Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]1[CH3:16])(=O)OCC)C.O.[OH-].[Li+].[CH:20]([CH:22]([N:26]([CH3:49])[C:27]([CH:29]([NH:34][C:35](=[O:48])[CH:36]([NH:46][CH3:47])[C:37]([CH3:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])=O>C(O)C.O>[CH3:47][NH:46][C@H:36]([C:35]([NH:34][C@H:29]([C:27]([N:26]([CH3:49])[C@H:22](/[CH:20]=[C:9]1\[N:10]([CH3:16])[C:11](=[O:15])[NH:12][C:13]\1=[O:14])[CH:23]([CH3:24])[CH3:25])=[O:28])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:48])[C:37]([CH3:38])([CH3:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C1/C(=O)NC(=O)N1C)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The yield, (3-methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester (0.915 g, 3.0 mmol) in ethanol (9 mL) is added to lithium hydroxide monohydrate (139 mg, 2.1 mmol) in 0.9 ml water to give a yellow solution. It is then added to N-{1-[(1-formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (˜1 mmol, from Reference Example 12) in 3 mL ethanol. The reaction mixture is stirred at room temperature for 60 hours. Solvent is evaporated. The residue is diluted with dichloromethane/water. The aqueous layer is extracted twice with dichloromethane. The combined organic extracts are washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a white solid, N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide:25 mg (4%) MS(ES+): (M+H)=514.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:20]2N(O)N=[N:23][C:21]=2[CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(N)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:23][CH:21]1[CH2:22][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 369.9 %

Procedure:
To a mixture of (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6 g, 26 mmol), HOBt (0.8 g, 6 mmol) and DCC (5.97 g, 29 mmol) in DCM (260 mL) was added cyclopropylamine (2.1 mL, 31 mmol) and DIPEA (6.8 mL, 39 mmol). The mixture was stirred at rt for overnight. The insolubles were filtered off, the filtrate was concentrated and extracted into ethyl acetate. The organic layer was concentrated and dried to give 6 g of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[N:15]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:14][CH2:13][S:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>OP(O)(O)=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[C:11]2[N:15]([CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][S:12]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=C(C)CN1CCSC1=Nc1ccc([N+](=O)[O-])cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)=CN1CCSC1=Nc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method C1a to give 2-(4-nitrophenyl)-1,3-thiazolidine. The thiazolidine was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2-(4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine. A mixture of 2-(4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine (0.20 g) in poly(phosphoric acid) (0.4 mL) was heated at 80 ° C. for 5 h. The reaction mixture was then dissolved in 0 ° C. water (20 mL) with the aid of sonication. The aqueous mixture was adjusted to pH 12 with a 1N NaOH solution, then extracted with EtOAc (3×25 mL). The combined organic phases were dried (K2CO3) and concentrated under reduced pressure. The residue (0.21 g) was purified by preparative HPLC to afford 2-(4-nitrophenylimino)-3-(2-methylprop-1-en-1-yl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=2)[CH3:19])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[N:12]=2)[CH:7]=1.[Cl:37]N1C(=O)CCC1=O.C(#N)C.[OH-].[Na+]>CO.[Cl-].[Na+].O.O>[Cl:37][C:10]1[O:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:17][C:18]([CH3:19])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:34])[F:35])=[N:22][N:21]=2)[CH3:36])=[N:12][C:11]=1[C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1coc(-c2cc(Cl)ccc2OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C(=O)O)c(Cl)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
Methyl 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylate (100 mg) and N-chlorosuccinimide (150 mg) were mixed with acetonitrile (4 ml), followed by heating to reflux for 48 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate. The resulting product was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1 to 1:10). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain a white solid. The resulting solid was dissolved in methanol (3 ml) and a 1M aqueous sodium hydroxide solution (1 ml) was added thereto, followed by stirring for 30 minutes. Water and saturated brine were added to the reaction solution, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain, as a white solid, 5-chloro-2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylic acid (8.2 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5](Cl)=[N:6][C:7]=1[Cl:8].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[Cl:8]
Reactant: N#Cc1ccc(N)cc1
Reactant: Clc1nc(Cl)c(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(Cl)n2)cc1

Procedure:
Drugs of the Future 2005, 30(5): 462-468 discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)-benzonitrile, which upon treatment with POCl3 yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine. It also discloses another process in which 5-bromo-2,4,6-trichloropyrimidine is reacted with 4-aminobenzonitrile in presence of diisopropylethylamine to give 4-(5-Bromo-4,6-dichloro-pyrimidin-2-ylamino)-benzonitrile, which is then reacted with 4-hydroxy-3,5-dimethylbenzonitrile to give 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile. The aminolysis of the same intermediate yields Etravirine.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[OH:16][CH:17]1[O:36][C@H:35]([CH2:37][OH:38])[C@@H:22]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])[C@H:20]([OH:21])[C@H:18]1[NH2:19].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:17]1([O:36][C@H:35]([CH2:37][OH:38])[C@@H:22]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])[C@H:20]([OH:21])[C@H:18]1[NH2:19])[OH:16])=[O:4]
Reactant: CCCCCCCCCCC(Br)C(=O)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCC(Br)C(=O)C1(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alpha-bromolauroyl chloride (0.50 g) was added drop-wise to a 30% aqueous solution of lactosamine (0.7 g) at zero degrees centigrade. The pH of the solution was kept above 9.0 by adding saturated sodium carbonate water solution. The reaction was stirred overnight at room temperature. It was then heated to 36° C. for an additional hour. The final product was obtained by extraction two times with n-butanol. After evaporating butanol, the remaining solid material was washed with cold ethanol. The final product was collected by filtration. The NMR spectra showed that the solid material is the expected product. The yield of the reaction was 75%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:47]([O:46][CH2:45][CH2:44][N:27]1[C:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:24]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:25]2[S:30][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][C:26]1=2)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(OCc3ccccc3)cc1OCc1ccccc1)n2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.12 g, 2.03 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 97 mg, 2.43 mmol) under ice-cooling and the mixture was stirred for 10 min. (2-Bromoethoxymethyl)benzene (0.53 ml, 3.24 mmol) was added and the mixture was stirred at room temperature for 4 hr. Ethyl acetate (25 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml), and dried over sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl 4-(2-benzyloxyethyl)-5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.21 g, yield 87%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:7])(C)(C)C>C(O)=O>[OH:7][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2noc(-c3cccc(C#N)c3)n2)nc1
Solvent: O=CO
Product: N#Cc1cccc(-c2nc(-c3ccc(C(=O)O)cn3)no2)c1
Temperature: 45 °C
Yield: 107.4 %

Procedure:
A mixture of 3-(5-tert-butoxycarbonylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (114 mg, 0.33 mmol) in formic acid (98%, 6 mL) was heated for 2 days at 45° C. The incomplete reaction was resubjected to additional formic acid (96%, 6 mL) for 1 day at 45° C. Co-evaporation of the solvent in vacuo using toluene afforded 103.6 mg of 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:41])[CH2:12][N:13]2[CH2:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@@H:14]2[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@H:16]2[CH2:17][N:13]([CH2:12][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=3)=[O:41])[C@@H:14]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@:15]2([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])[C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)CN2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
To a solution of rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester (0.35 g, 0.57 mmol) in tetrahydrofuran (30 mL) was added an aqueous solution (1 N) of NaOH (10 mL, 10 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 24 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid as a white solid (0.33 g, 96%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1267; Found: 600.1628.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:28]([O:29][CH3:30])=[O:31]
Reactant: COC(=O)C1CCNC(Cc2cccc(F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Methyl 2-(3-fluorobenzyl)piperidine-4-carboxylate (7.6 g, 30.24 mmol) was dissolved in DCM (200 mL) and DIPEA (6.32 mL, 36.29 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-fluorobenzyl)piperidine-1,4-dicarboxylate (9.30 g, 99%) as a brown oil. MS m/z 310 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][O-:25].[Na+].CO>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[O-]
Reactant: Nc1nc(OCCCO)nc2c1nc(Br)n2Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCCCO)nc2n1Cc1ccccc1
Reaction time: 10 h
Yield: 72 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(3-hydroxypropoxy)purine (140 mg, 0.37 mmol) in methanol (50 ml) was dissolved in 28%. sodium methoxide/methanol (3 ml) and the solution was refluxed on heating under stirring for 10 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added saturated brine. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (88 mg, yield 72%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(Cl)Cl>[C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH-:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CCN)cc1OC
Agent: CCOC(=O)CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(CC[NH-])cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 15.35 g of monoethyl tert.butyl malonate in 200 ml of anhydrous CH2Cl2 are stirred, at ambient temperature, 15.88 g of N,N'-carbonyldiimidazole in small batches. After 30 minutes, 14.8 g-of 2-(3,4-dimethoxyphenyl)ethylamine are added. After a further 15 hours the solvent is distilled off in vacuo. The residue is mixed with 200 ml of water, acidified with 2 N HCl and extracted with ethyl acetate. The organic phase is washed with water and concentrated by evaporation after drying over Na2SO4. The residue is triturated with petroleum ether (40 to 60° C.) and brought to crystallisation.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:32]I>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([CH3:32])[S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CI
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid-[1-(2-cyanopyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using methyl iodide in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]1[N:15](CCC#N)[N:14]=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Cl>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:11]1[N:12]=[N:13][NH:14][N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nnnn1CCC#N
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 400 mg of tert-butyl {(1R)-2-(benzyloxy)-1-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]ethyl}carbamate in 10 ml of dichloromethane was added 0.9 ml of 1,8-diazabicyclo[5.4.0]undeca-7-ene, followed by stirring at room temperature for 2 hours. The reaction mixture was added to a mixture of ice and 1 M hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure to obtain 343 mg of tert-butyl [(1R)-2-(benzyloxy)-1-(2H-tetrazol-5-yl)ethyl]carbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: CCCCCBr
Product: CCCCCOc1cc(CC)c(OCCCCCC(C)(C)C#N)cc1OCc1ccccc1
Yield: 100 %

Procedure:
1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl -6-pentyloxy benzene was prepared in 100% yield as a white solid from 1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and 1-bromopentane.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ncccc2F)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ncccc2F)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a 0° C. solution of 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (88 g, 500 mmol, 1.0 equiv) in THF (400 mL) was added LAH (2M in THF, 575 mL, 1.15 mol) in a dropwise manner over one hour. The reaction was then warmed to room temperature and stirred for 15 min. After the reaction was complete, it was cooled back down to 0° C. and quenched slowly with water (43 mL), 3 N NaOH (43 mL), and water (125 mL). The quenched reaction was stirred for 30 min and then filtered through Celite. The filtrate was concentrated and dried in vacuo to give (1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (80 g, 88%) as a crude yellow oil that was used without purification.
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)Cl)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15])[CH3:12]>O>[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O-:16])=[O:15])[CH3:12].[CH2:1]([Sn+:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(Cl)Cl
Reactant: CCCCC(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]
Product: CCCC[Sn+]
Reaction time: 2 h
Yield: 94 %

Procedure:
A 500-ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a Liebig condenser is charged with 28.2 g (0.1 mole) of monobutyltin trichloride and 200 ml of deionized water. The contents are warmed to 20°-30° C., and 32 g of a 25% aqueous solution of sodium hydroxide (0.2 mole) is gradually added dropwise. White crystals precipitate out. After the addition, the mixture is stirred at 20°-30° C. for 2 hours. Then, 100 ml of hexane is added, followed by gradual dropwise addition at 20°-30° C. of a separately prepared reaction mixture of 14.4 g (0.1 mole) of 2-ethylhexanoic acid and 4 g (0.1 mole) of sodium hydroxide in 100 ml of water. Care should be taken during the dropping that the flask contents are not made alkaline. After the addition, the mixture is stirred for an hour. The hexane layer is separated and concentrated to give 30 g of monobutyltin mono(2-ethylhexanoate) as a white filmy substance.