Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][CH:4]([F:32])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1.[C:33]1([CH2:39][CH:40]=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CN(C)C=O>[F:32][CH:4]([F:3])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH2:40][CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1
Reactant: O=CCc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCNC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCN(CCc3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (58 mg) and N,N-dimethylformamide (1.2 mL) were added phenylacetaldehyde (21 mg), sodium triacetoxyborohydride (75 mg), and acetic acid (0.29 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (chloroform:methanol=100:0-90:10) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-1-(2-phenylethyl)pyrrolidin-3-yl]pyrimidin-2-amine (30 mg) as a white powder.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>CCOC(C)=O>[NH:17]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C@H:18]([C:23]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dipeptide H-Leu-Gly-OCH3 : DIEA (21 mL) was added to a stirred solution of HCl.H-Gly-OCH3 (13 g) in EtOAc (500 mL). After 15 min, Boc-Leu-OH.H20 (20 g) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (25.5 g) were added in succession. The reaction mixture was stirred at room temperature for 18 h, and then filtered. The filtrate was washed serially with H20, 1N HCl, H20, 5% aqueous NaHCO3 and water. The dried (Na2SO4 +MgSO4) organic phase was concentrated to near dryness. Et20 was added to the concentrate and the mixture was stored at 4° C. for 18 h. The resultant precipitate was collected and dried to give Boc-Leu-Gly-OCH3 (15.6 g). The latter compound (15.5 g) was dissolved in CH2Cl2 (150 mL) and the solution cooled to 0° C. TFA (60 mL) was added dropwise to the cooled solution. The mixture was stirred at 0° C. for 1.5 h and then evaporated to dryness. TFA was removed from the residue by adding Dowex 1×2-400 ion exchange resin (40 g), prewashed with methanol (4×100 mL), 1N HCl (3×200 mL) and methanol (4×100 mL), to a solution of the crude residue in methanol (300 mL). (Note: Dowex is a trademark). The mixture was stirred at room temperature for 1h and then filtered. The filtrate was concentrated under reduced pressure to give TFA.H-Leu-Gly-OCH3 (17.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.Cl[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: Oc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(CCOc3ccc4nc(Cl)cnc4c3)CC2)nn1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoxaline (52 mg, 288 μmol), 3-[-4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine (76 mg, 317 μmol), potassium iodide (53 mg, 317 μmol) and potassium carbonate (199 mg, 1.44 mmol) in anhydrous dimethylformamide (2 ml) was heated at 90° under an Argon atmosphere for 2 days. Tlc (silica; ethyl acetate) showed new polar material. Removal of the solvent under high vacuum and then chromatography on silica (5 g; eluent: 30% hexane in ethyl acetate) gave the product as a white solid 68 mg (61%).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.308 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazine-2-carbonitrile (45 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=1.CC([O-])=O.[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[C:6]([C:28]1[CH:27]=[N:26][C:25]([NH2:24])=[CH:30][CH:29]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2]
Reactant: CCOC(=O)C=CCCCCCCc1ccc2cccnc2n1
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(CCCCCCc1ccc2cccnc2n1)c1ccc(N)nc1
Temperature: 115 °C

Procedure:
A mixture of 28-4 (0.3 g, 1.0 mmol), 2-amino-5-bromopyridine (0.3 g, 1.9 mmol), KOAc (0.3 g, 2.4 mmol) and Pd(OAc)2 (0.02 g, 0.1 mmol) in 6 mL DMF was purged with argon for 5 min and then heated at 90° C. for 7 hr and 115° C. for 48 hr. It was cooled, treated with 50 mL water and extracted with EtOAc (×3). The combined organic layers were washed with brine and dried over Na2SO4. After solvent removal, the residue was purified using silica gel flash chromatography (100% EtOAc to EtOAc/MeOH 10:1) to afford the desired product 28-5 as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:19][N:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]=[C:15]1[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CNc1ccccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cn1c(Cc2nc(N3CCOCC3)cc(=O)[nH]2)nc2ccccc21
Yield: 60.2 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 280 mg of N-methyl-1,2-phenylenediamine in place of the 4-bromobenzene-1,2-diamine. After purification by silica column chromatography, eluent: a gradient of the pure CH2Cl2 eluent to CH2Cl2/MeOH: 90/10, 225 mg of 2-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH:24]([CH3:26])[CH3:25]>CS(C)=O.O>[CH:24]([C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])([CH3:26])[CH3:25]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1F
Reactant: O=C1NCCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1N1CCCNC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
347 mg (3.47 mmol) of tetrahydropyrimidinone in 21 ml of DMSO are admixed at RT with 584 mg (5.21 mmol) of potassium tert-butoxide, and the mixture is stirred at RT for 45 min. 700 mg (3.82 mmol) of 1-fluoro-2-isopropyl-4-nitrobenzene are added and the mixture is stirred at 60° C. After 18 h, it is cooled and diluted with 250 ml of water. It is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure and the residue is purified by chromatography on silica gel (1:5→1:10 cyclohexane/ethyl acetate). This affords 140 mg (14% of theory) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.N1C=CC=CC=1>ClCCl.CC=C(C)C.C(#N)C1C=CC=CC=1.C(Cl)(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: CC=C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: N#Cc1ccccc1
Product: N#Cc1ccc(NC(=O)Cc2ccc(Br)cc2)cc1C(F)(F)F
Yield: 48.5 %

Procedure:
Dissolve 4-bromo-phenyl acetic acid (5 g, 23.3 mmol) in 125 mL dichloromethane. Add 1 mL DMF, stir to give a clear solution, then add oxalyl chloride (3.25 g, 2.23 mL, 25.5 mmol) portionwise via syringe and stir at room temperature for 15-30 minutes until gas evolution ceases. Remove volatiles on rotovap to yield a clear yellow oil. Dissolve the oil in 100 mL amylene-stabilized chloroform, chill on ice and fit flask with a dropping funnel. Fill the dropping funnel with a solution of 4-amino-2-trifluoromethyl-benzonitrile (4.65 g, 25 mmol) and pyridine (6.05 g, 6.19 mL, 76.5 mmol) in 200 mL amylene-stabilized chloroform. Add the benzonitrile solution to the cold acid chloride solution with stirring over 30 minutes, remove the ice bath and stir overnight at room temperature. Dilute the reaction mixture with 200 mL dichloromethane, wash twice with 250 mL portions of 1 N NaHSO4, once with aqueous saturated sodium chloride, then dry over MgSO4 and concentrate to a brown solid. Purify on Biotage 75L® silica cartridge in 4.5:4.5:1 CH2Cl2:hexanes:diethyl ether to yield 4.33 g (48%) of the title compound as a pale yellow-ivory solid. LCMS (ES) m/z 381,383 (M−1).
Reaction SMILES: [CH:1]([S:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>>[NH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][CH:15]([S:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(SC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCC(SC(c2ccccc2)c2ccccc2)CC1

Procedure:
The above phthalimide was treated with hydrazine hydrate in the same manner as in Reference Example 4, to obtain the title compound, i.e. 1-(2-aminoethyl)-4-benzhydrylthiopiperidine at a yield of 92%.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:44]2[N:43]=[C:42]([Cl:45])[N:41]=[C:23]([NH:24][C@H:25]([CH3:40])[CH2:26][S:27][C:28]3[S:29][C:30]4[CH:36]=[C:35]([O:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:31]=4[N:32]=3)[C:22]=2[N:21]=[CH:20]1)(=O)C.C[O-].[Na+]>CO>[C:16]([O:15][CH2:14][C@H:8]1[O:7][C@@H:6]([N:19]2[C:44]3[N:43]=[C:42]([Cl:45])[N:41]=[C:23]([NH:24][C@H:25]([CH3:40])[CH2:26][S:27][C:28]4[S:29][C:30]5[CH:36]=[C:35]([O:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:31]=5[N:32]=4)[C:22]=3[N:21]=[CH:20]2)[C@H:5]([OH:4])[C@@H:9]1[OH:10])(=[O:18])[CH3:17]
Reactant: CCOc1ccc2nc(SC[C@@H](C)Nc3nc(Cl)nc4c3ncn4[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)sc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc2nc(SC[C@@H](C)Nc3nc(Cl)nc4c3ncn4[C@@H]3O[C@H](COC(C)=O)[C@@H](O)[C@H]3O)sc2c1
Yield: 18 %

Procedure:
Partial deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine (described in Example 19) using sodium methoxide in methanol provided the title 5'-O-acetyl-N-[(R)-1-(6ethoxy2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine (0.070 g, 18%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.34-1.41 (6H, m, --CH2CH3 and --CHCH3), 2.03 (3H, s, --COCH3), 4.60 (1H, q, H-2'), 4.68 (1H, m, -CHCH3), 5.42, 5.62 (2H, 2d, 2'- and 3'-OH), 5.86 (1H, d, H-1'), 7.04 (1H, dd, Ar-H), 7.57, 7.72 (2H, 2d, Ar-H), 8.38 (1H, s, H-8), 8.52 (1H, d, N--H). HPLC retention time 25.6 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:29]([F:30])[CH2:28][C@@:27]2([CH3:31])[CH:7]([C@H:8](O)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:29]([F:30])[CH2:28][C@@:27]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2[C@H](O)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)C[C@H]1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)C[C@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To the solution of the acetate (7) (92 mg, 0.198 mmol) in pyridine (2 ml) was added dropwise phosphorusoxychloride (0.06 ml) at 0° and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added ice and ethyl acetate. The organic phase was washed with 2N-HCl, saturated NaHCO3 and brine, and dried over MgSO4. The residue obtained upon evaporation of the solvent was purified by column chromatography on silica gel (5 g). Elution with benzene-ethyl acetate (20:1) gave the olefine (8) (90 mg, 98%), mp 116°-119° (MeOH); δ0.68(3H s, 18H3), 0.87(6H, d, J=6 Hz, 26- and 27-H3), 0.93(3H, d, J=6 Hz, 21-H3), 1.06(3H, s, 19-H3), 2.08(3H, s, acetyl), 4.10-5.00(1 H, broad, 2β-H), 4.86(1H, m, 3α-H), and 5.42(1H, m, 6-H); m/z 386.3370(M+ -AcOH). (CH27H43F required M, 386.3347).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:27][C:28]1[N:33]=[C:32]([Cl:34])[C:31]([CH2:35]I)=[CH:30][N:29]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:26])[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][C:31]1[C:32]([Cl:34])=[N:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of phenylacetic acid methyl ester (1.50 g, 10.0 mmol) (Aldrich) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester as a colorless oil. (Yield 1.00 g, 64.5%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].S(Cl)(C)(=O)=O>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCN(CC)C(CO)c1cccc2c(C)c(C)oc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCN(CC)CC(c1cccc2c(C)c(C)oc12)N(CC)CC
Temperature: -30 °C
Yield: 50.8 %

Procedure:
0.8 g (2.7 mmol) of 2,3-dimethyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran, 2.67 ml (19.2 mmol) of triethylamine and 50 ml of dichloromethane are placed in a 100 ml round-bottomed flask. The solution is cooled to -30° C. using a dry ice bath and 99 ml (12.8 mmol) of mesyl chloride are added dropwise. The temperature is allowed to return to 0° C. and the solution is concentrated under vacuum. 20 ml of diethylamine are added to the residue and the solution obtained is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature and concentrated under vacuum, 50 ml of water are added and extraction is carried out with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 10% methanol in dichloroethane). 0.434 g (Yield: 55%) of 2,3-dimethyl-7-[1,2-di(diethylamino)ethyl]benzofuran is obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]([CH3:24])[C:21](=[O:23])C>[Cu]I>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([CH:2]2[CH2:3][CH2:24][N:20]([C:21]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:23])[CH2:19][CH2:7]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Cu]I
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(I) (0.206 g, 0.302 mmol), and copper(I) iodide (0.115 g, 0.603 mmol) in a dry microwave vial was flushed with nitrogen. N,N-dimethylacetamide (3 mL) was added followed by (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (9.52 mL, 9.05 mmol, approximately 1 M solution in N,N-dimethylacetamide prepared as described in the Journal of Organic Chemistry, 2004, 69, 5120). The vial was sealed and heated at 80° C. overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. This was left stirring for 30 min. The aqueous phase was washed with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by radial silica gel chromatography eluting with hexane containing 5 to 30% EtOAc afforded tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (0.376 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])C(OC)=O.Cl>O>[F:15][C:14]1[C:9]([CH2:4][C:3]([OH:19])=[O:2])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(C(=O)OC)c1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(O)Cc1c(F)cccc1[N+](=O)[O-]
Yield: 86.7 %

Procedure:
2-(6-Fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (12 g, 44 mmol) in a 6N aqueous solution of hydrochloric acid (200 mL) was heated at reflux for 4 hours. The mixture was cooled, diluted with 250 mL of water and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 7.6 g of (6-fluoro-2-nitro-phenyl)-acetic acid (54%). MS (ESI) m/z 200 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=[C:6]3[C:5]3([O:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>O1CCOCC1>[CH3:15][C:12]1([CH3:16])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH:22]=[CH2:23])=[CH:3][C:4]=3[C:5]3([O:17][CH2:18][CH2:19][CH2:20][O:21]3)[C:6]2=[N:14][CH2:13]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CN=C2N(C1)c1ccc(Br)cc1C21OCCCO1
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.6 %

Procedure:
To the stirred solution of 8′-bromo-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2- a]indole](2.576 g, 7.330 mmol) in dioxane (70 mL) was added tributyl (vinyl) tin (3.490 g, 10.995 mmol) and the solution was degassed with N2 for 15 min. Pd(PPh3) 4 was added and the mixture was stirred at 100° C. for 6 hr. The reaction was diluted with EtOAc, washed with brine and concentrated. The resulting residue was dissolved in EtOAc and stirred with 1M KF solution (20 mL) overnight. The reaction was filtered and the filtrate was washed with brine. The organics were dried over Na2SO4 and concentrated to give the title compound as white solid (1.720 g, 79%). NMR (400 Mz, DMSO-d6): consistent.