Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.79 (m, 2H), 8.27 (dd, 2H), 7.88 (m, 2H), 7.61 (m, 1H), 7.55 (m, 2H), 7.18 (m, 1H), 7.12 (m, 3H), 7.03 (d, 1H), 6.88 (d, 1H), 6.79 (s, 1H), 4.38 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 502 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cnc(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
Then, 0.15 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) was dissolved in 0.88 ml of pyridine, to which 52 μl of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with 2N hydrochloric acid, water, saturated sodium hydrogen-carbonate solution, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 45 mg (yield, 25%) of 3-(2,4-dichloro-5-methanesulfonylaminophenyl)1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-343; m.p., 189.2° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[N:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CN(C=O)C.C(O)(C)C.O.CO>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[N:14][CH:13]=1
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: COc1cc2c(Cl)cnnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The starting material 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride was obtained by adding 1-chloro-3-morpholinopropane (190 mg, 0.95 mmol), (prepared as described in U.S. Pat. No. 4,004,007), to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (0.2 g, 0.95 mmol), (prepared as described for the starting material in Example 10), in DMF (5 ml) containing potassium carbonate (327 mg, 2.3 mmol) and potassium iodide (15 mg, 0.095 mmol). After heating at 80° C. for 2 hours, potassium carbonate (65 mg, 0.47 mmol) and more 1-chloro-3-morpholinopropane (95 mg, 0.47 mmol) were added. After stirring for 4 hours at 80° C. the reaction mixture was cooled and 7M hydrogen chloride in isopropanol (407 μl) was added. The solution was poured onto a Diaion (trade mark of Mitsubishi) HP20SS column, using water/methanol (100/0 to 0/100 as a gradient) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline as an hydrochloride salt (175 mg, 44%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]#[CH:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:19])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:26]=1
Reactant: C#CCCC(=O)OC
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 29.4 %

Procedure:
To a stirred solution of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (6.0 g, 22.7 mmol) and pent-4-ynoic acid methyl ester (3.8 g, 34 mmol) in CH2Cl2 (80 ml) was added triethylamine (0.2 ml) followed by Clorox bleach (80 ml). After 4 h at room temperature the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (25 ml×3). The combined organics were dried over MgSO4; filtered and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40 chromatography using a silica gel column and eluting with 10-20% EtOAc/hexane gave 2.5 g of the title compound as a waxy pale yellow solid. MS [M+1]+375.3; 1H nmr (400 MHz, CDCl3) δ0.91 (m, 6H), 1.51-1.76 (m, 3H), 2.67 (t, J=7.5 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 3.67 (s, 3H), 4.89 (m,1H), 5.08 (m, 3H), 5.92 (s, 1H), 7.31 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1)(=[O:32])=[O:31]
Reactant: CC1(C)OC(=O)Nc2ccc(N)cc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
To a stirred solution of 6-amino-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.05 g, 0.24 mmol) in methylene chloride (2 mL) at 0° C. was added triethylamine (0.05 mL, 0.36 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.06 g, 0.24 mmol) was added. The solution was stirred for 2 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 50% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as a white solid (0.008 g, 8%). 1H NMR (DMSO-d6): δ 10.57 (s, 1H), 10.16 (s, 1H), 7.97 (dd, J=7.9, 1.3 Hz, 1H), 7.92 (dd, J=8.0, 1.3 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 1.46 (s, 6H). MS (ESI) m/z 401/403/405 ([M+H]+); MS (ESI) m/z 399/401/403 ([M−H]−).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCC)CCC)CC>ClC1C=CC=CC=1.[Pd](Cl)Cl>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Pd]Cl
Agent: CCCN(CCC)CCC
Solvent: Clc1ccccc1
Product: Cc1ccc(C=Cc2ccccc2)cc1
Yield: 30 %

Procedure:
The procedure described in Example 1 is followed, except that 15.46 g (0.1 mol) of p-toluic acid chloride, 13.02 g (0.125 mol) of styrene, 14.3 g (0.1 mol) of tri-n-propylamine and 0.177 g (0.001 mol) of palladium chloride are used. After a reaction time of 3 hours at 130° C., in 50 ml of chlorobenzene as the solvent, 5.8 g (0.03 mol) of 4-methylstilbene, corresponding to a yield of 30% of theory, are obtained; melting point 117° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[N:29][CH:30]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][C:27]1[CH:28]=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:26]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1cncc(CCN2CCCC2)c1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Yield: 45.3 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (262 mg, 0.845 mmol) was reacted with 5-[2-(pyrrolidin-1-yl)ethyl]pyridin-3-amine (161 mg, 0.845 mmol) to afford the desired product (178 mg, 45%) as a white solid: ESI MS m/z 465 [C24H25BrN4O+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C@@:14]2([C:26]#N)[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH2:38]>O1CCCC1>[C:8]1([C@@:14]2([CH:26]=[O:38])[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 300 mL toluene and (1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbonitrile (12.0 g, 45.57 mmol, 1 eq), accessed via the method of Preparation 3B, at 0° C. was added 59.3 mL 1M diisobutylaluminum hydride (59.3 mmol, 1.3 eq) in tetrahydrofuran. The mixture was stirred at 0° C. for 4 h and then at ambient temperature for 18 h before dilution with 500 mL toluene and 500 mL water. The mixture was stirred for 30 min and then filtered through a pad of celite. The organics were isolated, dried over Na2SO4, filtered and concentrated to give the title compound (7.8 g, 29.3 mmol, 64%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.39-7.19 (m, 10H), 4.33-4.23 (m, 2H), 3.36-3.33 (m, 1H), 3.03-2.98 (m, 1H), 2.16-2.11(m, 1H), 1.77-1.73 (m, 1H), 1.46-1.43 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH2:18])[N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CN(C)C(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[N:17]=3)[CH:14]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(COc2ccc3nc(N)cn3c2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a solution of 6-[(4-methoxybenzyl)oxy]imidazo[1,2-a]pyridin-2-amine (8.5 g, 31.6 mmol) in N,N-dimethylacetamide (80 mL) was added a solution of cyclopropanecarbonyl chloride (3.43 mL, 37.9 mmol) in N,N-dimethylacetamide (20 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with water, and the precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound (8.9 g, 83%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Br)[CH2:33][CH3:34].Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: CCC[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-propyl magnesium bromide was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (R)-methyl 3-hydroxy-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (4 g, 0.01 mol) and methylene chloride (40 mL, 0.5 mol) and 1H-imidazole (1.6 g, 0.023 mol) and tert-butyldimethylsilyl chloride (2.3 g, 0.015 mol) were added at 0° C. and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with methylene chloride. Solvent was removed under reduced pressure to yield pure product. MS m/z=407.5 (M+H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16]O.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[Br:2][CH2:16][CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCCc1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
A solution of phosphorus tribromide (3.52 g, 0.013 mol) in chloroform (6.25 ml) was added dropwise at -10° to a stirred solution of 2-naphthalene-ethanol (4.3 g, 0.025 mol) in chloroform (20 ml), containing dry pyridine (0.13 ml, 0.0016 mol). Following the addition, the mixture was stirred at -10° for 2 h, and was then stood at ambient temperature overnight. Next day, the reaction mixture was poured into water (62.5 ml) and the organic layer was separated. The aqueous solution was then extracted with chloroform (3×6.25 ml), and the organic layer and chloroform extracts were combined and washed with sodium hydroxide solution (62.5 ml., 2M), and with water (62.5 ml). The chloroform solution was dried (MgSO4), and the chloroform was then evaporated under reduced pressure to afford 2-(2-bromoethyl)naphthalene which was used without further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CB(O)O.ClCCl.[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]2[CH:28]=[CH:29][C:30](Br)=[C:31]([CH3:32])[C:21]1=2)=[O:19])([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]2[CH:28]=[CH:29][C:30]([CH3:1])=[C:31]([CH3:32])[C:21]1=2)=[O:19])([CH3:16])[CH3:15]
Reactant: Cc1c(Br)ccc2c1N(C(=O)OC(C)C)CCCC2=O
Reactant: O=C([O-])[O-]
Agent: CB(O)O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCCC2=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add cesium carbonate (456 mg, 3.0 mmol), methyl boronic acid (90 mg, 1.5 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (82 mg, 0.1 mmol) to a solution of 8-bromo-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (341 mg, 1.0 mmol) in dioxane (8 mL). Stir the mixture under nitrogen at 110° C. for 1 h and 30 min. Cool down the mixture to room temperature and filter over Celite® washing with ethyl acetate. Evaporate the solvent and purify the crude by chromatography, eluting with hexane/ethyl acetate to afford the title compound (239 mg, 87%). MS (ES+): 276 (M+H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34]O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34][Br:1])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (0.767 g, 4.8 mmol) in carbon tetrachloride at ice-water bath temperature is treated sequentially with a solution of triphenylphosphine (1.26 g, 4.8 mmol) in carbon tetrachloride and a solution of 3-[1-(p-chlorophenyl)-cyclopropyl]-2-fluoro-2-propen-1-ol, (Z)—(0.907 g, 4 mmol) in carbon tetrachloride, heated to and stirred at reflux for 70 minutes, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered, and the filtrate is concentrated in vacuo to obtain a residue. The residue is dissolved in petroleum ether and passed through a plug of silica gel (eluted with hexanes) to obtain an oil. Flash column chromatography of the oil using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as a colorless oil (0.73 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@:20]4([CH3:44])[C@@H:29]3[CH2:28][CH2:27][C@H:26]3[C@@:21]4([CH3:43])[CH2:22][CH2:23][C@@:24]4([C:40]([OH:42])=[O:41])[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:25]43)[C:16]2([CH3:46])[CH3:45])=[O:13])[C:9]1([CH3:48])[CH3:47])=[O:7])(C)(C)C>Cl.O1CCOCC1.CCOC(C)=O>[C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@:20]4([CH3:44])[C@@H:29]3[CH2:28][CH2:27][C@H:26]3[C@@:21]4([CH3:43])[CH2:22][CH2:23][C@@:24]4([C:40]([OH:42])=[O:41])[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:25]43)[C:16]2([CH3:46])[CH3:45])=[O:13])[C:9]1([CH3:48])[CH3:47])([OH:7])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@@H]6C[C@H](C(=O)OC(C)(C)C)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@@H]6C[C@H](C(=O)O)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 59 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-((1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Example 3, about 0.160 g, 0.239 mmol) in 2M HCl in Dioxane (10 ml) was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, the organic layer dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by Silica gel column chromatography (100-200 Mesh, Elution: 20% EtOAc in Hexane) to afford the title compound as a white solid. Wt: 0.086 g; Yield: 59.0%; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, 1H), 4.61 (s, 1H), 4.47-4.43 (m, 1H), 3.03-2.97 (m, 1H), 2.87-2.74 (m, 2H), 2.63-2.51 (m, 1H), 2.31-2.24 (m, 2H), 2.19-1.90 (m, 3H), 1.69 (s, 3H), 1.78-1.68 (m, 5H), 1.52-1.41 (m, 12H), 1.29-1.02 (m, 9H), 0.97 (s, 3H), 0.93 (s, 3H), 0.85 (s, 9H); Mass: [M+Na]+ 633 (100%); IR (KBr, cm−1): 3427, 2951, 1730, 1706, 1698, 1456, 1376, 1242, 1190, 1107, 1020, 885; M. Range: 282.5-289.3° C.; HPLC: 92.2% % at RT 8.76 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1.[CH:18]1([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[O:23])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]1([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]4[CH3:17])[C:5]4[CH2:10][S:9][CH2:8][C:6]=4[N:7]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CSC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CSC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine (100 mg, 0.37 mmol) in DME/H2O (4:1, 10 mL) was added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (124 mg, 0.41 mmol), and Na2CO3 (118 mg, 1.11 mmol) followed by addition of PdCl2(dppf) (15 mg, 0.02 mmol). The resulting mixture was heated to 70° C. and stirred overnight under nitrogen. The solvent was removed under reduced pressure to give a residue which was partitioned between ethyl acetate and water. The organic layer was washed with brine dried (Na2SO4) and concentrated to give a crude product which was purified by preparative TLC (DCM/MeOH=20/1) to give the desired product, as a yellow solid (20 mg, 13%).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:32]3[N:33]=[CH:34][C:35]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:31]3[N:30]=[CH:29][C:28]=2[C:40]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)=[O:41])=[C:22]([CH3:54])[CH:21]=1.N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:32]3[N:33]=[CH:34][C:35]([S:36]([NH:39][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:6])(=[O:38])=[O:37])=[C:31]3[N:30]=[CH:29][C:28]=2[C:40]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:44][CH2:43]2)=[O:41])=[C:22]([CH3:54])[CH:21]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(N)(=O)=O)cnn12
Reactant: O=C(O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(=O)(=O)NC(=O)C3CC3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Cyclopropanecarboxylic acid (0.066 g, 0.768 mmol) was dissolved in DMF (0.8 mL), and 1,1′-carbonyldiimidazole (0.125 g, 0.768 mmol) was added. After stirring at room temperature for 30 min, 7-(4-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.078 g, 0.154 mmol) obtained in step 5 and 1,8-diazabicyclo[5.4.0]undeca-7-en (0.140 g, 0.922 mmol) were added, and the mixture was stirred at 80° C. for 3 hr. 5% Aqueous citric acid solution was added to quench the reaction, and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (0.026 g, 29%).