Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[OH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Nc1ccc(OCCCO)cc1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCCO)cc3)ncn2)c1
Yield: 18 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.35 g) was reacted with 4-(3-hydroxypropoxy)aniline.(1.0 g). The product so obtained was chromatographed on silica and triturated under methylene chloride to give 4-[4'-(3-hydrox-ypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 18% yield, m.p. 196°-200° C.;
Reaction SMILES: Cl/C=C\Cl.C(OC(OCC)C#C)C.C(N)CCC.Cl/[CH:20]=[CH:21]\[C:22]#[C:23][CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:26]([O:25][CH:24]([O:28][CH2:29][CH3:30])[C:23]#[C:22]/[CH:21]=[CH:20]\[C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH3:27]
Reactant: CCOC(C#C/C=C\Cl)OCC
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: C#CC(OCC)OCC
Solvent: CCCCN
Product: CCOC(C#C/C=C\C#C[Si](C)(C)C)OCC

Procedure:
The diynene acetal X may be synthesized using the following procedure. Cis-1,2-dichloroethylene is reacted with 3,3-diethoxypropyne in the presence of copper iodide, palladium tetrakis(triphenylphosphine) and n-butylamine, at room temperature and in the absence of light. The product, (Z)-5-chloro-1,1-diethoxy-4-pentene-2-yne is treated with trimethylsilylacetylene in the presence of copper iodide, palladium tetrakis(triphenylphosphine), and n-butylamine at room temperature and away from light to provide (Z)-7,7-diethoxy-1-trimethylsilyl-3-hepten-1,5-diyne. The corresponding anion is then generated by treatment with an alkali metal hydroxide, such as lithium hydroxide.
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cocc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2cocc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydrocyclopenta[c]furan (6.2 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][Si:8]([O:11][CH2:12][CH3:13])([CH3:10])[CH3:9])(=O)C.CC[O-].[Na+]>C(O)C>[SH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:11][CH2:12][CH3:13])([CH3:10])[CH3:9]
Reactant: CCO[Si](C)(C)CCCSC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](C)(C)CCCS
Yield: 66 %

Procedure:
Added, at ambient temperature, to a solution of S-(ethanoyl)mercaptopropylethoxydimethylsilane C (65.4 g, 0.297 mol) in absolute ethanol (230 ml) is solid sodium ethylate (2.02 g, 0.030 mol) under argon. The reaction medium is brought to reflux for 2.5 hours. After returning to ambient temperature, the precipitate of NaCl is filtered and washed with heptane (350 ml). After evaporating the solvents under reduced pressure at 45° C., the oil obtained is purified by vacuum distillation (60° C./10 mbar). The 3-mercaptopropylethoxydimethylsilane D with CAS number [141137-15-7] (34.7 g, 0.195 mol) is obtained with a yield of 66%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.32 g of p-chlorobenzyl chloride and 15 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.51 g of 1-sec-butoxy-3-chloro-4-(4-chlorobenzyloxy)benzene. Yield, 78%. nD20.6 1.5630.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>[N+](C)([O-])=O>[C:17]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, 2-methoxynaphthalene (64 g, 0.41 mol) easily available from a reagent manufacturer was dissolved in nitromethane (150 ml) dried with a molecular sieve 3A. Under an ice bath, aluminum chloride (80 g, 0.60 mol) was added. Subsequently, decanoyl chloride (92 ml, 0.45 mol) was dropped into the solution under the ice bath. The solution was stirred under room temperature for 5 hours, and water (100 ml) was dropped into the solution under the ice bath. The reaction solution was extracted with methylene chloride (200 ml×4), and the obtained organic layer was washed with water (100 ml×3). The organic layer was dried with anhydrous magnesium sulfate, and filtered. Then, the solvent was distilled away under reduced pressure. The obtained yellow solid was recrystallized from hexane to obtain 2-decanoyl-6-methoxynaphthalene (102 g, 82%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:25])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.O.[OH-].[OH-].[Pd+2]>[CH3:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:25])[C:18]=1[C:13]1[N:14]=[C:15]([O:16][CH3:17])[C:10]2[CH2:9][NH:8][CH2:27][CH2:26][C:11]=2[N:12]=1
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(-c2c(C)cccc2C)nc2c1CNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-benzyl-2-(2,6-dimethylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (7.08 g, 19.70 mmol) in THF (100 mL) and H2O (12.50 mL), was added 20% Pd(OH)2 wet (50% dry basis, 2.77 g, 1.970 mmol), followed by acetic acid (2.26 mL, 39.4 mmol). The reaction was stirred at r.t. under hydrogen atmosphere for 30 min, then heated to 40° C. for 16 h. The reaction mixture was cooled to r.t. and filtered through a Celite® pad which was washed with methanol. The organic solvent in the filtrate was removed under reduced pressure. The reaction mixture was diluted by 200 mL DCM and neutralized by saturated aqueous NaHCO3. The mixture was extracted twice by DCM. The combined organic layers were dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC (Methanol/DCM=0 to 10%) to provide 2-(2,6-dimethylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.22 (m, 1 H), 7.05-7.11 (m, 2 H), 5.75 (s, 1 H), 3.88 (s, 3 H), 3.72 (s, 2 H), 3.01 (t, J=5.8 Hz, 2 H), 2.68 (t, J=5.7 Hz, 2 H), 2.03 (s, 6 H). MS (ESI+) m/z 270.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:9][CH:8]=1>C(O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:4][CH2:3][C:2](=[O:5])[CH3:1])[CH2:28][CH2:29]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=CC(C)=O
Solvent: CCO
Product: CC(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 2.1 parts of 3-buten-2-one, 9.7 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 120 parts of ethanol was stirred for 3 hours at reflux temperature. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 5 parts (42%) of 4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone; mp. 131.3° C. (intermediate 91).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30](=[O:35])[NH:31][NH:32]2)=[C:28]([F:36])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([C:30](=[O:35])[NH:31][NH:32]4)=[C:28]([F:36])[CH:27]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1cc(F)c2c(=O)[nH][nH]c2c1
Product: CCC(C(=O)Nc1cc(F)c2c(=O)[nH][nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.31 mmol, 1.1 eq.) of 6-amino-4-fluoro-1,2-dihydro-3H-indazol-3-one were reacted according to General Method 6. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 6 mg (4% of theory)
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6]12[CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2=O)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(C1C=CC=CC=1NN)C>>[CH2:17]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:23]=1[NH:15][C:7]1[C:6]3([CH2:5][C:4]([OH:3])=[O:14])[CH2:12][CH:11]3[CH2:10][CH2:9][C:8]2=1)[CH3:16]
Reactant: CCOC(=O)CC12CC1CCCC2=O
Reactant: c1ccc2[nH]ccc2c1
Agent: CCc1ccccc1NN
Product: CCc1cccc2c3c([nH]c12)C1(CC(=O)O)CC1CC3

Procedure:
The title compound was prepared from 2-oxobicyclo[4.1.0]heptane-1-acetic acid ethyl ester by a Fisher indole reaction with 2-ethylphenylhydrazine followed by ester hydrolysis as described in Example 1, Step 6, m.p. 154°-156° C. (foams).
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.N([O-])=O.[Na+].OC1C(OC2C=CC=CC=2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:39])=O>>[Cl:39][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1
Reactant: COc1cnc(Oc2ccccc2)c(N)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1cnc(Oc2ccccc2)c(O)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(Oc2ccccc2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-phenoxy-6-methoxypyrazine with phosphorus oxychloride by the method of Preparation 13, Step B, gives 2-chloro-3-phenoxy-6-methoxypyrazine.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.CCCCCC.C(OCC)(=O)C>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])\[CH3:6])/[CH:3]=[O:4]
Reactant: COc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-en-1-ol (Compound 82, 117 mg, 0.37 mmol) in dichloromethane/acetonitrile (6:1, 7 mL) at 25° C. were added 4-methylmorpholine N-oxide (85 mg, 0.74 mmol), tetrapropylammonium perruthenate (12 mg, 0.04 mmol), and 4 Å molecular sieve powder (60 mg). The mixture was stirred at 25° C. for 1 h and applied directly to chromatography. Flash chromatography (silica gel, 100% hexane to 5% ethyl acetate in hexanes) gave rise to the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:31])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[C:19]([CH3:30])[CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([OH:39])[CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.CCO.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:31])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[C:19]([CH3:30])[CH:18]=4)[CH3:13])[N:9]=[C:10]([C:35]3[CH:36]=[C:37]([OH:39])[CH:38]=[C:33]([F:32])[CH:34]=3)[C:3]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Cc1ccc2c(-c3ccccc3)c(C(C)n3nc(I)c4c(N)ncnc43)oc(=O)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3ccccc3)c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c2c1
Temperature: 80 °C
Yield: 23.7 %

Procedure:
3-(1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-7-methyl-4-phenyl-1H-isochromen-1-one (intermediate D29, 0.100 g, 0.19 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (0.036 g, 0.229 mmol) and PPh3 (0.030 g, 0.114 mmol) were dissolved in a mixture of DMF (10 ml), EtOH (4 ml) and water (4 ml); Na2CO3 (0.101 g, 0.95 mmol) was added and the mixture was degasses under nitrogen. Pd(OAc)2 (0.009 g, 0.038 mmol) was added and the reaction was heated at 80° C. for 15 min. 1M HCl was added (pH≈2) and the mixture was partitioned between EtOAc and water. The organic phase was extracted with EtOAc and the combined organic layers were washed several times with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by flash chromatography on Biotage silica gel cartridge (DCM to DCM:MeOH=97:3) to afford the title compound (0.023 g, 0.045 mmol, 24%).
Reaction SMILES: [OH: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.Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O: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
Reactant: CC(=O)CBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCC(C)=O)c1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 2.8 g of methyl 3-hydroxyphenylacetate, 3.5 g of bromoacetone, 4 g of potassium carbonate and 30 ml of dimethylformamide, the title compound was obtained having an Rf=0.41 (thin layer chromatography over silica gel, using a 2:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:15]N1C(=O)CCC1=O>CCO.O1CCOCC1>[Cl:15][C:11]1[N:12]=[C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][C:10]=1[CH2:13][OH:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCc1ncc(CO)[nH]1
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH/1,4-dioxane (1:1; 600 mL) was added N-chlorosuccinimide (7.9 g, 59 mmol). After being stirred for 1 hour at room temperature the solvents were removed on a rotary evaporator and the solid residue was partitioned between ethyl acetate and water (300 mL each). The organic phase was washed with water (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc/hexane, 60 mL) gave 5.7 g (45%) of white crystals; m.p. 134°-140°. NMR (200 MHz, CDCl3 /CD3OD) δ4.50 (s, 2H); 4.00-3.80 (br s, 2H); 2.65 (t, 2H, 5 Hz); 1.80-1.60 (m, 2H); 1.40-1.20 (m, 8H); 0.90-0.80 (m, 3H). Mass Spec. 230.
Reaction SMILES: [O:1]=[S:2]1(=[O:55])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]CNC[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3CC5(CC(C(O)=O)(C(O)=O)C5)C=3)=CC4)CC2)[CH2:4][CH2:3]1.[NH2:56][C@:57]12[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:58]1[C@@H:59]1[C@@:72]([CH3:75])([CH2:73][CH2:74]2)[C@@:71]2([CH3:76])[C@@H:62]([C@:63]3([CH3:91])[C@@H:68]([CH2:69][CH2:70]2)[C:67]([CH3:78])([CH3:77])[C:66]([C:79]2[CH2:84][CH2:83][C:82]([C:85]([O:87][CH2:88][CH3:89])=[O:86])=[C:81]([CH3:90])[CH:80]=2)=[CH:65][CH2:64]3)[CH2:61][CH2:60]1>>[O:1]=[S:2]1(=[O:55])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:56][C@:57]23[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:58]2[C@@H:59]2[C@@:72]([CH3:75])([CH2:73][CH2:74]3)[C@@:71]3([CH3:76])[C@@H:62]([C@:63]4([CH3:91])[C@@H:68]([CH2:69][CH2:70]3)[C:67]([CH3:77])([CH3:78])[C:66]([C:79]3[CH2:84][CH2:83][C:82]([C:85]([O:87][CH2:88][CH3:89])=[O:86])=[C:81]([CH3:90])[CH:80]=3)=[CH:65][CH2:64]4)[CH2:61][CH2:60]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(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(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above in Step 2 for the preparation of 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid (example A14), using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-methylcyclohexa-1,3-dienecarboxylate as the reactant. (quantitative yield). MS: m/e 735.8 (M+H)+, 3.41 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.65 (s, 1H), 5.28 (dd, J=6.0, 1.5 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.15-2.97 (m, 8H), 2.73-2.51 (m, 4H), 2.50-2.38 (m, 3H), 2.22 (q, J=8.3 Hz, 2H), 2.15 (s, 3H), 2.06-1.18 (m, 25H), 1.11-1.04 (m, 6H), 1.00 (s, 3H), 0.98-0.95 (m, 6H), 0.88 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:3][CH2:4][CH:5]([C:8]4[C:9](=[O:18])[NH:10][C:11]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:6][CH2:7]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as off-white solid in 46% yield. MS m/e (M+H)+=574.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 11.76 (s, 1H), 8.36 (s, 1H), 7.70 (d, J=5.80, 1H), 7.61 (d, J=7.63, 1H), 7.43 (t, J=7.63, 1H), 7.28 (d, J=7.93, 1H), 7.24 (s, 1H), 7.15 (t, J=7.32, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=16.79, 1H), 4.55 (d, J=12.21, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.15 (m, 2H), 3.03 (m, 3H), 2.88 (m, 1H), 2.63 (m, 1H),2.34(d, J=16.17 1H), 1.91 (d, J=1.22, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: C([O:6][CH2:7][C@@H:8]1[CH2:13][C@H:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:11][CH2:10][C@@H:9]1[N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[C:20]1=[O:39])(=O)C(C)C.[OH-].[Na+].[NH4+].[Cl-]>CO>[OH:6][CH2:7][C@@H:8]1[CH2:13][C@H:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:11][CH2:10][C@@H:9]1[N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[C:20]1=[O:39]
Reactant: CC(C)C(=O)OC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of ((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-(2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)methyl isobutyrate (Example 7a, 4 mg) in MeOH (1 mL) was added 1N-NaOH (0.1 mL), and the mixture was stirred for 9 h at rt. After neutralizing with sat. NH4Cl, it was extracted with EtOAc (2×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH—MeOH—CH2Cl2 to afford the titled compound 1-((1S,2R,4R)-2-(hydroxymethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one. MS found: (M+H)+=480.2.