Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.CO>ClCCl>[Br:1][C:2]1[C:3]([CH2:10][O:11][CH2:21][O:22][CH3:23])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(CO)n1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCOCc1nc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of (3-bromo-6-methoxypyridin-2-yl)methanol (10.6 g, 48.6 mmol) synthesized by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) in dichloromethane (150 mL) was successively added dropwise with N,N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g, 165 mmol) under ice cooling. The mixture was warmed to room temperature, stirred for 16 hours, and then added with methanol (30 mL), and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1→20:1) to obtain 3-bromo-6-methoxy-2-[(methoxymethoxy)methyl]pyridine (12.1 g, 95%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C[O-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:21][OH:22])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Temperature: 1 °C

Procedure:
16.8 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were suspended under stirring and argon atmosphere in 101 ml N,N-dimethylformamide and 13.48 g hydroxylamine hydrochloride were added in one portion. 34.2 ml Sodium methanolate were then added over 60 minutes to the yellow suspension, which turned to a colorless suspension. It was stirred one more hour at r.t., then cooled to 0-2° C. and 202 ml deionized water were added over 30 minutes. After stirring one more hour at 0° C., the precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime (VIII)) was filtered off, washed twice with 40 ml deionized water and dried under vacuum at 70° C. for 18 hours. Crude product: 17.84 g as a white powder. m.p. >250° C.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@H:7]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)[NH:8][C:9](=[O:32])[CH:10]([CH2:27][S:28][C:29](=[O:31])[CH3:30])[CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[C:29]([S:28][CH2:27][CH:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:9]([NH:8][C@H:7]([C:6]([OH:45])=[O:5])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:32])(=[O:31])[CH3:30]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
A solution of Nα-[ 2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-Nε -tert-butyloxycarbonyl-L-lysine tert-butyl ester (1 g) in trifluoroacetic acid (5 ml) is stored at room temperature for one hour and then concentrated to dryness in vacuo to yield Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-lysine trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:26])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude benzhydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 500 mL of toluene and the solvent again was removed under vacuum to eliminate excess thionyl chloride, providing crude α-(4-bromophenyl)-3-(tert-butyldimethyl-silyloxy)benzyl chloride as a dark oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-chlorobenzylamine (0.121 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((2-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 137 mg. To a solution of tert-butyl 4-((2-chlorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.15 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((2-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((2-Chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 45 mg; 13C-NMR (CD3OD, rotamers): δ 25.8, 26.9, 40.0, 40.1, 42.9, 43.4, 43.7, 46.0, 51.1, 53.0, 54.6, 113.77, 113.84, 114.0, 114.1, 126.6, 126.8, 127.08, 127.13, 127.3, 127.4, 128.1, 129.0, 129.2, 129.8, 130.0, 130.2, 131.9, 132.2, 135.0, 135.3, 159.1, 173.4, 173.8.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14]Cl)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14][S:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: N#Cc1ccc(S)cc1
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CCl)n2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C

Procedure:
A mixture of 1.5 g (4.1 mMol) of 2-chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide and 0.65 g (4.8 mMol) of p-cyanothiophenol was heated in 10 ml of dimethylformamide and 10 ml of diisopropylethylamine for 1 hour to 100° C. The solvent was distilled off in vacuo, the crude product was dissolved in 30 ml ethyl acetate, washed with 30 ml water, and after concentration purified by flash chromatography (silica gel; methylene chloride/ethanol (49:1 to 19:1). Yield: 1.5 g (79% of theory) of brown oil, Rf value: 0.65 (silica gel; ethyl acetate/ethanol/ammonia =90:10:1)
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:10]=1[O:11][CH:12]([CH3:16])[C:13]([OH:15])=O.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:37]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOCC.C(N(CC)CC)C>[CH2:42]([O:41][C:39](=[O:40])[CH:38]([C:13](=[O:15])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:9]=1[CH3:8])[CH3:16])[C:37]([O:45][CH2:46][CH3:47])=[O:44])[CH3:43]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Cl)ccc1OC(C)C(=O)O
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Into a 200 ml round-bottomed flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a calcium chloride tube 100 ml of toluene, 10.1 g of triethyl amine and 21 g of 2-(2'-methyl-4'-chloro-phenoxy)-propionic acid are weighed in. The reaction mixture is cooled under 0° C. and 10.8 g of ethyl chloro formiate are added dropwise at such a rate that the temperature should be between -1° C. and 0° C. The thick suspension formed is stirred for a further period of 20 minutes, whereupon a mixture of diethyl-ethoxy-magnesium-malonate prepared from 17.6 g of diethyl malonate and 50 ml ether is added dropwise at such a rate that the temperature should not exceed 0° C. The reaction mixture is allowed to stand at room temperature for 16 hours and worked up as described in Example 1. Thus 31 g of the desired compound are obtained in the form of a pale yellow oil, yield 88%, nD25 =1.348.
Reaction SMILES: CO[CH:3]([O:15][CH3:16])[C:4]1[C:9](CO)=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.[CH3:17][O:18][C:19]([C:21]#[C:22][C:23]([O:25][CH3:26])=[O:24])=[O:20].CC(O)=O>>[O:15]1[CH:16]2[C:9]3[C:4]([CH:3]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:19]([O:18][CH3:17])=[O:20])=[CH:5][C:6]1[O:14][CH2:13][O:12][C:7]=1[CH:8]=3
Reactant: COC(OC)c1cc2c(cc1CO)OCO2
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)O
Product: COC(=O)C1=C(C(=O)OC)C2OC1c1cc3c(cc12)OCO3
Yield: 176.5 %

Procedure:
The substrate 2 (23.7 g, 105 mmol) was dissolved in excess DMAD (251 g, 1.76 mol) and glacial AcOH (23.2 mL, 0.4 mol), and the mixture was stirred for 2 h at 80° C. Excess DMAD was removed by vacuum distillation, and flash chromatography (30% EtOAc/hexanes) gave 3 (56.4 g, 90%) as a yellow solid. On a smaller scale, 2 (5.53 g, 24.1 mmol) gave 3 in 92% yield (13.6 g): mp 117-119° C.; 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 6H), 5.86 (s, 2H), 5.90 (d, J=1 Hz, 1H), 5.95 (d, J=1 Hz, 1H), 6.95 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 53.0, 85.7, 102.2, 105.2, 141.4, 146.2, 152.5, 163.5. Anal. Calculated for C15H12O7: C, 59.21; H, 3.98. Found: C, 59.27; H, 4.11.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CS(C)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][CH:16]([CH:19]=[O:20])[CH2:17][CH2:18]1
Reactant: OCC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)phenyl]piperidin-4-yl}methanol (2.41 g) and triethylamine (3.08 mL) in dimethyl sulfoxide (30 mL) was added sulfur trioxide pyridine complex (3.52 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.60 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[C:30]([C:11](=[O:12])[C:10]4[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2cccc3c2n1C(CN1CCOCC1)CO3
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(C)n3c4c(cccc24)OCC3CN2CCOCC2)cc1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a suspension of 7.5 g (0.056 mole) of aluminum chloride in 100 ml of methylene dichloride (MDC) was added, rapidly with stirring, a solution of 6.2 ml (0.038 mole) of 4-methoxybenzoyl chloride. When addition was complete the mixture was stirred for one hour at room temperature and the resulting solution then added dropwise over a ten minute period with stirring to a solution of 8.5 g (0.031 mole) of 3-(4-morpholinylmethyl)-5-methyl-2,3-dihydropyrrolo-[1,2,3-de]-1,4-benzoxazine in 100 ml of MDC. The resulting mixture was then heated under reflux for thirty minutes, cooled and poured into 300 ml of ice water with stirring. The organic solvent was removed in vacuo, and the residual aqueous medium was diluted with ethyl acetate and neutralized by the addition of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered through silica, taken to dryness in vacuo and chromatographed on silica gel, eluting with 1:1 hexane:ethyl acetate. There was thus obtained about 7 g of crude product which was recrystallized from ethyl acetate/hexane to give 6.0 g of 3-(4-morpholinylmethyl)-5-methyl-6-(4-methoxybenzoyl)-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, m.p. 182°-189° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]2[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]#[N:36])=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(cc1-n1cccc1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-pyrrol-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M10) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[OH:28][CH2:27][C@@H:11]1[CH2:10][C@H:9]([S:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CS[C@H]2C[C@@H](CO)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
(2S,4S)-4-(4-Methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid (10 g) and triethylamine (3.59 ml) were dissolved in tetrahydrofuran (25 ml), followed by stirring at -15 to -10° C. To the mixture, ethyl chlorocarbonate (2.46 ml) was added at the same temperature, followed by stirring at the same temperature for 15 minutes and then at 0-5° C. for one hour. The reaction mixture was filtered through Celite and the residue was washed with tetrahydrofuran (15 ml). The tetrahydrofuran solution was cooled to 0-5° C., followed by the addition of a solution, which had been obtained by dissolving sodium borohydride (1.9 g) in water (20 ml), in three portions below 25° C. The resulting mixture was stirred at room temperature for one hour. Ethyl acetate (100 ml) was added to the reaction mixture. The resulting mixture was washed successively with water, 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saline; and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography through a silica gel column. From the fractions eluted with a 1:1 solvent mixture of ethyl acetate and cyclohexane, (2S,4S)-2-hydroxymethyl-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.3 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].CO[C:39]1O[C:41](OC)=[CH:42][CH:43]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.CCOC(C)=O>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([N:17]4[CH:39]=[CH:43][CH:42]=[CH:41]4)[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COc1ccc(OC)o1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)[C@@]2(Cc3ccc(OC(F)(F)F)cc3)C[C@H](n3cccc3)CN12

Procedure:
To a solution of the compound from Example 63 (0.25 g) in acetic acid (5 mL) was added sodium acetate (0.26 g) and 2,5-dimethoxyfuran (0.14 mL). After 20 minutes at reflux, the reaction was cooled, diluted with EtOAc, neutralized with solid NaHCO3. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel; 95:5 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.145 g): MS (m/z) 525 [MH+]. mp 129.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:20]=[CH:8][C:6]1[CH:5]=[N:4][C:3]([C:10]([C:11]#[N:12])([CH3:14])[CH3:13])=[C:2]([Cl:1])[CH:7]=1)[CH3:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C#N)c1ncc(C=O)cc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Yield: 95.5 %

Procedure:
A solution of 2-(3-chloro-5-formyl-pyridin-2-yl)-2-methyl-propionitrile (0.58 g, 2.78 mmol) from step 3 above and (carbethoxymethylene)triphenylphosphorane (1.26 g, 3.61 mmol) in dry THF (12 mL) was heated to 55° C. and maintained at this temperature overnight. The solvents were removed and the residue was purified by flash column chromatography (0-20% EtOAc in hexanes) to give the product (0.74 g, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J=7.7 Hz, 3 H), 1.87 (s, 6 H), 4.29 (q, J=14, 7.7 Hz, 2 H), 6.53 (d, J=16 Hz, 1 H), 7.65 (d, J=16 Hz, 1 H), 7.87 (d, J=2 Hz, 1 H), 8.58 (d, J=2 Hz, 1 H). ESIMS (MH+): 279.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.[OH-].[Na+].Cl>C(O)CC>[OH:7][CH2:8][CH2:9][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CBr
Reactant: OCCNCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: O=C(O)CN(CCO)CCO

Procedure:
Methyl bromoacetate (152.98 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles) are added and the mixture is stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid is washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml, 1.3 moles). Upon cooling, N,N-bis-(2-hydroxyethyl)aminoacetic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.O=[Pt]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3occc3c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)C1(c2ccc3c(c2)CCO3)CC1
Reaction time: 72 h
Yield: 46.6 %

Procedure:
To a solution of 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (700 mg, 3.47 mmol) in MeOH (10 mL) was added PtO2 (140 mg, 20%) at room temperature. The stirred reaction mixture was hydrogenated under hydrogen (1 atm) at 10° C. for 3 days. The reaction mixture was filtered. The solvent was evaporated under vacuum to afford the crude product, which was purified by preparative HPLC to give 1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (330 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 1 H), 7.10 (d, J=10.8 Hz, 1 H), 6.73 (d, J=11.2 Hz, 1 H), 4.57 (t, J=11.6 Hz, 2 H), 3.20 (t, J=11.6 Hz, 2H), 1.67-1.63 (m, 2 H), 1.25-1.21 (m, 2 H).