Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.22 g, 0.42 mmol) and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride (0.13 mmol, 0.42 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane, 2% methanol/dichloromethane, and then 4% methanol/dichloromethane to give the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1([C:10]([O:12]C)=[O:11])[CH2:9][CH2:8]1)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1)=[O:6]
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
KOH (42 mg, 0.75 mmol) was added to a solution cyclopropane-1,1-dicarboxylic acid dimethyl ester (100 mg, 0.63 mmol) in methanol. The resulting mixture was stirred for 4 hours at ambient temperature then concentrated. The residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (71%) of cyclopropane-1,1-dicarboxylic acid methyl ester.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[CH3:26][C:27]([O:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)([C:29]([OH:31])=[O:30])[CH3:28]>>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[CH3:1][CH2:2][O:30][C:29]([C:27]([O:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)([CH3:26])[CH3:28])=[O:31]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
The preceding example is repeated starting from 3.36 g of apovincamine and 2.14 g of clofibric acid. The final product (3.5 g) is a low melting solid, m.p. 65° C., which is insoluble in water and soluble in alcohol, with an apovincamine content of 61%.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO

Procedure:
There are a variety of known techniques for converting a nucleoside into an anhydronucleoside. For example, the anhydronucleoside can be prepared by mixing thymidine with triphenylphosphine and azeotropically drying with portions of acetonitrile (MeCN). The resulting mass is suspended in MeCN and then cooled. The mixture is rapidly stirred and diisopropylazodicarcobxylate in MeCN is added dropwise to the mixture. The resulting mixture is treated with water to form a suspension that is filtered to afford anhydrothymidine. (Grierson, J. R., Shields, A. F., Nuclear Medicine and Biology, 2000, 27 143–156; Balagopala, M. I., Ollapally, A. P., and Lee, H. J., Nucleosides-Nucleotides, 1996, 15(4) 899–906).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1N)=[O:12])[CH3:9].[ClH:20]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1[Cl:20])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of t-butyl nitrite (29.5 mL, 248 mmol), cuprous chloride (17.6 g, 177.8 mmol) and anhydrous acetonitrile (490 mL) was added 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (25 g, 148 mmol) in portions over 30 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 h, then at 65° C. for 1 h. The mixture was then poured into 6N HCl (600 mL) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo, and the crude residue was purified by flash chromatography eluting with a gradient of 0-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (18 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13]I>>[CH3:13][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:11]=[O:12])=[C:2]1[Cl:1]
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: Cn1c(Cl)c(C=O)c2ccccc21
Yield: 93.8 %

Procedure:
Prepared from (1) (18 g), methyl iodide (17.1 g) and Nail (2.88 g) yielding (3) (18.2 g), m.p. 88°-90° C.
Reaction SMILES: ClC1N=C2C(C3C=C(C(F)(F)F)C=CC=3Cl)=CC=CN2N=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38](N)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Agent: FC(F)(F)c1ccc(Cl)c(-c2cccn3nc(Cl)nc23)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2CC1

Procedure:
748-(2-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.62 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepin-3-carboxylic acid tert-butyl ester (0.59 g, 2.25 mmol), with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (0.26 g, 0.47 mmol) as the ligand in a manner analogous to Example 2d (0.089 g, 8.5%). MP=88-89° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.65 (s, 1H), 8.87 (d, 1H), 8.1 (m, 1H), 7.88 (d, 1H), 7.75 (m, 2H), 7.45 (d, 1H), 7.40 (s, 1H), 7.20 (t, 1H), 7.10 (d, 1H), 3.50 (m, 4H), 2.75 (m, 4H), 1.40 (s, 9H). MS=558 (MH)+.
Reaction SMILES: [CH:1]1([N:7]([CH2:27][CH:28](OC)[O:29]C)[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH:1]1([N:7]([CH2:27][CH:28]=[O:29])[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CC=O)C3CCCCC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (50.3 g) in tetrahydrofuran (150.9 mL) was added to a solution of p-toluenesulfonic acid monohydrate (86.3 g) in tetrahydrofuran (100.1 mL) at 20° C. to give a solution. A line wash of tetrahydrofuran (50.3 mL) was then added and the solution stirred at ambient temperature for 1 h before being added to a solution of sodium hydroxide (19.6 g) and sodium chloride (100.6 g) in water (502.9 mL) at 5° C. A line wash of tetrahydrofuran (25.1 mL) was then added and the solution warmed to 20° C. 1-Butanol (100.6 mL) was added and the layers separated. The separated organic layer can be evaporated to dryness to afford the sub-titled compound as an orange/brown oil or the solution used directly in the next Step. MS [M+H]+=398.2 (MultiMode+)
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]2)=[N:12][CH:13]=1)([O-])=O>CO.C(OCC)(=O)C.[Fe]>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[N:15][N:14]([C:11]2[N:12]=[CH:13][C:8]([NH2:5])=[CH:9][N:10]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Glacial acetic acid (2.78 g, 46.3 mmol) was slowly added to a solution of 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.5 g, 5.8 mmol) and iron powder (1.94 g, 34.7 mmol) in methanol (30 mL). The reaction was stirred at room temperature for 3 hours. The reaction was then diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was neutralized with saturated aqueous potassium carbonate. The organic layer was separated and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-amine (850 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.68 (s, 1H), 8.16 (s, 2H), 7.87 (s, 1H), 3.82 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12]C)=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(C=O)c(O)c1Cl

Procedure:
3-chloro-2,4-dimethoxybenzaldehyde (2.75 g) is refluxed for 30 minutes in 20 ml of dichloroethane containing 1.8 g of AlCl3. The reaction mixture is then poured into H2O and extracted with CH2Cl2. Evaporation and recrystallization from isopropanol gives 3-chloro-2-hydroxy-4-methoxybenzaldehyde, mp 125° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])=[CH:13][C:12]([CH:25]=O)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=1.CO.[CH3:29][NH2:30].[BH4-].[Na+].[ClH:33].C(=O)([O-])O.[Na+]>C(O)C>[ClH:33].[ClH:33].[CH3:29][NH:30][CH2:25][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[N:10]([S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: O=Cc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccnc2)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Product: CNCc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccnc2)c1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (340 mg) was dissolved in ethanol (34 mL), a 40% methylamine methanol solution (695 mg) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (102 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (10 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3) and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as pale-red crystals (yield 288 mg, 69%).
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH2:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:42][C:29]1[CH:30]=[C:31]([N:34]2[CH2:38][C@H:37]([CH2:39][NH:40][C:7](=[O:9])[CH3:8])[O:36][C:35]2=[O:41])[CH:32]=[CH:33][C:28]=1[CH:26]1[CH2:27][N:24]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:25]1
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4-dimethylaminopyridine were added to a stirred solution of (S)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38 °/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2 CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1(C)C=CC=CC=1.O>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 90 %

Procedure:
A solution of 3-bromopropylamine hydrobromide (547.5 g, 2.5 mol) in 500 mL of toluene and 600 mL of water was cooled to 6° C. and then aqueous potassium carbonate (1L, 5M, 5 mol) and benzyl chloroformate (1L, 2.63 mol) were added simultaneously at a rate such that the reaction temperature remained below 16° C. The mixture was allowed to warm to room temperature and then stirred for 80 minutes and 1.3L of additional water was added. The aqueous later was separated and extracted with toluene (1×300 mL). The combined organic layers were washed with 1N hydrochloric acid (2×300 mL), saturated sodium bicarbonate (1×300 mL) and saturated aqueous sodium chloride (1×300 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was extracted with hexanes (3×1L). The extract was concentrated under reduced pressure at 50° C. to give benzyl (3-bromopropyl)aminoformate (612.9 g, 2.25 mol) as a liquid.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCCCCC>[CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCc1ccc2ccccc2c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 2-(2-propenyl)-1-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N'-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, 95%), bp 135°-140° (0.1 torr).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.CCOCC>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-methoxybenzyl chloride (8.52 mL, 62.8 mmol) in DMF (40 ml) was added sodium azide (4.08 g, 62.8 mmol). The suspension formed was stirred at RT for 24 hrs. The reaction mixture was diluted with ether (400 ml) and washed with water (2×200 mL) and brine (20 ml). The organic layers were dried (MgSO4) and concentrated (water bath temp 20° C.) under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:33])[CH3:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:31](=[O:33])[CH3:32])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: CNc1cc(OC)c(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)-pyridin-2-amine (1 eq) and diisopropylethylamine (4 eq) in methylene chloride was brought to 0° C. Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5 minutes. Reaction brought to room temperature and water added. Organic layer washed with brine, dried over sodium sulfate and concentrated to yield N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC=3.21 min; MS: MH+=333.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 20 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in acetone (5 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 130.3° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cu](C#N)[C:10]#[N:11].N>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)nc1
Temperature: 50 °C

Procedure:
36 g (209 mmol) 2-bromo-5-methylpyridine and 37.5 g (418 mmol) copper cyanide are refluxed for two hours in 500 ml dimethylformamide. After cooling down to 50° C., 10% aqueous ammonia solution (500 ml) is added with stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo The product is purified by column chromatography (silica, eluent: cyclohexane/ethyl acetate 9:1).