Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1

Procedure:
A mixture of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (1.10 g, 4.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10 g, 5.02 mmol), (PPh3)4Pd (580 mg, 0.5 mmol) and a Na2CO3 solution (2.6 ml, 2M solution) in toluene (20 ml) was heated under reflux for 40 h. Upon cooling, the mixture was diluted with water (30 mL) and the product extracted with ethyl acetate (3×40 ml). The organic layers were combined, washed with brine (30 ml), dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with a hexane-ethyl acetate (2:3) to furnish the desired product from the polar fractions (0.86 g, 63%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light yellow solid (23 mg, 26%), MS (ISP) m/z=350.5 [(M+H)+], mp 298° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: COC(=O)/C=C/[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 94.2 %

Procedure:
Palladium-carbon (containing 50% water, 124 mg) was added to a solution of tert-butyl (E)-(2R,5S)-2-(3,4-difluorophenyl)-5-(2-methoxycarbonylvinyl)pyrrolidine-1-carboxylate (0.95 g) in ethyl acetate (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for six hours. Palladium-carbon in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain 0.90 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]([O:9][CH2:10]OC(C2C=CC=CC=2)=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([Cl:24])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]([O:9][CH2:10][Cl:24])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(OCOC(=O)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCl)c1ccccc1
Yield: 35 %

Procedure:
1-acetoxy-1-bromoacetone was extremely difficult or impossible to make by the standard preparation of 1-acyloxyalkyl bromide compounds, since the standard route would require preparation of pure anhydrous pyruvaldehyde, CH3COCHO, to be reacted with acetyl bromide. Anhydrous pyruvaldehyde is extremely hygroscopic, unstable, and prone to polymerization. All the above preparations of 1-acyloxyalkyl halides carried out with trimethylsilyl bromide and a catalytic quantity of anhydrous zinc chloride at room temperature overnight; if the starting 1,1-diester was solid, a chlorinated solvent (CH2Cl2, CHCl3, or CCl4) was added to make a homogeneous reaction mixture. Products were characterized by boiling point, NMR, and halide titration. Different Lewis acids were tested in the case of methylene dibenzoate. ZnCl2, ZnI2, ZrCl4, and SnCl4 all proved effective, AlCl3 less so. BF3.Et2O and Cu2Br2 were ineffective. 1-acyloxyalkyl chlorides can also be obtained by this general procedure, though more vigorous conditions are required and lower yields result. Thus C6H5COOCH2OCOC6H5 and Me3SiCl reacted in CCl4 with AlCl3 catalysis at 100° (sealed vessel) for 60 hrs. and gave a 35% yield of C6H5COOCH2Cl.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1F
Product: O=C(Nc1ccccc1F)c1ccccc1[N+](=O)[O-]
Yield: 70.2 %

Procedure:
Using the procedure described in Example 93, Part A, 2-fluoroaniline (20.7 mmol) and 2-nitrobenzoyl chloride (22.8 mmol) yielded 3.78 g (70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](OC)(=[O:19])[C:15]([O:17][CH3:18])=[O:16].C[O-].[Na+]>CO.C(Cl)Cl>[F:13][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12]
Reactant: COC(=O)C(=O)OC
Reactant: COc1c(F)cc(C(C)=O)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3,5-fluoro-4-methoxyacetophenone from Step 1 (6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g, 52.05 mmol) in methanol (80 mL), was added sodium methoxide solution (13.4 mL of 25% solution, 58.99 mmol) in one portion and the reaction stirred overnight. The crude reaction was diluted with methylene chloride, washed with potassium bisulfate (0.1N solution), brine, dried over MgSO4, filtered, and concentrated in vacuo yielding methyl 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off white crystalline solid which was used as is. A mixture of 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and 4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70 mmol) dissolved in methanol was warmed to reflux for 9 hours. Upon allowing the clear reaction to cool to room temperature, a crystalline precipitate formed which was collected by vacuum filtration yielding 5.45 g, (37% based upon the 3,5-difluoro-4-methoxyacetophenone) of methyl 1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate as an off-white solid: mp 185°-190° C.; 1H NMR (CDCl3 /300 mHz) 7.95 (d, J=8.86, 2H), 7.49 (d, J=8.86, 2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s, 2H, 4.04 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3 /300 mHz) -126.66. Anal. Calc'd for C17H13 F2N3O3S: C, 51.06; H, 3.57; N, 9.92. Found: C, 51.06; H, 3.54, N, 9.99.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][N:10]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 4′-[(7-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (2-bromoethyl)benzene (0.19 mL) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.055 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.27 g, 43%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH:7]1[CH:16]([NH2:17])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8]1)=[O:6])[CH3:3]>C(O)C>[NH2:17][C@@H:16]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][C@H:7]1[C:5]([O:4][CH2:2][CH3:3])=[O:6]
Reactant: CCOC(=O)C1CC2(CCC1N)OCCO2
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CC[C@H]1N)OCCO2
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Sodium metal (27.7 g, 1.2 mole) was reacted with ethanol (1 1), then ethyl-8-amino-1,4-dioxaspiro-[4.5]-decane-7-carboxylate (137.7 g, 0.6 mole) in ethanol (400 ml) was added. The mixture was refluxed for 11/2 hours, then cooled to room temperature, poured into ice, and made basic. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 118.0 g (85.7%) of the title product.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][O:5][C:4]1=[S:9])[CH3:2].[C:10]1([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[CH:21][C:19]2[O:20][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[O:5][C:4]1=[S:9])[CH3:2]
Reactant: CCN1C(=O)COC1=S
Reactant: O=Cc1ccc(-c2ccccc2)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN1C(=O)C(=Cc2ccc(-c3ccccc3)o2)OC1=S
Yield: 45 %

Procedure:
To a mixture of 3-ethyl-2-thioxooxazolidin-4-one 3 (145 mg, 1.0 mmol), 5-phenyl-2-furaldehyde 4 (172 mg, 1.0 mmol) and sodium acetate (410 mg, 5.0 mmol) was added acetic acid (5 mL). The reaction mixture was refluxed for 30 h, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. The desired product 5 (JL101) was obtained by recrystallization from an ethyl acetate/hexanes mixture in 45% yield (135 mg, light yellow needles). 1H NMR (400 MHz, CDCl3): 7.81-7.76 (m, 2H), 7.44 (dt, J=8.0, 1.6 Hz), 7.36 (t, J=6.0 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H), 6.80 (s, 1H), 3.97 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([C:13]#[N:14])=[CH:3][C:4]=1[CH3:12]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Temperature: 120 °C
Yield: 73 %

Procedure:
A suspension of 4-bromo-2-methyl-6-nitroaniline (11.5 g, 50 mmol), Zn(CN)2 (770 mg, 150 mmol), and Pd(PPh3)4 (2.32 g, 2.0 mmol) in DMF (100 mL) was sealed and heated at 120° C. for 70 h. After cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography with CH2Cl2 to afford the title compound (6.4 g, 73%). ESI-MS m/z 178 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([NH2:31])([CH3:30])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C:27]([CH3:30])([CH3:26])[CH2:28][NH2:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(C)(N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(C)(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.86 (d, J=6.82 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.26 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 3.58 (t, J=4.80 Hz, 2 H), 3.33 (m, 2 H), 3.27 (s, 2 H), 2.43 (s, 3 H), 1.27 (s, 6 H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[N:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:20]=1OS(C(F)(F)F)(=O)=O)([O-:10])=[O:9].[NH2:37][CH2:38][C:39]([CH3:42])([CH3:41])[OH:40]>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[S:30]([O:29][C:12]1[C:11]([N+:8]([O-:10])=[O:9])=[C:20]([NH:37][CH2:38][C:39]([OH:40])([CH3:42])[CH3:41])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1)(=[O:32])=[O:31]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Triethylamine (1.36 mL, 9.8 mmole) was added to a solution of 5,6,7,8-tetrahydro-3-nitro-2,4-bis[(trifluoromethyl)sulfonyloxy]quinoline (4.2 g, 9.4 mmole) in methylene chloride (180 mL). 2-Amino-α,α-dimethylethanol (0.88 g, 9.8 mmole) was added to the reaction mixture which was then stirred at ambient temperature overnight. The reaction mixture was evaporated to provide a residue which was purified by silica gel chromatography eluting with hexane: ethyl acetate 40:60 to provide 3.8 g of the desired product.
Reaction SMILES: O=S1(=O)CCN(CC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)CC1.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][CH:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:48])[CH3:47]
Reactant: CS(=O)(=O)C1CCN(CCCl)CC1
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in above for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperidine (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (24 mg, 36%). LCMS: m/e 723.56 (M+H)+, 2.28 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.77-3.63 (m, 2H), 3.62-3.54 (m, 3H), 3.50 (d, J=5.5 Hz, 1H), 3.35 (td, J=11.4, 3.7 Hz, 1H), 3.08-2.89 (m, 2H), 3.02 (s, 3H), 2.50 (d, J=13.1 Hz, 1H), 2.42-2.29 (m, 2H), 2.28-1.03 (m, 28H), 1.21 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 1.01 (d, J=11.3 Hz, 1H), 0.93 (d, J=6.7 Hz, 4H), 0.86 (d, J=6.7 Hz, 4H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][Si:15]([CH3:24])([CH3:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1N2CCN(CC2)C1>C1(C)C=CC=CC=1>[CH3:14][Si:15]([CH3:24])([CH3:23])[C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[CH:18][CH:17]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: C[Si](C)(C)c1ccc(N)cc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(NC(=O)NC(=O)c2c(F)cccc2F)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 6.0 g of 2,6-difluorobenzoylisocyanate in 20 ml of toluene was added dropwise at room temperature to a mixture of 5.4 g of 4-trimethylsilylaniline, 50 ml of toluene and 100 mg of Dabco®. The reaction mixture obtained was subsequently stirred at 60° C. for 3 hours. The reaction mixture was concentrated by evaporation, and the residue was recrystallised from acetone to obtain 1-(4-trimethylsilylphenyl)-3-(2,6-difluorobenzoyl)-urea of the formula ##STR8## as a white powder having a melting point of 187°-189° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][C:3]1([C:15]([O:17][CH3:18])=[O:16])[C:2](=[O:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: CI
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
A solution of O1-tert-butyl O3-methyl 4-oxopiperidine-1,3-dicarboxylate (1 g, 3.88 mmol) in DMF (100 mL) was cooled to 0° C. followed by portion wise addition of NaH (60% dispersion of mineral oil, 0.16 g, 3.88 mmol). The resulting mixture was stirred at the same temperature for 15 min followed by addition of MeI (0.7 mL, 11.64 mmol) at 0° C. then stirred at rt for 44 h. After completion of reaction (by TLC), water (100 mL) was added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the product as a yellow oil (0.9 g). MS: 272.12 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18](Cl)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CN1CCc2cc(Cl)nnc2C1)N1CCN(C2CCC2)CC1
Product: O=C(CN1CCc2cc(N3CCOCC3)nnc2C1)N1CCN(C2CCC2)CC1

Procedure:
A solution of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine (0.2 g) in morpholine (5 ml) is heated at 200° C. in a microwave for 2 hr. The excess morpholine is removed in vacuo. The crude mixture is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.60 (1H, s), 3.86 (2H, s), 3.82 (4H, t), 3.50-3.70 (8H, m), 3.40 (2H, s), 2.62-2.84 (5H, m), 2.24-2.32 (4H, m), 1.60-2.06 (6H, m); MS (+VE) m/z 401.2 (M++1).
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])=[C:4]([OH:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].[CH:21](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[C:1]([C:3]([C:19]#[N:20])=[C:4]([O:18][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in TI-IF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+]>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-formylbenzonitrile (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise. The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile. This material was taken forward to the next step without further purification). LC/MS M+1=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).