Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[OH-:17].[Na+].OO>C1COCC1>[OH:17][CH2:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(CO)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of tert-butyl 3-methylidene-8-azabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 3.6 mmol) in dry THF (30 mL) at 0° C. was added a solution of borane-THF complex (4.7 mL, 1 M) and the resulting reaction was allowed to stir at room temperature for 48 hrs. The reaction was cooled to 0° C. then treated with NaOH (5.4 mL, 2 M) and hydrogen peroxide solution (1.8 mL, 35%). After stirring at room temperature for 3 hrs, the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) to give the desired product (0.9 g, 90%). LCMS (ESI) m/z: 239.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12]C(=O)C.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: CC(=O)Nc1ccc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc2ccccc2c1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of 2-naphthylamine (1.43 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) in 10 mL of CH2Cl2 is cooled to 0° C. under an atmosphere of nitrogen. To this solution is added dropwise a solution of acetyl chloride (0.86 g, 11 mmol) in 10 mL of CH2Cl2. The mixture is allowed to warm to room temperature and stirred overnight. The mixture is concentrated in vacuo and then 1 N HCl is added to the residue to bring the mixture to pH 4. The mixture is extracted 3 times with 20 mL of EtOAc and the combined organic layers are washed with 20 mL each of H2O, saturated aqueous NaHCO3 and saturated brine. The organic layer is dried over MgSO4, filtered and the solvents are removed in vacuo to give 2-acetylaminonaphthalene as a solid which is used without further purification. A solution of NaClO3 in (0.33 g, 30 mmol) in 0.77 mL of H2O is added dropwise to a mixture of 1.0 g of 2-acetylaminonaphthalene in 5 mL of concentrated HCl and 6 mL of HOAc at 0° C. The mixture is allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The mixture is poured over 20 g of ice and is extracted three times with 20 mL of CH2Cl2. The combined organic layers are washed with 20 mL each of water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The mixture is filtered and the solvents are removed in vacuo to give an oil which is purified by flash chromatography on silica gel (CH2Cl2) to give 1-chloro 2-acetylaminonaphthalene as a solid. A mixture of 0.17 g (0.77 mmol) of 1-chloro 2-acetylaminonaphthalene in 3.9 mL of 6 N HCl is heated to 85° C. and is stirred for 8 hours. The mixture is cooled to 0° C. and solid Na2CO3 is carefully added to bring the mixture to pH 8. The mixture is extracted 3 times with 20 mL of CH2Cl2. The combined organic layers are washed with 15 mL of saturated brine, dried over Na2SO4 and the solvents are removed in vacuo to give 1-chloro 2-aminonaphthalene as a solid.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=1[Cl:61]>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=3[Cl:61])[N:39]=2)[N:36]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3cccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as light brown gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH2:25])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:23][CH3:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCN
Product: CCNCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Ethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amine as white solid, MS: 405 (MH+, 1Br).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)C)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:6][NH:7][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC[C@H]1CC[C@H](CO)CC1
Reaction time: 3.5 h

Procedure:
A solution of 1.45 g (5.34 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 10 ml dioxane was treated at 10° C. with 13.4 ml (53.4 mmol) of HCl in dioxane (4M). After 3.5 h at RT, the reaction was evaporated to give 1.6 g (quantitative) of trans-[4-(2-Methylamino-ethyl)-cyclohexyl]-methanol hydrochloride, MS: 172 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A solution of Compound 9 (22.96 g, 100 mmol), cyclohexylamine (15.31 g, 154 mmol) and TEA (13.57 g, 134 mmol) in 100 mL acetonitrile was refluxed overnight. The reaction mixture was poured into icy water and the precipitated crystals were collected by means of filtration, washed three times with water then was dried over phosphorous pentoxide in high vacuum to yield Compound 10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[N:11][OH:12])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15].C(=O)([O-])O.[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[CH:26]=1>C(O)(C)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:32][C:31]([C:29]3[CH:28]=[C:27]([Cl:37])[CH:26]=[C:25]([Cl:24])[CH:30]=3)([C:33]([F:34])([F:36])[F:35])[O:12][N:11]=2)=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15]
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1C(F)(F)F
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a solution of 4-(chloro(hydroxyimino)methyl)-2-trifluoromethyl-benzoic acid methyl ester (Example I12) (4.21 g) in isopropanol (100 ml) was added sequentially sodium hydrogen carbonate (2.90 g) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (4.22 g) (prepared according to WO 2005/085216). The reaction mixture was stirred at 60° C. for 16 hours. The isopropanol was removed by distillation. The residue was purified over silica gel (eluent: ethyl acetate/heptane gradient from 0:1 to 2:3) to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-trifluoromethyl-benzoic acid methyl ester (4.30 g). 1H-NMR (CDCl3, 400 MHz): 8.00-7.44 (m, 6H), 4.12 (d, 1H), 3.96 (s, 3H), 3.74 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:30](=[O:41])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1)[C:30]([C:10]1[N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])[CH:16]=[CH:17][C:12]=2[N:11]=1)=[O:41]
Reactant: O=C(O)c1ccccc1-c1ccc2ncn(CCc3ccccc3)c2c1
Reactant: COc1cc(OC)cc(C(=O)N(C)OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc(OC)cc(C(=O)c2nc3ccc(-c4ccccc4C(=O)O)cc3n2CCc2ccccc2)c1

Procedure:
2-[1-(2-phenylethyl)-1H-benzimidazole-6-yl]benzoic acid and N,3,5-trimethoxy-N-methylbenzamide were subjected to a reaction in the presence of lithium diisopropylamide to give the compound having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]=[CH2:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH2:13][CH2:14][CH3:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: C=CCc1c(OC)cccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCc1c(OC)cccc1C(=O)O
Yield: 37.5 %

Procedure:
Methyl 3-(methyloxy)-2-prop-2-en-1-ylbenzoate (100 mg, 0.48 mmol) in methanol (2 mL) was hydrogenated over 5% palladium on carbon for 15 h under atmospheric pressure. The reaction mixture was filtered and 35% aqueous potassium hydroxide (1 mL) was added. The mixture was refluxed for 1 h and then concentrated. The pH was adjusted to 2 with 6N HCl. The precipitate was filtered, washed with water and dried to give 3-(methyloxy)-2-propylbenzoic acid (35 mg, 38% yield). MS (EI) for C11H14O3: 193 (M−H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.C[O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH:18][C:19](=[O:38])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]34[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]5)[CH2:29]3)[CH2:35]4)=[CH:24][CH:23]=2)[CH:12]=1.Cl>C1(C)C=CC=CC=1>[C:28]12([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([NH:18][C:13]4[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=4[OH:17])[C:10]([N:2]([CH3:3])[CH3:1])=[O:9])=[O:38])=[CH:23][CH:24]=3)[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
Dimethyl amine (0.06 ml, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium (in 2.0 M Hexane, 0.15 ml, 0.31 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-4-hydroxy-benzoic acid methyl ester (30.1 mg, 0.07 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80° C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(Hexane:EtoAC:MeOH=15:3:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-N,N-dimethyl-benzamide as a white solid (10.4 mg, 23.2% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1.C(O)(C)C.C(O)(=O)C(C(C(O)=O)O)O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: O=c1ccc2c(C3CO3)cc(OCc3ccccc3)cc2[nH]1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)cc1

Procedure:
150 mg (0.51 mmol) 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 208 mg (1.2 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine are combined with 1 mL isopropanol and irradiated with microwaves for a total of 1 hour at 135° C. Then the reaction mixture is combined with ethyl acetate and 0.5 molar tartaric acid, whereupon a precipitate is formed. The organic phase is discarded and the solid and the aqueous phase are extracted with dichloromethane/methanol. The combined organic phases are evaporated down and combined with 8 mL ethyl acetate. The insoluble solid is suction filtered and dried. Yield: 130 mg (54%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[O-:13][Mn](=O)(=O)=O.[K+]>CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CC2)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: O=C1CC2(CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 6′-bromo-2′,3′-dihydrospiro[cyclopropane-1,1′-indene] (5.7 g, 25.6 mmol) in acetone (78 mL) and 1.5 M aq. MgSO4 (29 mL) was added KMnO4 (4.46 g, 28.2 mmol). The reaction was stirred overnight at room temperature. Upon completion, the reaction was filtered over celite and concentrated. The residue was partitioned between water (100 mL) and EtOAc (200 mL), and the layers were separated. The organic was washed with brine, dried over Na2SO4, then filtered and concentrated. 6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one (2.11 g, 39% yield) was isolated as a white solid after flash chromatography over silica gel (5% EtOAc/hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=8.3 Hz, 1H), 7.45 (dd, J=8.0, 1.5 Hz, 1H), 7.14 (d, J=1.3 Hz, 1H), 2.76 (s, 2H), 1.15-1.34 (m, 4H); MS (EI) m/z=238.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.CN(C)C=O.S(Cl)([Cl:21])=O.[CH:23]([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>COCCOC>[Cl-:21].[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH:23]([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: O=S(Cl)Cl
Agent: COC(=O)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: [Cl-]
Temperature: 10 °C
Reaction time: 0.63 h

Procedure:
A suspension of 1.997 kg (11.08 mol) of terephthalic acid monomethyl ester in 15.60 kg of 1,2-dimethoxyethane was stirred in a nitrogen atmosphere while being cooled at 10° C. To the suspension was added 400 mL (5.17 mol) of N,N-dimethylformamide and 1.323 kg (10.56 mol) of thionyl chloride in this order, and then the container was washed with 1.00 L of 1,2-dimethoxyethane. The suspension was stirred under heating at 60 to 73° C. for 1 hour and 2 minutes and then stirred while being cooled. 1.36 kg (10.52 mol) of N,N-diisopropylethylamine was added dropwise to the solution while cooling at 0° C., and the container was washed with 1.00 L of 1,2-dimethoxyethane. Then the reaction solution was stirred at 25° C., and the stirring was stopped 38 minutes after the internal temperature had reached 20° C. The reaction mixture was transferred into a plastic container, and 22.00 kg of “monomethyl terephthalate chloride/N,N-diisopropylethylamine” solution (terephthalic acid monomethyl ester chloride content: 1.84 kg) was obtained as a slightly tannish solution.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C1COCC1>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:5]=1
Reactant: COC(=O)c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
NaH (60% w/w in mineral oil; 0.532 g, 13.30 mmol) was added (portionwise, over 2 min) to a solution of methyl 3-iodo-1H-indole-5-carboxylate (3.64 g, 12.09 mmol) in THF (30 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 5 min. p-Toluenesulfonyl chloride (2.54 g, 13.30 mmol) was then added (portionwise, over 2 min), and the resulting mixture was stirred at 0° C. for 1 h. H2O (50 mL) was carefully added to the mixture at 0° C. and the reaction was warmed to 25° C. THF was removed in vacuo, and the resulting tan mixture was vacuum filtered. The collected solid was washed with H2O (150 mL) and dried in vacuo to provide crude methyl 3-iodo-1-tosyl-1H-indole-5-carboxylate (5.94 g) as a tan solid: MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.03-8.11 (2H, m), 7.97-8.02 (1H, m), 7.79 (2H, d, J=8.2 Hz), 7.75 (1H, s), 7.26 (2H, d, J=8.2 Hz), 3.94 (3H, s), 2.36 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH:13]=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:11]([CH3:13])[CH:10]=[N:9]2
Reactant: CC(=O)C=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CC#N
Product: Cc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 61A (9.4 g, 50 mmol) in acetonitrile (100 mL) was treated with 40% aqueous pyruvic aldehyde (11.0 mL, 60 mmol) dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated and the residue was suspended in IPAc (100 mL) and filtered. The filtrate was washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with heptane:EtOH:MeOH (8:2:1) to provide the title compounds. MS 224 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.75–7.93 (m, 4H), 2.78 (s, 3H), 2.76 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141.17, 140.45, 139.34, 133.17, 132.15, 131.15, 130.75, 130.16, 129.71, 123.66, 122.38, 22.89.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Brc1cccc(CNC2CCCCC2)c1
Reaction time: 18 h

Procedure:
Reaction of 1-bromo-3-(bromomethyl)benzene with cyclohexylamine following the method described in Example 9 except cesium carbonate was used as base and at 90° C. for 18 h gave N-(3-bromobenzyl)cyclohexylamine as a white solid. Yield (0.70 g, 65%): 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J=1.6 Hz, 1H), 7.38-7.41 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 3.73 (s, 2H), 2.38-2.46 (m, 1H), 1.92-1.95 (m, 2H), 1.70-1.78 (m, 2H), 1.58-1.66 (m, 1H), 1.06-1.30 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])=[CH:11][C:10]=2[N:9]=1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1nc(CC)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 6.42 mmol) in N,N-dimethylformamide (50 mL). To the solution was added in succession, a solution of palladium acetate (144 mg, 0.642 mmol) and tri-ortho-tolylphosphine (390 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL), triethylamine (2.7 mL) and a solution of ethyl acrylate (0.77 g, 7.7 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (150 mL) and washed with saturated aqueous potassium carbonate (100 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 1.9 g of ethyl (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as an off-white crystalline solid, mp 209-210° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:27]3[N:26]=[CH:25][N:24]=[C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=3[N:12]=[CH:11]2)[CH2:7][C@@H:6]1[OH:28])=[N+:2]=[N-:3].[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N1C=CN=C1>CN(C)C=O>[N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:27]3[N:26]=[CH:25][N:24]=[C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=3[N:12]=[CH:11]2)[CH2:7][C@@H:6]1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.5 %

Procedure:
A mixture of 8.9 g (24 mmol) of 5'-Azido-N6-benzoyl-2',5'-dideoxyadenosine (which can be prepared as in reference 36), 5.4 g (35 mmol) of t-butyldimethylsilyl chloride, and 3.3 g (48 mmol) of imidazole in 100 ml of anhydrous dimethylformamide (DMF) was stirred at room temperature (RT) for 20 hr. The solvent was removed under vacuum, and the residue was partitioned between one half saturated brine and EtOAc (2×200 ml). The combined organic layers were washed with brine, dried with sodium sulfate (dried), and evaporated (evap.). Purification by chromatography on silica (silica gel (240-400 mesh) from EM Science) using 20 to 40% EtOAc/DCM gave 11.1 g of 5'-Azido-N6-benzoyl-3'-O-t-butyldimethylsilyl-2',5'-dideoxyadenosine as a white foam: NMR (300 MHz,d6-DMSO) δ11.25 (br, 1H), 8.78 (s,1H), 8.71 (s, 1H), 8.05 (m, 2H), 7.5-7.7 (m, 3H), 6.52 (t, 1H,J=7 Hz), 4.72 (m, 1H), 4.02 (m,1H), 3.67 (dd,1H, J=13,7 Hz), 3.56 (dd,1H,J=13,5 Hz), 3.09 (m, 1H), 2.43 (m,1H), 0.92 (s,9H), 0.14 (s,6H).