lithium hydroxide monohydrate (15 mg, 0.34 mmol) was added to a solution of methyl 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-propanoate (Description 5, 82 mg, 0.23 mmol) in methanol (15 mL), tetrahydrofuran (5 mL) and water (5 mL) and the mixture was stirred at room temperature overnight. Further lithium hydroxide monohydrate (15 mg, 0.34 mmol) was added and the mixture was stirred at 75° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (25 mL). 1-Hydroxybenzotriazole (549 mg, 1.84 mmol), triethylamine (255 μl, 1.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (348 mg, 1.84 mmol) and 4-(phenylmethyl)-4-piperidinol (352 mg, 1.84 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with hydrochloric acid (1M), aqueous sodium carbonate (10%) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50), to give the title compound (98 mg, 83%). 1H NMR (360 MHz, CDCl3) δ 8.28 (1H, d, J 2.2 Hz), 7.90 (1H, d, J 2.2 Hz), 7.27-7.48 (2H, m), 7.36-7.26 (5H, m), 7.16-7.14 (2H, m), 4.36 (1H, m), 3.65 (3H, s), 3.36 (1H, m), 3.19 (1H, m), 3.00 (2H, m), 2.86 (1H, m), 2.67 (2H, s), 2.48 (2H, t, J 7.7 Hz), 1.46 (2H, m), 1.39 (1H, m), and 1.22 (1H, m). m/z (ES+) 522, 524 (M+1).
Reaction SMILES: Br[CH2:2][C:3](=[O:15])[C:4]([CH3:14])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:5].[P:16]([O:21]C)([O:19][CH3:20])[O:17][CH3:18]>C1(C)C=CC=CC=1>[CH3:18][O:17][P:16]([CH2:2][C:3](=[O:15])[C:4]([CH3:14])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:5])([O:19][CH3:20])=[O:21]
Reactant: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CP(=O)(OC)OC
Yield: 90 %

Procedure:
A solution of 14 (1.55 g; 5.25 mmol) and trimethyl phosphite (514 μl; 782 mg; 6.31 mmol) in toluene (20 ml) was refluxed for 3 days. The mixture was purified by column chromatography (5-15% 2-propanol/hexane) to give 1.54 g (4.75 mmol; 90% yield) of 2. 1H NMR (400 MHz, CDCl3) δ 0.65 (6H, q, J=7.9 Hz), 0.98 (9H, t, J=7.9 Hz), 1.36 (6H, s), 3.40 (2H, d, JH—P=20.7 Hz) 3.80 (6H, d, JH—P=11.2 Hz); 13C NMR (101 MHz, CDCl3) δ 6.4, 6.9, 26.8, 33.7 (d, JC—P=137.8 Hz), 52.8 (d, JC—P=6.7 Hz) 80.0, 207.1 (d, JC—P=6.0 Hz); MS (EI) m/z 324 ([M−Et]+, 98), 238 (65), 211 (61), 173 (100); exact mass calculated for C11H24O5PSi ([M−Et]+) 295.1126. found 295.1126.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]([CH3:23])([CH3:22])[C:8](=[O:21])[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].C(O)C>ClCCl>[Cl:4][CH:9]([C:8](=[O:21])[C:7]([CH3:23])([CH3:22])[CH3:6])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: CC(C)(C)C(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Sulfuryl chloride (54.1 g, 0.4 mol) was added dropwise with vigorous stirring over a 60 minute period to a solution of N-[4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline, prepared as above (109 g, 0.378 mol) in dichloromethane (600 mL) at -10° C. The reaction mixture was maintained at this temperature for 3 hours after the addition had been completed. After this time, the mixture was allowed to warm to 0° C. and ice (approximately 50 mL) was added, with stirring. The organic layer was separated and washed with 50% saturated aqueous sodium chloride solution (2×500 mL), then dried over magnesium sulfate. Evaporation of the solvent afforded a brown oil which was stirred with ethanol (150 mL) to induce crystallization of the product. The resultant mixture was stored at 0° C. overnight. The solid product was removed by filtration, washed with cold ethanol and dried to afford N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (104.2 g, 85.4% yield) as a white crystalline solid which melted at 64.5°-65.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: CS(O[C@H:6]1[C:25]2[C@:20]([CH3:27])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[N:38]([C:6]1[C:25]2[C@:20]([CH3:27])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:39]=[N-:40]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In a manner similar to that described in Example 1D, treat 6β,7β-dimethanesulfonyloxy-17α-acetoxy-1,4-pregnadiene-3,20-dione with sodium azide in dimethylformamide. Isolate and purify the resultant product in a manner similar to that described in Example 1D to obtain 6-azido-17α-acetoxy-1,4,6-pregnatriene-3,20-dione.
Reaction SMILES: CC(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22]
Reactant: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OCC
Reaction time: 4 h

Procedure:
diethyl [({[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}amino)methyl]phosphonate (360 mg, 0.628 mmol) was taken up in DCM (6 mL)/TFA (2 mL). After 4 hours at room temperature, the solvent was removed in vacuo, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give diethyl [({[4-({[2-amino-5-(2-thienyl)phenyl]amino) carbonyl}phenyl]methyl}amino)methyl]phosphonate as a beige solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.67 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.43 (m, 3H), 7.32 (dd, J=4.8 and 0.6 Hz, 1H), 7.26 (dd, J=8.4 and 1.8 Hz, 1H), 7.21 (m, 1H), 7.01 (dd, J=5.4 and 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.12 (s, 2H), 3.99 (m, 4H), 3.81 (s, 2H), 2.81 (d, J=12.0 Hz, 2H), 2.40 (br s, 1H), 1.20 (t, J=7.2 Hz, 6H). MS: cal'd 474 (MH+), exp 474.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.Cl.[CH3:19][NH2:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:19][NH:20][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CNCCCN1CCSc2cc([N+](=O)[O-])ccc21
Yield: 74.3 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.1 g, 4.03 mmol), methylamine hydrochloride (0.545 g, 8.07 mmol), potassium iodide (0.669 g, 4.03 mmol), and potassium carbonate (2.79 g, 20.16 mmol) in dry acetonitrile (25 mL) was stirred at 80° C. in a sealed tube for 6 hours. The reaction was brought to room temperature and diluted with water (100 mL), and the product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by flash column chromatography (1:9 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title compound (0.8 g, 74%) as a thick syrup. 1H NMR (DMSO-d6) δ 7.84-7.81 (m, 2H), 6.86 (d, 1H, J=9.9 Hz), 3.78-3.75 (m, 2H), 3.50 (t, 2H, J=7.5 Hz), 3.08-3.04 (m, 2H), 2.48 (t, 2H, J=6.9 Hz), 2.27 (s, 3H), 1.74-1.64 (m, 2H); ESI-MS (m/z, %): 268 (MH+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][Si:12]([CH3:31])([CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[O:13][Si:14]([CH3:24])([CH3:23])[CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]1[CH2:22][O:21]1>C(O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:22][CH:20]([OH:21])[CH2:19][O:18][CH2:17][CH2:16][CH2:15][Si:14]([CH3:23])([CH3:24])[O:13][Si:12]([CH3:31])([CH3:11])[CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Reactant: NCCOCCOCCO
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CNCCOCCOCCO
Temperature: 70 °C

Procedure:
2-(2-(2-Amino-ethoxy)-ethoxy)-ethanol (4.25 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) mixed with ethanol (10 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities and excess raw material.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([CH2:14][C:15]2([NH:25][CH:26]=[O:27])[CH2:18][CH:17]([C:19](N(OC)C)=[O:20])[CH2:16]2)=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2([NH:25][CH:26]=[O:27])[CH2:16][CH:17]([C:19](=[O:20])[CH2:8][CH2:7][CH:6]=[CH2:5])[CH2:18]2)=[CH:28][CH:29]=1
Reactant: CON(C)C(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Reactant: C=CCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Temperature: 0 °C
Reaction time: 0.2 h
Yield: 97.5 %

Procedure:
Magnesium powder (0.548 g, 22.6 mmol) was placed into a round-bottomed flask with a small piece of iodine. Dry THF was added to cover the magnesium and the solution was heated to a gentle reflux until the color had dissipated (approximately 30 minutes). While refluxing, a second solution of 4-bromo-1-buten (2.3 mL, 22.6 mmol) in dry THF (5 mL) was added. After 12 min, the mixture was cooled 0° C. and added to a solution of 3-(4-chlorobenzyl)-3-formamido-N-methoxy-N-methylcyclobutanecarboxamide (0.5 g, 1.61 mmol) in dry THF (30 mL). After 2 h, the reaction was allowed to warm to room temperature and stir overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (×2). The combined organic layers were washed successively with 1M HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated to give the crude product (0.48 g) that was used to the next step without further purification. ESI MS found for C17H20ClNO2 m/z [306.3 (M+1), 328.3 (M+Na+), 304.5 (M−1)].
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=O)=[O:5])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:18][O:19][C:20]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:8](=[O:10])[C@H:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:26]
Reactant: CCOC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OC)c1ccccc1
Yield: 56.7 %

Procedure:
Reaction of 2.0 g of (R)-ethoxycarbonylamino-phenyl-acetic acid and 1.50 g of (L)-proline methyl ester hydrochloride according to the procedure described for example 91b gave 1.70 g (57%) of the title compound as a colorless oil. (+)-APCI-MS: 335 (MH+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)=O)=[CH:15][CH:14]=1.[NH2:30][C:31]1[C:32]([Cl:37])=[N:33][CH:34]=[CH:35][CH:36]=1.O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:37][C:32]1[C:31]([N:30]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Nc1cccnc1Cl
Reactant: CSc1nccc(C(=O)Cc2ccc(F)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nccc(C(Cc2ccc(F)cc2)=Nc2cccnc2Cl)n1
Yield: 49.8 %

Procedure:
A mixture of p-toluenesulfonic acid (10 mg), 2-(4-Fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethanone (200 mg, 0.76 mmoles) and 3-amino-2-chloropyridine (90 mg, 0.7 mmoles) in 3 mL of toluene was refluxed overnight with a Dean-Stark removal of water/toluene azeotrope. The reaction mixture was further concentrated, the brown residue suspended in an ethyl acetate/hexane mixture (9/1) and filtered. The solid was solubilised in ethyl acetate and purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 130 mg of (2-Chloro-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethylidene]-amine as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]2[C:26](=[CH:27][CH:28]=1)[O:25][C:12]1([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:29]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:26](=[CH:27][CH:28]=1)[O:25][C:12]1([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH2:11][C:10]2=[O:29])=[O:4]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl chloridocarbonate was added to a solution of tert-butyl 6-amino-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in pyridine and stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the residue was purified by silicagel column chromatography (hexane/EtOAc) to obtain the intended compound as pale yellow foam.
Reaction SMILES: [CH:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][C:9]([CH3:40])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:40])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:41][CH:42]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(C)(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 72.5 %

Procedure:
In a similar manner to that described in Example 6, ethyl 2-(4-isopropylphenoxy)-2-methyl-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (486 mg), which is the product of Example 17, was reacted with aqueous potassium hydroxide solution (85%, 0.17 g) and the reaction mixture was treated. The residue was washed with diisopropyl ether to give the title compound (335 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.[I-:16].[Na+].I>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[I:16][C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Reactant: [I-]
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Ic1cc2c(nn1)Oc1ccccc1O2
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
Under an argon atmosphere, 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (5.0 g), sodium iodide (6.79 g) and hydrogen iodide (55%) (57.98 g) were added and the mixture was stirred at 140° C. for 1 hr. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 3-iodo[1,4]benzodioxino[2,3-c]pyridazine (1.95 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33](Cl)=[O:34]>C([O-])(O)=O.[Na+].C1COCC1>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([C:3]2[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[O:18][CH3:19])/[C:6](=[O:11])[NH:7]3)=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc(O)cc3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc(O)cc3)c21
Yield: 42.4 %

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (28 mg, 0.08 mmol) (from Example 41 supra) was acylated with 2-thiopheneacetyl chloride (25.7 mg, 0.16 mmol) (Aldrich) in saturated aqueous NaHCO3 (0.16 mL) and THF (2 mL) at room temperature for 3 h to give (Z)-N-[2,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-5-yl]-2-thiopheneacetamide (yield: 16 mg, 42%).
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1.[Cl-].[NH4+]>CCOCC>[OH:14][C:10]1([CH3:1])[C:9]2[CH:15]=[CH:16][C:6]([O:5][CH3:4])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: CI
Reactant: COc1ccc2c(c1)OCCC2=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc2c(c1)OCCC2(C)O

Procedure:
Methyl iodide (145 g; 64.2 ml) in dry ether (50 ml) was added dropwise with stirring to magnesium turnings (22 g) in dry ether (730 ml). After the initial reaction had ceased the reaction mixture was refluxed for 1/2 hour, cooled and 2,3-dihydro-7-methoxy-4-oxo-4H-1-benzopyran, (77.9 g) in dry ether (440 ml) was added dropwise with stirring. After addition the reaction mixture was refluxed for 1 hour, cooled and the complex was decomposed by the addition of ammonium chloride solution. The ethereal layer was separated, washed with water and dried. Evaporation of the solvent left 76 g of the title compound as an oil (89%). MS and NMR analysis were correct for the required compound.