Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cccc(C2CCCN2)c1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1cccc(F)c1

Procedure:
The title compound, white solid, m.p. 96° C. and MS: m/e=305 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([NH:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:33]>>[ClH:33].[NH2:17][CH2:16][CH2:15][NH:14][C:12]([C:8]1[N:9]=[CH:10][S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1ccccc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1ncsc1-c1ccccc1
Reaction time: 1 h
Yield: 94 %

Procedure:
4.3 g (12.37 mmol) of t-butyl [2-(5-phenyl-4-thiazolecarboxamido)ethyl]carbamate were dissolved in 10 ml of methylene chloride, treated with 5.0 ml of trifluoro-acetic acid and stirred at 20° for 16 hours and at 60° for 1 hour. Subsequently, the mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of ethanol, treated with 3 ml of 17.5% (w/v) ethanolic hydro-chloric acid and evaporated. The residue was recrystallized from methanol, whereby 3.3 g (94%) of N-(2-aminoethyl)-5-phenyl-4-thiazolecarboxamide hydrochloride were obtained as white crystals, melting point 243°-245°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
3-[(3-aminophenyl)[[3-( 1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzoyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 15 mg (23%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-phenyl]benzamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C25H21F8N2O3: 549.1424 [M+H]+, found: 549.1436. 1H NMR (CDCl3) δ3.6 (dd, 1H), 3.8 (dd, 1H), 4.4 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.8 (d, 1H), 7.0-7.4 (m, 7H), 7.8 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1.C(=O)=O>O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCC1)C(=O)O
Agent: C=O
Agent: O=C=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: C=C(CCCC1CCCCC1)C(=O)OCC
Temperature: 60 °C

Procedure:
51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester, 6.4 g of paraformaldehyde, 50 ml of pyridine and 2.1 g of piperidine are warmed to 60° C. When the evolution of carbon dioxide is complete (approx. 1 hour), the mixture is stirred for a further hour at 60° C. and is poured into 800 ml of water and the mixture is extracted with 4 times 200 ml of petroleum ether. The combined organic phases are washed with 200 ml of water, 200 ml of 2 N hydrochloric acid, 200 ml of water and 200 ml of saturated sodium bicarbonate solution and are dried over sodium sulphate and concentrated. The residue is purified by chromatography on a silica gel column. (Migrating agent 80:20 petroleum ether/ethyl acetate). This gives 36.7 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester in the form of a nearly colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:26][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CCN
Product: CCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 0.92 h

Procedure:
A solution of 325 mg (1.0 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 10 ml of a 23% by volume methanolic solution of ethylamine was allowed to stand at room temperature for 3 hours and 55 minutes, after which the solvent was removed by distillation under reduced pressure. The residue was then recrystallizated from diisopropyl ether, to afford 321 mg of the title compound as white crystals, melting at 126°-127° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]([OH:22])(=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=1>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]([O-:22])(=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([O-:17])=[O:16])[CH:13]=1
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(O)c1cccc(C(=O)O)c1
Product: O=C([O-])c1cccc(C(=O)[O-])c1
Product: O=C([O-])c1ccccc1O
Temperature: 132 °C

Procedure:
The procedure was repeated with 1 mole of salicylic acid and 3 moles of isophthalic acid to produce 520 g of a light colored, translucent glassy product. DSC: Tg at 100° C. (second heat), 132° C. (third heat).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:16]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 22.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (1.6 g, 8.64 mmol) (Example 113, Step B) in 25 mL of DMSO was added, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (2.6 g, 13 mmol), and K2CO3 (3.6 g, 26 mmol). The mixture was heated to 130° C. for 24 h. The mixture was then poured into 400 mL of H2O and extracted with EtOAc. The product was isolated by flash chromatography to give the title compound of step A (0.7 g, 1.96 mmol, 22%). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.66 (d, J=4.58 Hz, 1H), 3.87 (s, 3H), 3.40-3.52 (m, 4H), 3.33 (d, J=9.34 Hz, 2H), 3.24 (d, J=4.58 Hz, 2H), 2.19 (s, 3H), 1.80-1.90 (m, 2H), 1.36 (s, 5H), 1.30 (s, 4H).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:44]([CH3:47])(=[O:46])=[O:45])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:35][CH2:34][C@@H:33]([O:36]C4CCCCO4)[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:31][CH2:32][C@@H:33]([OH:36])[CH2:34][CH2:35]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (1.0 N in water, 1.02 mL) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (135 mg, 0.204 mmol) in 1,4-dioxane (5.0 mL). After 1 hour the reaction was concentrated to give a white solid. The solid was triturated with ethanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (90 mg, 90%). LCMS m/z 493.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.70 (m, 12 H) 1.79 (br. s., 1 H) 2.09-2.24 (m, 1 H) 2.42 (ddd, J=13.07, 11.12, 4.68 Hz, 1 H) 3.12 (s, 3 H) 3.68-3.83 (m, 2 H) 3.87 (d, J=6.63 Hz, 2 H) 4.10 (d, J=6.44 Hz, 1 H) 6.55-6.75 (m, 2 H) 6.94-7.10 (m, 2 H) 7.61-7.80 (m, 3 H) 11.15 (br. s., 1 H)
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([OH:13])[SiH](C)C)=[CH:6][CH:5]=1)C=C.[Br:16]Br>C(O)CC1C=CC=CC=1>[Br:16][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH2:9][OH:13])=[CH:6][CH:5]=1
Reactant: C=CCc1ccc(CC(O)[SiH](C)C)cc1
Reactant: BrBr
Solvent: OCCc1ccccc1
Product: OCCc1ccc(Br)cc1

Procedure:
Hydroboration of 4-allyldimethylsilylphenethyl alcohol (1 Scheme 8) followed by Suzuki coupling reaction with the linker (2 Scheme 29) resulted in polymer-bound phenethyl alcohol compound (3 Scheme 29) which can be cleaved with bromine to give 4-bromophenethyl alcohol (4 Scheme 29).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]([C:17]([O:19]CC)=[O:18])=[C:9]([C:11]([CH2:15][CH3:16])([OH:14])[CH2:12][CH3:13])[N:10]=1)[CH2:3][CH2:4][CH3:5]>CO.C(OC(C)C)(C)C>[CH2:2]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:8]([C:17]([OH:19])=[O:18])=[C:9]([C:11]([CH2:12][CH3:13])([OH:14])[CH2:15][CH3:16])[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CCCCc1nc(C(O)(CC)CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
1.71 ml of 1N aqueous hydrochloric acid were added to a solution of 0.65 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of methanol, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the concentrate was again dissolved in 10 ml of methanol. The resulting solution was mixed with 4.28 ml of a 1N aqueous solution of sodium hydroxide and then allowed to stand overnight at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure to remove the methanol. The pH of the concentrate was adjusted to a value of 3 by the addition of dilute aqueous hydrochloric acid, and the crystals which precipitated were collected by filtration. The crystals thus obtained were suspended in diisopropyl ether and then again collected by filtration and dried to give 0.35 g of the title compound, melting at 181°-183° C.
Reaction SMILES: C(O)C.[CH2:4]1[CH2:22][O:21][C:6]2([CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[O:5]1>[Pd].C1(C)C=CC=CC=1>[CH2:22]1[CH2:4][O:5][C:6]2([CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH3:20])=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[O:21]1
Reactant: CCCc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 104.2 %

Procedure:
To a mixed solution comprising 250 ml of ethanol and 250 ml of toluene was dissolved 80 g of the 1,1-ethylenedioxy-4-(4-n-propylphenyl)-4-cyclohexene, 5 g of palladium/carbon (5%) was added as catalyst thereto, and subjected to a catalytic reduction under hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain 84 g of 1,1-ethylenedioxy-4-(4-n-propylphenyl)cyclohexane.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(N(C(C)C)C(C)C)C.[CH:17]1([CH2:20][CH2:21][O:22][C:23]2[CH:50]=[CH:49][C:26]([C:27]([NH:29][CH:30]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:31]([NH:33]CCO)=[O:32])=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl.C1COCC1>[C:5]([O:4][CH2:1][CH2:2][NH:33][C:31](=[O:32])[CH:30]([NH:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH:17]2[CH2:18][CH2:19]2)=[CH:50][CH:49]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:46])[F:47])=[CH:40][CH:39]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 52 %

Procedure:
Acetic anhydride (50 μL, 0.526 mmol) and N-ethyl-N,N-diisopropylamine (84 μL, 0.479 mmol) were added to a methylene chloride:THF (1:1, V/V, 4 mL) solution of 4-(2-cyclopropylethoxy)-N-{2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide (116 mg, 0.239 mmol) prepared in Example 4. The mixture was stirred at room temperature for 65 hours. The reaction solution was evaporated, and the residue was purified by thin layer chromatography for separation (ethyl acetate, developed once) to give 65 mg of the title compound (white powder, yield: 52%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[C:6]([CH3:19])[CH:5]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:11][C:12]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:16])[O:14]2)=[C:6]([CH2:19][Br:28])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CBr)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
The solution of 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (3.71 g, 13.4 mmol), NBS (2.39 g, 13.4 mmol), and AIBN (235 mg) in CCl4 (20 ml) was heated at 80° C. for 14 hours. The mixture was cooled to 25° C., and was filtered and washed with CCl4. The solution was concentrated under reduced pressure, and was diluted with EtOAc. The solution was washed with water and brine and was dried with Na2SO4. Concentration gave 3-Bromomethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (4.9 g).
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19](C(OCC)=O)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.[CH3:27][O:28][C:29](=[O:38])[CH2:30]C1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.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>[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:19]1[CH:25]=[CH:26][C:16]([C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3([O:4][CH2:1][C:3]4[CH:9]=[CH:8][CH:5]=[CH:6][CH:7]=4)[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methylindole (1.0 g, 7.6 mmol) in 8.0 mL of CH2Cl2 was added N,N-dimethylamino pyridine (0.186 g, 1.52 mmol), 2.12 mL (15.24 mmol) of triethylamine and 0.97 mL (1.18 g, 8.39 mmol) of benzoyl chloride. The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with 500 mL of CH2Cl2 and washed with 200 mL of saturated aqueous NaHCO3 and 200 mL of brine. The organic phase was dried over MgSO4, filtered, and concentrated to a yellow oil. The resultant oil was flash chromatographed eluting with 20% ethyl acetate in hexane yielding 1.73 g (96%) of the titled compound as a white powder.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1)(=O)C.Cl.[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18]Cl>>[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18][NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:13])[CH3:14])[N:6]=1
Reactant: CC(=O)Nc1nc(C)cc(N(C)C)n1
Reactant: CN(C)C(C)(C)CCl
Agent: Cl
Product: Cc1cc(N(C)C)nc(NCC(C)(C)N(C)C)n1

Procedure:
Following the procedure of Example 1 part A using 2-acetamido-4-methyl-6-dimethylaminopyrimidine and 2-methyl-2-dimethylaminopropyl chloride hydrochloride, there is obtained 2-(2-methyl-2-dimethylaminopropylamino)-4-methyl-6-dimethyl minopyrimidine.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[N:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(O)C.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:4][C:3]1[N:6]=[C:7]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=[CH:15][N:16]2[CH:2]=1
Reactant: COC(=O)c1cccnc1N
Reactant: CC(=O)CBr
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccn2cc(C)nc12
Temperature: 25 °C
Yield: 66.7 %

Procedure:
Bromoacetone (6.5 g, 42.7 m moles) and methyl 2-aminonicotinate (4.8 g, 31.5 m moles) were added to ethanol (50 ml), and the mixture was refluxed under heating for 17 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Saturated aqueous solution of sodium bicarbonate (50 ml) was added to the residue, and the mixture was extracted with chloroform (100 ml×3). The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (eluent:chloroform and then chloroform/methanol=9/1) to give the object compound (4.0 g, yield 85%) as an oily substance.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]CC)=O)[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.Cl.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]1.C(N(CC)CC)C.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[OH:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([N:26]2[CH2:2][CH2:3][C@:4]3([CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:5]3)[C:20]2=[O:22])[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (1.0 g, 0.0030 mol, prepared by using procedures analogous to those described for the synthesis of example 1, steps 1 and 2), trans-4-aminocyclohexanol hydrochloride (0.50 g, 0.0033 mol), and triethylamine (0.48 g, 0.0048 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) was stirred at rt for 30 min. To the mixture was added sodium triacetoxyborohydride (1.6 g, 0.0075 mol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture then was warmed to 80° C. with stirring for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with dichloromethane and the solution was washed with 1N HCl, water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in-vacuo and the resulting residue was purified by flash column chromatography to afford 1.04 g of the desired product. Further purification by chiral HPLC was carried out (Chiralcel OD-H column (3.0×25 cm, 5 micron particle size, Chiral Technologies; Item number 14475) eluting with 15% ethanol/hexanes (isocratic, 26 mL/min.); Detection: 220 nm; retention time: 10.0 minute for peak 1, 12.5 minute for peak 2). The first peak to elute was found to be the R configuration and the second peak was found to be the S configuration and used for analog synthesis. LC-MS: 387.3 (M+H)+.
Reaction SMILES: [Si:1]([C@@:8]1([OH:32])[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[O:11][C@@H:10]([N:22]2[CH:29]=[CH:28][C:26](=O)[NH:25][C:23]2=[O:24])[C@@H:9]1[O:30][CH3:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C@@H:33]1([N:42]2[CH:49]=[CH:48][C:46](=O)N[C:43]2=O)O[C@H](CO)[C@@H](O)[C@H:34]1O.CN1CCCCC1.C1(C)C=CC(S([Cl:66])(=O)=[O:64])=CC=1>C(#N)C.C(N(CC)CC)C>[Cl-:66].[Si:1]([C@@:8]1([OH:32])[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[O:11][C:10]([N:22]2[CH:29]=[CH:28][C:26]([N+:42]3([CH3:43])[CH2:33][CH2:34][CH2:46][CH2:48][CH2:49]3)=[N:25][C:23]2=[O:24])([OH:64])[C@@H:9]1[O:30][CH3:31])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@]1(O)[Si](C)(C)C(C)(C)C
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN1CCCCC1
Product: CO[C@H]1C(O)(n2ccc([N+]3(C)CCCCC3)nc2=O)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@]1(O)[Si](C)(C)C(C)(C)C
Product: [Cl-]
Reaction time: 1 h

Procedure:
To the solution of 750 mg of 3′,5′-O-bis (t-butyldimethylsilyl)-2′-O-methyl uridine in 10 mL of acetonitrile was added 0.23 mL (1.2 times moles based on the uridine derivative) of 1-methylpiperidine and 0.45 mL of triethylamine, and the mixture was cooled. The solution of 614 mg of p-toluenesulfonyl chloride in 5 ml of acetonitrile was added dropwise with ice cooling, and the mixture was stirred for 1 hour. After the disappearance of the starting material, an 1 mL aliquot of the reaction solution was concentrated, and the residue was triturated with ether to remove the precipitated crystals by filtration. The filtrate was concentrated, and the residue was then washed with n-hexane and dried to give [[3,5-O-bis(t-butyldimethylsilyl)-2-O-methylribofuranos-1-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-1-methylpiperidinium chloride (a reaction intermediate):