Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To the stirred solution (5-bromo-pyridin-3-yl)-methanol (3.0 g, 16 mmol) in CH2Cl2 (30 mL) is added triethylamine (2.4 g, 24 mmol). The reaction mixture is cooled to 0° C., methanesulfonyl chloride (2.2 g, 19 mmol) is added slowly at 0° C. Then the reaction mixture is warmed up to room temperature for 3 hrs. Ice cold water is added and the mixture is extracted with CH2Cl2. Organic layers are combined, dried over Na2SO4 and concentrated to give 3.0 g of the crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester which is used without purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21](O)=[O:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:63]([N:65]1[CH:69]=[CH:68][C:67]([NH2:70])=[N:66]1)[CH3:64]>CN(C=O)C>[CH3:35][C:34]([Si:31]([CH3:33])([CH3:32])[O:30][CH2:29][C@@H:28]([O:27][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:26]=1)[C:21]([NH:70][C:67]1[CH:68]=[CH:69][N:65]([CH2:63][CH3:64])[N:66]=1)=[O:22])[CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CCn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3.00 g, 7.21 mmol), HATU (3.41 g, 9.01 mmol) and 1-ethyl-1H-pyrazol-3-amine [Chem. Heterocycl. Compd. (Engl. Transl.), 11, 1975, 212] (1.20 g, 10.8 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 3 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL), ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:5 to 1:2 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)ccc1Cl
Reaction time: 8 h
Yield: 55 %

Procedure:
2-Chloro-5-methylphenol (5.0 g, 35.0 mmol) was dissolved in 50% CH2Cl2/methanol (100 mL) and trimethylsilyl diazomethane (2.0 M in hexanes, 25 mL) was added dropwise until a persistent yellow color was observed. The solution was stirred overnight. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (3.0 g, 55%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.25 (d, 1H), 6.95 (d, 1H), 6.74 (dt, 1H), 3.81 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno[3,2-b]-pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.38 (1H, d, J=5.5 Hz), 7.84–7.74 (2H,m), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.6 Hz), 6.60 (1H, d, J=5.5 Hz), 4.45–4.42 (1H, m), 3.93–3.91 (2H, m), 3.71–3.60 (8H, m), 3.45 (2H, m), 2.56 (3H, s), 2.02–1.98 (2H, m), 1.72–1.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 509. found 509.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>C(O)(=O)CC>[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2c(O)ccnc2c1
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: Cc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (6 mL of 70%) was slowly added to a hot (125° C.) solution of 7-methyl-4-quinolinol (10.5 g) in propionic acid (125 mL). The reaction mixture was stirred for about 1.5 hours and then it was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed well with ethanol and water and then dried to provide 6.9 g of 7-methyl-3-nitro-4-quinolinol as a pale yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[C:3]([CH:2]([CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of ethyl acetoacetate (10 g, 76.8 mmol) in tetrahydrofuran (50 ml) at 0° C. was added sodium hydride (4 g, 60% in mineral oil, 100 mmol) portionly. The reaction mixture was stirred for minutes, and 2-bromoacetophenone (16.8 g, 84.5 mmol) in tetrahydrofuran (20 ml) was added dropwisely. After warming the mixture to room temperature, it was stirred for 4 hours. The resulting solution was quenched with water and normal work-up accomplished with diethyl ether. The organic layer was dried with MgSO4, and purified by silica gel column chromatography (EtOAc:Hx=1:5) to produce desired compound (19 g, 98%) as light yellow color oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:24]Br>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([Br:24])[S:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2cscc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)csc2Br)cc1
Reaction time: 0.25 h

Procedure:
3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl) thiophene from Example 6 (9.3 mg) was dissolved in acetic acid (10 ml) and heated to 90° C. at which time Br2 in acetic acid (1.0 M, 27 μl) was added in one portion. The reaction was stirred for 15 minutes at which time the solvent was removed at reduced pressure. The residue was dissolved in a minimum of ethyl acetate and chromatographed on silica, eluting with 2.5% isopropanol in hexane, yielding 3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl)-5-bromothiophene. CI MS (M+H):423/425.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].CO.[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:2][C@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])=[CH:18][CH:17]=1
Reactant: C[C@@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
In a 250 mL, 4 necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, D-alaninamide hydrochloride (6.1 g) and methanol (80 mL) are charged and stirred for 15 min at 20° C. Triethylamine (5 g) is added at such a rate that the temperature remains below 30° C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (10 g, Example 10 b) is added portion wise in about 30 min. After stirring for 3 hours at 20° C., the mixture is cooled to 5° C. After stirring for 3 hours at this temperature, the solid is filtered and washed with small amount of pre-cooled methanol. The wet solid is dried under vacuum for 12 hours a 25° C., yielding 6.4 g of title compound as white solid, with 46.4% yield; m.p 111.9.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16][Mg]I>C(OCC)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:16])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](C)Oc1cc(C)ccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (50 mg, 0.245 mmol) in diethyl ether (2 mL) was added methylmagnesium iodide (0.245 mL, 0.734 mmol) and the mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 25% EtOAc/hexane to obtain 1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethanol (50 mg, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J=7.7, 3.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 5.88 (ddtd, J=17.2, 10.3, 7.0, 3.5 Hz, 1H), 5.22-5.10 (m, 2H), 5.10-4.96 (m, 1H), 4.62-4.47 (m, 1H), 2.94 (dd, J=18.8, 5.4 Hz, 1H), 2.64-2.38 (m, 2H), 2.34 (s, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.37 (dd, J=6.0, 4.0 Hz, 3H).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[CH:17]=[CH2:18].Cl>CN(C=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:19]([CH2:16][CH:17]=[CH2:18])[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22]=1[OH:21])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
To a 50 ml. solution of NaOEt (0.3 g. Na-0.013 mole) was added 2.08 g. (0.013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. DMF was added to form a solution and then 1.85 g. (0.0065 mole) of 1-(2-propenyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute HCl and the resulting precipitate collected on a filter and rinsed with water. Recrystallization from ethyl acetate gave 1.0 g. of product--m.p. 177°-180° C.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[C:48]([N:38]1[CH2:39][CH2:40][CH:35]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[CH:16][CH:15]=2)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:36][CH2:37]1)(=[O:50])[CH3:49]
Reactant: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCN(C(C)=O)CC1
Reaction time: 1 h

Procedure:
A room temperature solution of Example 47A (50.0 mg, 0.094 mmol) in dichloromethane (2 mL) was treated with triethylamine (26.2 μL, 0.19 mmol) and acetyl chloride (10.0 μL, 0.14 mmol), stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[NH:5][CH:6]=1.N1([C:14](N2C=CN=C2)=[O:15])C=CN=C1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:7][NH:8][C:14](=[O:15])[N:5]2[CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1cc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)cn21
Yield: 36.1 %

Procedure:
A solution of (4-bromo-1H-pyrrol-2-yl)methanamine (Enamine, Ltd., Kiev, Ukraine; 57.7 mg, 0.330 mmol), di(1H-imidazol-1-yl)methanone (CDI; Aldrich; 58.8 mg, 0.363 mmol), and NaH (60% wt. in mineral oil; 15.8 mg, 0.396 mmol) in THF (3.0 mL) was stirred under argon at 23° C. for 15 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-60% EtOAc/hexanes) to provide 6-bromo-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (23.9 mg, 0.119 mmol, 36% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (1H, br. s.), 7.29 (1H, s), 6.16 (1H, d, J=1.2 Hz), 4.35 (2H, s). m/z (ESI, +ve) 200.9/202.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12].[N+:18]([O-])([OH:20])=[O:19].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12]
Reactant: O=[N+]([O-])O
Reactant: Nc1nccc(Oc2cc(F)ccc2F)c1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1nccc(Oc2cc(F)c([N+](=O)[O-])cc2F)c1I
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
A chilled (−10° C.) mixture of 4-(2,5-difluorophenoxy)-3-iodopyridin-2-amine (2.31 g, 6.64 mmol) in sulfuric acid (15 ml) was treated with nitric acid (0.35 ml, 7.96 mmol) while maintaining the temperature below 0° C. After stirring for 20 minutes, the mixture was poured into ice-cold 2 N aq. NaOH solution (100 mL of 2 N NaOH in ice) with stirring. The pH of the resultant solution was then made basic by careful addition or NaHCO3. After stirring for 30 min, the suspension was filtered, washed with water (3×10 mL) and dried to afford 4-(2,5-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine as light red solid (2.05 g, 79% yield). MS (ESI) m/z: 393.9 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH:11]=1.CO[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1>C1COCC1>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]3)[CH:11]=2)[O:23]1
Reactant: O=S1(=O)CCC(n2cc(I)cn2)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CCS(=O)(=O)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 1.23 mL, 2.45 mmol) was slowly added to a solution of 4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (0.50 g, 1.533 mmol) in THF (6.0 mL) at −10° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was then cooled to 0° C., 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.402 mL, 2.45 mmol) was added, and the reaction stirred at room temperature for an additional 1.5 h. The reaction solution was then concentrated in vacuo to remove the THF. The crude solid was dissolved in ether (200 mL) and filtered. The filtrate was slowly concentrated until a white precipitate formed. The solution was allowed to stand for 2 h, and the precipitate was filtered and dried in vacuo to afford 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (0.34 g, 68%) as a white powder. MS (ESI, pos. ion) m/z 327 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=[O:6].[Br:23]Br>>[Br:23][CH:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([F:22])=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(F)c(Br)c1)N1CCCC(c2ccccc2)=N1
Reactant: BrBr
Product: O=C(c1ccc(F)c(Br)c1)N1CCC(Br)C(c2ccccc2)=N1

Procedure:
The title compound was prepared as described in Example 22 starting with 1- (3-bromo-4-fluorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine and bromine to give a solid: mp 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), 1N HCl (2×100 mL) and brine. Dried over MgSO4. Solvent was evaporated to reveal methyl 3-(methanesulfonyl)phenylacetate. (3.36 g, 100%). 1H NMR (500 MHz, CDCl3) δ 7.32 (1H, dd), 7.2-7.1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2].[N+]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O-])=O.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:25][CH2:26]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH2:30][C:29](=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)C=CC4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)CC(=Cc5ccccc5)C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In 5 mL of THF, 200 mg (0.43 mmol) of N-(3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-maleimide obtained in Example 21-1 was dissolved, and 85 mg (0.62 mmol) of nitromethylbenzene and 66 mg (0.43 mmol) of DBU were added, followed by stirring the mixture at room temperature for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 196 mg (yield: 82%) of the captioned compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([C@@H:7]1[CH2:8][C@H:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:10][CH2:11][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(Cl)cc12

Procedure:
Example 2ah, Step 1: A sample of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide was combined with 4,6-dichloroquinazoline (1.2 equivalents) and triethylamine (1.2 equivalents) in ethanol. The resultant solution was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)-2-(6-chloroquinazolin-4-ylamino)acetamide. MS found: (M+H)+=446.44; 1H NMR (400 MHz, CDCl3) δ(TMS): 0.52-1.77 (m, 25H), 2.36-2.48 (m, 1H), 3.92-4.06 (m, 3H), 6.52-6.63 (M, 1H), 7.37-7.55 (m, 3H), 7.70-7.73 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: NCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)NCCO
Yield: 80.8 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ethanolamine (0.26 ml, 4.3 mmol) to give the title compound as a solid (170 mg, 80%), except that the mixture was heated at 45° C. for 20 hours. NMR Spectrum 1.65 (d, 3H), 3.22 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.72 (m, 3H), 8.11 (s, 1H), 8.48 (m, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 10.72 (br s, 1H); Mass spectrum MH+ 490.