Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1, 98 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL) and EtOH (0.12 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white solid. HPLC (Condition 4) tR=4.94 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=532.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.08 (m, 6H) 1.58-1.83 (m, 2H) 1.99-2.15 (m, 1H) 3.05-3.23 (m, 3H) 3.25-3.35 (m, 1H) 4.29 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.75-7.87 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[CH:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH:18]2[CH2:17][CH2:16][CH:15]=[CH:14]2)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(C2C=CCC2)cc(Br)cc1S(=O)(=O)O
Temperature: 80 °C

Procedure:
A mixture containing 30 g (79.4 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid, 35 ml (397 mmol) of cyclopentene, 19.5 g (199 mmol) of potassium acetate, 6.24 g (23.8 mmol) of triphenylphosphine and 2.67 g (11.9 mmol) of palladium (II) acetate in 160 ml of N,N-dimethylformamide is heated at 80° C. for 48 hours, under a nitrogen atmosphere. The reaction medium is then concentrated under reduced pressure and the residue is taken up in a mixture containing 200 ml of methanol, 200 ml of 1N hydrochloric acid and 10 ml of 95% sulphuric acid solution. The mixture is evaporated again under reduced pressure and filtered, and the precipitate thus obtained is purified by chromatography on an RP 18 reverse-phase column, eluting with an acetonitrile/water mixture (3:7). The residue is recrystallized from a methanol/pentane mixture.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:7]=1.[NH2:18][NH2:19]>O1CCOCC1>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:5]1[N:4]=[N:3][C:2]([NH:18][NH2:19])=[CH:7][CH:6]=1
Reactant: NN
Reactant: Fc1ccc(C#Cc2ccc(Cl)nn2)c(F)c1
Solvent: C1COCCO1
Product: NNc1ccc(C#Cc2ccc(F)cc2F)nn1
Temperature: 80 °C
Yield: 95.5 %

Procedure:
A flask was charged with 3-chloro-6-((2,4-difluorophenyl)ethynyl)pyridazine (1.60 g, 6.38 mmol) and 1,4-dioxane (15 mL) to give a tan solution. Anhydrous hydrazine (2.00 mL, 63.8 mmol) was added and the mixture was heated at about 80° C. for about 1 h. The mixture was cooled to ambient temperature and was concentrated in vacuo to about half the original volume. Water (20 mL) was added, followed by sonication, and filtration. The solids were collected and dried in a vacuum oven overnight at about 50° C. to afford the title compound (1.50 g, 95%): LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 247.1 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2].[N:34]1(CCO)CCOC[CH2:35]1>>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:34]([CH3:35])[CH2:30][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(OCCN3CCOCC3)cc2[nH]1
Reactant: OCCN1CCOCC1
Product: CN1CCN(CCOc2ccc3cc(C(=O)N[C@H]4CCCC[C@H]4C(=O)NCC#N)[nH]c3c2)CC1

Procedure:
N-((1S,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexyl)-6-(2-morpholin-4-ylethoxy)-1H-indole-2-carboxamide using Mitsunobu coupling with 2-morpholin-4-yl-ethanol.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:41])([F:40])[C:33]1[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[CH:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:34][CH:35]=2)=[CH:17][CH:18]=1)[CH3:11]
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1F
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCOCc1ccccc1F
Temperature: 95 °C

Procedure:
33.4 g of 2-(2-fluorobenzyloxy)ethyl-2-(4-hydroxyphenoxy)propionate was dissolved in 120 ml of dimethylformamide, 15.2 g of potassium carbonate were added thereto, then the mixture was heated at 95° C. for one hour with stirring. 27.1 g of 4-trifluoromethyl chlorobenzene were added to the solution which was then heated to 95° to 100° C. for five hours. After cooling the reaction solution to room temperature, it was poured into ice-water, then extracted with toluene. The toluene layer was washed successively with 1% strength by weight sodium hydroxide solution and water, and was dried and filtered. The toluene was distilled off under reduced pressure, and further volatile by-products were removed at 100° C./0.1 mmHg. The end product of 2-(2-fluorobenzyloxy)ethyl-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionate was obtained in a yield of 20.7 g. (nD20 1.5235)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)=O.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C@H:25]([NH2:27])[CH3:26])=[CH:16]1>C(O)(=O)C>[CH3:26][C@H:25]1[NH:27][C@@H:1]([C:3]2[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[C:16]2[NH:15][C:23]3[C:18]([C:17]=2[CH2:24]1)=[CH:19][CH:20]=[CH:21][CH:22]=3
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc([C@@H]2N[C@H](C)Cc3c2[nH]c2ccccc32)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
(E)-Methyl 3-(4-formylphenyl)acrylate (obtained as described in Example 2, preparation of starting materials) (18.56 g, 97.57 mmol) was added to a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (17 g, 97.57 mmol) in acetic acid (250 mil) at 23° under nitrogen. The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (500 ml), and washed sequentially with saturated NaHCO3 (300 ml×2), 2M NaOH (aq) (300 ml), water (300 ml), and saturated brine (300 ml). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 7% methanol in DCM. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1S,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (25.1 g, 74.3%) as a beige foam. The product was mostly cis isomer, containing about 12% trans isomer which was inseparable. 1H NMR (400 MHz, DMSO, 30° C.) δ 1.25 (3H, d), 2.37-2.48 (1H, m), 2.74 (1H, d), 3.12 (1H, s), 3.73 (3H, s), 5.18 (1H, s), 6.64 (1H, d), 6.97 (2H, dd), 7.19 (1H, d), 7.36-7.46 (3H, m), 7.64-7.75 (3H, m), 10.19 (1H, s), no NH observed. m/z: ES+ [M+H]+ 347.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.ClCCl>CN(C)C1C=CN=CC=1.CN(C=O)C.ClCCl>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:32][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=[C:15]([S:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:9][CH:10]=3)[C:20]=2[C:21]#[N:22])=[CH:24][CH:25]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
758 mg (1.348 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(propylamino)pyridine-3,5-dicarbonitrile (Example 12), 765 mg (4.043 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 82 mg (0.674 mmol) of 4-dimethylaminopyridine were initially charged in 10.3 ml of DMF/dichloromethane (1:1). 336 mg (1.752 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at RT overnight. The reaction solution was freed from dichloromethane and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 929 mg (94% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:17][CH:16]=1.P(Br)(Br)[Br:28]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:28])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCO)cc1
Reactant: BrP(Br)Br
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCBr)cc1

Procedure:
According to the method described for Reference Example 25, 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1-pentanol was allowed to react with phosphorus tribromide to give 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl bromide. Recrystallization from ether-hexane gave colorless needles, m.p.58°-59° C.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[N:20][CH:21]=1>>[CH3:22][C:19]1[N:20]=[CH:21][C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1ccc(Br)cn1
Product: Cc1ccc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)cn1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 5-bromo-2-methyl-pyridine (purchased from Emka Chemie) were coupled according to the procedure described in Example 1A to provide the title product. MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: C([O:4][CH:5]([CH:12]=[CH2:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+].C(O)C>COC1C=CC(O)=CC=1.O>[CH:12]([CH:5]([OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:13]
Reactant: C=CC(OC(C)=O)c1ccccc1
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC(O)c1ccccc1
Temperature: 65 °C
Yield: 90 %

Procedure:
120 grams (0.6876 mol) of vinylbenzyl acetate, inhibited with 10 mg of MEHQ were added to a one liter 3-neck round bottom flask equipped with a condenser, mechanical stirrer and thermometer, followed by 50 grams (1.25 mol) of sodium hydroxide. 50 mL of water and 300 mL of ethanol were then added and the contents of the flask heated at reflux (65° C.) for 2 hours. After the mixture was allowed to cool to room temperature, water was added. The content of the flask was poured into a separatory funnel and extracted with chloroform several times. The chloroform extract was subsequently washed several times with water and dried over magnesium sulfate. Removal of the chloroform on the rotary evaporator afforded 83 grams of the vinylbenzyl alcohol product (95% yield). The purification was accomplished by vacuum distillation.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][N:13](CC2C=CC=CC=2)[CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl.[Pd]>[CH:1]1([NH:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccccc1OCCN(CCCCC(=O)NC1CCCCC1)Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1OCCNCCCCC(=O)NC1CCCCC1
Reaction time: 2 h

Procedure:
A catalyst composed of palladium on 10% moist carbon (1.5 g) is added to a solution of N-cyclohexyl-5-[benzyl{2-(2-methoxyphenoxy)ethyl}amino]pentan-amide (3 g, 6.8 mmole) in glacial acetic acid (30 ml) and the mixture is hydrogenated for 2 hours at 20° C. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The residue obtained in the form of a salt of acetic acid is taken up in dichloromethane (50 ml) and the base is liberated by treatment with a saturated solution of sodium hydrogen carbonate. The organic phase is collected, washed with water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The expected product is obtained in the form of a white powder after crystallisation in diethylether (0.95 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: COc1cccc(CN)c1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNC(=O)c2ccc(Br)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (100 mg, 0.465 mmol) in DCM (2 mL) were added (3-methoxyphenyl)methanamine (70.2 mg, 0.512 mmol), DIEA (0.244 mL, 1.395 mmol) and HATU (212 mg, 0.558 mmol) at RT. The reaction was stirred under argon at RT for 1 h. The crude product was purified by normal phase chromatography. 58A was obtained as white solid (155 mg, 0.464 mmol, 100% yield). LCMS (ESI) m/z: 336.0 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.30-7.24 (m, 1H), 6.92 (dd, J=7.6, 0.6 Hz, 1H), 6.88 (t, J=1.8 Hz, 1H), 6.84 (dt, J=8.1, 1.3 Hz, 1H), 6.38 (br. s., 1H), 4.60 (d, J=5.7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:10])[CH2:7][C:8]#[N:9].B>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:10])[CH2:7][CH2:8][NH2:9]
Reactant: N#CCC(O)c1cccs1
Agent: B
Solvent: C1CCOC1
Product: NCCC(O)c1cccs1
Yield: 81 %

Procedure:
To 10 ml of a THF solution of 1.53 g (10 mmol) of the optically active 3-(2-thienyl)-3-hydroxypropanenitrile obtained in Example 6, slowly added was 1.23 ml (13 mmol) of borane.dimethylsulfide complex. After removing the dimethylsulfide by reducing the pressure, the reaction mixture was refluxed for 2.5 hours. The reaction was stopped by addition of a methanol/hydrochloric acid solution, and the methanol was distilled off under vacuum. After neutralizing with a SN aqueous solution of sodium hydroxide, the solvent was distilled off, a further aqueous solution of sodium hydroxide was added to make the reaction solution basic, and this was then extracted with methylene chloride. This methylene chloride solution was dried with anhydrous sodium sulfate, and the solvent was then distilled off under vacuum to give 1.28 g (yield 81%, 1H-NMR) of optically active 1-(2-thienyl)-3-aminopropanol.
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]1[CH:31]=[N:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>ClCCl>[N:30]1[CH:31]=[CH:26][CH:27]=[C:28]([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:29]=1
Reactant: O=C=Nc1cccnc1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
3-(Biphenyl-4-yloxy)azetidine hydrochloride (3 g, 11.47 mmol) was suspended in dichloromethane (45 mL) under a nitrogen atmosphere, treated with triethylamine (4.0 mL, 28.68 mmol) and stirred for 10 minutes at room temperature. The mixture was cooled to 0° C. and treated portionwise with pyridine-3-isocyanate (1.15 g, 9.56 mmol). Stirred at 0° C. for 10 minutes, then at rt for 16 hours. The solution was diluted with further dichloromethane (200 mL), washed with H2O (2×100 mL), followed by brine (50 mL), dried (over MgSO4), and solvent evaporated in vacuo to yield an off-white solid. The solid was triturated with diethyl ether, then stirred for 3 days with MP-isocyanate resin in a dichloromethane/methanol/acetonitrile mixture. The mixture was filtered and reduced to dryness in vacuo. The resulting solid was triturated successively with diethyl ether, then acetonitrile and filtered to give the urea (1.2 g, 36%) as a white solid; Rf 0.10 (5% MeOH-DCM); LCMS retention time 2.08 minutes, m/z 346.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 8.97 (s, 1H), 8.75 (d, 1H, J=2.3 Hz), 8.21 (d, 1H, J=4.7 Hz), 8.05-8.01 (m, 1H), 7.65-7.60 (m, 4H), 7.44 (t, 2H, J=7.9 Hz), 7.39 (dd, 1H, J=8.3 and 4.7 Hz), 7.32 (t, 1H, J=7.3 Hz), 6.96 (d, 2H, J=8.8 Hz), 5.14-5.08 (m, 1H), 4.49 (dd, 2H, J=9.5 and 6.5 Hz) and 3.97 (dd, 2H, J=9.5 and 3.8 Hz); 13C nmr (100 MHz; DMSO-d6) 156.2 (C), 155.9 (C), 141.4 (CH), 139.6 (C), 138.9 (CH), 137.3 (C), 133.4 (C), 128.9 (CH), 128.1 (CH), 126.9 (CH), 126.8 (CH), 126.3 (CH), 123.9 (CH), 115.1 (CH), 65.6 (CH) and 56.4 (CH2).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1.[Cl-].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[Zn+]>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>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1
Reactant: Fc1ccc([Zn+])c(F)c1
Reactant: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: Cc1cc(-n2cc(-c3ccc(F)cc3F)nc2C)cc2ccc(=O)[nH]c12

Procedure:
This compound, m.p. 262°-5°, was prepared similarly to Example 11 using 6-(4-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, 2,4-difluorophenyl zinc chloride and tetrakis(triphenylphosphine)palladium (O) as the starting materials:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=3[N:17]=[CH:16]2)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:45](O)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[N:21]=[C:19]([O:20][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:18]=3[N:17]=[CH:16]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1OC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(OCc4ccccc4)nc(N)nc32)C[C@@H]1OC(C)=O
Temperature: 85 °C

Procedure:
3′,5′-Di-O-acetyl-O6-benzyl-2′-deoxyguanosine (4) was prepared following the method of Zajc et al., Tet. Lett. 1992, 33, 3409-3412. To a mixture of 3′,5′-di-O-acetyl-2′-deoxyguanosine (5.71 g, 16.3 mmol), triphenylphosphine (5.91 g, 22.5 mmol) and benzyl alcohol (2.5 mL, 24.1 mmol) in 100 mL 1,4-dioxane under argon was slowly added diisopropylazodicarboxylate (4.5 mL, 22.8 mmol). The mixture was heated to 85° C. for two hr and was then cooled and concentrated to a thick paste on a rotary evaporator. The product was isolated as a light brown solid (1.78 g, 24.8%) following silica gel column chromatography with 10% ethyl acetate/chloroform. 1H-NMRδH(DMSO-d6) 8.09 (s, 1H, H-8), 7.51-7.35 (m, 5H, Ar), 6.54 (s, 2H, N2H2, exchange with D2O), 6.24 (dd, J=6.0, J′=8.5, 1H, H-1′), 5.50 (s, 2H, OCH2Ar), 5.33-5.32 (m, 1H, H-3′), 4.32-4.27 (m, 1H, H-4′), 4.22-4.18 (m, 2H, H-5′), 3.06-2.98 (m, 1H, H-2′α), 2.50-2.44 (m, 1H, H-2′β), 2.09 (s, 3H, COCH3), 2.02 (s, 3H, COCH3); MS, m/z 442.1 [M+H]+, 464.1 [M+Na]+; Anal. Calcd. for C21H23N5O6: C, 57.14; H, 5.25; N, 15.86.