Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCCCO3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCCCO3)CS[C@H]12)c1csc(N)n1
Yield: 53.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate (80 mg) was reacted with iodomethyl pivalate (72 mg), followed by purifying the reaction product in accordance with the procedure of Example 2, giving the titled compound (50 mg; 53%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5]Br.C1N2CN3CN(C2)CN1C3.Cl.[OH2:22]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:22]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-dibromobenzylbromide (Lancaster) (20 g, 0.061 mole) in H2O (27 mL) and glacial acetic acid (27 mL) was added hexamethylenetetramine (Aldrich). The reaction mixture was heated at reflux for 2 hours. Concentrated HCl (22 mL) was then added and the refluxing was continued for 30 minutes. After cooling to room temperature, the reaction mixture was poured into H2O (230 mL) and stirred for 10 minutes. The resulting precipitate was filtered, washed with H2O and dried to yield 3,5-dibromobenzaldehyde (11.45 g) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:41]1([C:47](Cl)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:41]1([C:47]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CN(C(=O)C3CCCCC3)c3ccc(OCCN4CCCC4)cc3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of toluene-4-sulfonic acid 4-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methyl}-phenyl ester (0.120 g, 0.26 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added cyclohexanecarbonyl chloride (0.138 mL, 1.03 mmol). The reaction mixture was stirred for 3 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Flash filter chromatography afforded the title compound of Step A. MS 577.1 (M+1)+
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[CH:7][CH:6]=1)[CH3:3].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([NH:17][CH2:16][CH2:15][NH2:18])=[O:12])=[CH:7][CH:6]=1)[CH3:1]
Reactant: NCCN
Reactant: CCOC(=O)c1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(C(=O)NCCN)o1
Temperature: 80 °C
Yield: 104.6 %

Procedure:
A mixture consisting of 49.0 g (248 mmol) of ethyl 5-(dimethylaminomethyl)-2-furancarboxylate and 150 g (2.496 mol) of anhydrous ethylenediamine was heated at 80° C. for 2 hours. After cooling, the excess ethylenediamine was distilled off under reduced pressure to give 54.8 g (98.0%) of 5-(dimethylaminomethyl)-N-(2-aminoethyl)-2-furancarboxamide (Compound a) as light yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:36]4[CH:35]=[CH:34][C:32]5[N:33]=[C:29]([C:28]([F:40])([F:39])[F:27])[NH:30][C:31]=5[CH:37]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 2-trifluoromethyl-3H-benzimidazol-5-ylamine (91 mg, 0.45 mmol) at 105° C. for 132 h to afford the title compound. Yield of TFA salt: 15 mg (26%) of brown powder; LC/MS: 529 (M+H); HPLC: 97% pure, RT=2.16 min; 1H NMR: (DMSO, δ) 9.68 (s, 1H), 9.07 (s, 1H), 8.53 (m, 2H), 8.02 (s, 1H), 7.86 (d, J=8.0, 1H), 7.83 (dd, J=9.1, 1.8, 1H), 7.75 (m, 3H), 7.25 (d, J=4.7, 1H), 7.03 (d, J=4.7, 1H), 1.12 (s, 9H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[CH2:7][CH2:8]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCCCCN1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1

Procedure:
A mixture of 6 g (20 mmol) of 2-[4-(4-bromobutyl)-1-piperazinyl]-pyrimidine, 2.36 g (20 mmol) of benzimidazole and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide is refluxed for 14 hours. The reaction mixture is evaporated under vacuum, chloroform is added, the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 4.8 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-benzimidazole are obtained, which may be recrystallised from ethyl ether, with a melting point of 85°- 88° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:20][OH:21].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:20][OH:21])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NO
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCCc2cc(OCCn3ccnc3)ccc21
Yield: 83.2 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10 mL of pyridine was treated with 0.41 g (5.9 mmol) of hydroxylamine×HCl and the solution heated at reflux overnight. The solution was diluted with H2O and the product collected and dried. There was obtained 0.88 g (83% yield) of the product as a white solid, mp 177-179° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 272 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: Nc1cc(Cl)ccn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1
Temperature: 160 °C
Reaction time: 144 h
Yield: 10.8 %

Procedure:
2-Amino-4-chloropyridine (2.57 g) was dissolved in dimethylsulfoxide (30 ml), and then 2-chloro-4-nitrophenol (6.94 g) and N,N-diisopropylethylamine (14 ml) were added thereto, followed by stirring at 160° C. for 6 days. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate) to provide the titled compound (574 mg, 11%) as brown powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1.O>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)c(OCCN2CCOCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a solution of 4-(2-hydroxyethyl)morpholine (5.72 g, 43.62 mmol) in THF (25 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)-amide (1.0 M in hexanes) (21.80 ml, 21.80 mmol). The reaction mixture is stirred for 15 minutes, and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (30 g, 8.72 mmol). The reaction vessel is sealed and heated at 80° C. for 3 hours. The reaction is cooled to room temperature and quenched by the addition of water (200 ml). A yellow precipitate is formed. The mixture is diluted to 350 ml with water and cooled to 0° C. The yellow precipitate is collected by filtration. The solid is slurried in 100 ml of 3:1 hexane:EtOAc and stirred for 10 minutes. The mixture is filtered, and the collected solid is dried in the vacuum oven overnight to afford the title compound as a yellow solid (2.11 g, 59%). Mass (m/z): 411.1 (M++1), 409.1 (M+−1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:33])=[C:30](O)[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:33])=[C:28]([CH:27]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Reactant: Oc1cc(Br)ccc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4F)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 5-bromo-2-fluorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1cccnc1

Procedure:
3-Bromopyridine and 2-fluorobenzeneboronic acid were coupled using the procedure described in Example 31 to afford 3-(2-fluorophenyl)pyridine as a pale yellow oil which crystallised on standing: δH (360 MHz, DMSO) 7.33-7.40 (2H, m), 7.46-7.55 (2H, m), 7.61 (1H, ddd, J 8, 8 and 2), 7.96-8.01 (1H, m), 8.61 (1H, dd, J 5 and 2), 8.77 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Br)([CH3:29])=[CH2:28]>C(OCC)C>[C:27]([CH:6]1[N:7]2[CH2:20][CH2:19][C:18]3[C:13]([C:8]2=[CH:9][C:10]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[C:5]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)([CH3:29])=[CH2:28]
Reactant: C=C(C)[Mg]Br
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added isopropenylmagnesium bromide solution (0.5 M in tetrahydrofuran, 52 mL, 26 mmol) dropwise. After stirring at 0° C. for 2 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (500 mg, 98%). LC/MS m/e calcd for C23H23NO4 (M+H)+: 378.44, observed: 378.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.72-2.83 (m, 2 H) 3.00-3.09 (m, 1 H) 3.12-3.20 (m, 1 H) 3.71 (s, 3 H) 3.77 (s, 3 H) 4.61 (s, 1 H) 4.92 (d, J=1.52 Hz, 1 H) 5.19 (s, 1 H) 5.80 (s, 1 H) 6.00 (d, J=2.27 Hz, 2 H) 6.69 (d, J=8.59 Hz, 1 H) 6.77 (s, 1 H) 6.85 (d, J=8.34 Hz, 1 H) 7.23 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
A solution of 15 gm (63.3 mMol) 2-bromonaphthalene in 100 mL tetrahydrofuran was cooled to −78° C. and then 47.4 mL (75.9 mMol) n-butyllithium (1.6 M in hexane) were added. After stirring for about 1.5 hours, a solution of 19 mL (82.2 mMol) triisopropylborate in 30 mL tetrahydrofuran was added via addition funnel. The reaction mixture was allowed to warm to room temperature and was stirred for about 18 hours. The reaction mixture was then partitioned between ethyl acetate and 2 N hydrochloric acid. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residual solid was suspended in hexanes and the mixture subjected to sonication. The suspension was then filtered to provide 8.3 gm (76%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:28][C@@H:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Product: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1Cl

Procedure:
3-(3,4-Dichlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].NC(N)=[S:17].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][SH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(N)=S
Reactant: COc1ccc(CCCO)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCCS)cc1OC
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of 5.00 g (25.5 mmoles) of 3-(3,4-dimethoxyphenyl)propanol, 1.94 g (25.5 mmoles) of thiourea, and 8.5 ml of 48% hydrobomic acid is heated on steam bath for 1 hour, allowed to stand overnight at room temperature, and then heated again on a steam bath for 2 hours. After cooling, the reaction mixture is treated with 76.5 ml of 1 M sodium hydroxide and heated on the steam bath for 11/2 hours. After cooling, the reaction mixture is made acidic with 1 N hydrochloric acid and extracted with methylene chloride (followed by a brine wash). Silica gel chromatography using 10% ethyl acetate/Skellysolve B as eluent gives 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[C:16]([Mg]Cl)#[CH:17].O>O1CCCC1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[C:16]#[CH:17])=[CH:13][CH:14]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1ccc(OCCCN(C)C)cc1

Procedure:
To a solution of 4-(3-dimethylaminopropoxy)benzaldehyde (0.83 g, 4 mmol) (Aldrich) in dry tetrahydrofuran (30 mL) under argon at room temperature was added ethynylmagnesium chloride (5 mmmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich) dropwise. The resulting solution was stirred for 1.5 h at which time 100 mL water was added, and the THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne which was used directly, without further purification. (Yield 831 mg, 89%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 22 h
Yield: 57.1 %

Procedure:
Combine 1-fluoro-2-nitro-benzene (4.34 g, 30.79 mmol), 2-amino-5-methyl-benzonitrile (4.07 g, 30.79 mmol), lithium hydroxide monohydrate (2.58 g, 61.58 mmol) and DMSO (50.0 ml). Stir the mixture at 55° C. for 22 hours then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum then purify it on silica gel using dichloromethane/hexanes (75:25) to give 4.45 g (57%) of an orange solid: mp 135–139°; mass spectrum (ion spray): m/z=254.0 (M+1).
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52](OCC#N)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (200 mg, 0.314 mmol) in water (6.25 ml) and a solution of (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (454 mg, 1.26 mmol) in THF (3.15 ml) were added to buffer A (113 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then lyophilized. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-A) (129 mg, 46%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][N:33]1[C:37]([CH3:38])=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[C:37]=3[CH3:38])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: Cc1c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)cnn1C

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 242. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 4.84 (dd, J=10.6, 3.8 Hz, 1H), 4.55-4.32 (m, 1H), 4.28-4.14 (m, 1H), 4.13-3.94 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.29-3.16 (m, 1H), 2.61 (s, 3H), 2.12-2.02 (m, 1H), 1.91-1.78 (m, 1H), 1.75-1.64 (m, 4H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:9]1([CH:8]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:15]#[N:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1cccnc1

Procedure:
The compound was prepared substantially in accordance with the procedure in Example 12A, using 3-chloropyridine (9.5 ml, 100 mmol), benzyl cyanide (11.6 ml, 100 mmol) and potassium t-butoxide (22.4 g, 200 mmol) in 200 ml of DMF.