Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18](OCC)=[O:19])=[N:8]1.[OH-].[Na+]>O1CCCC1>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([CH2:18][OH:19])=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(C)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1nc(CO)cc1-c1ccccc1
Reaction time: 1 h

Procedure:
A stirred suspension of sodium borohydride (1.28 g) in dry tetrahydrofuran (80 mL) was treated with calcium chloride (1.88 g). The mixture was stirred for 1 hour then treated with a solution of ethyl 1-methyl-5-phenylpyrazol-3-ylcarboxylate (5.2 g, prepared according to the procedure described by Martins et al., J. Heterocycl. Chem. (1999), 36(1), 217-220) in dry tetrahydrofuran (40 mL). After stirring at room temperature for 3 days and at reflux temperature for 8 hours the mixture was treated with sodium hydroxide solution (50 mL, 1N). This mixture was stirred at room temperature for 1 hour, then evaporated to remove the organic solvents and then extracted three times with dichloromethane (140 mL). The combined extracts were washed with water, then dried over magnesium sulfate and then evaporated to give the title compound as a white solid, m.p. 95-99° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[N:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=O)[CH2:9]1.C[Al](C)C.O>C1(C)C=CC=CC=1>[CH2:6]1[N:7]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:9]2)[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]12
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: NCC1CCCN1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(C2=NCC3CCCN23)C1
Temperature: 110 °C
Yield: 43.2 %

Procedure:
To a solution of pyrrolidin-2-ylmethanamine (250 mg, 2.5 mmol) in toluene (8.5 mL) was added 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (635 mg, 2.5 mmol) under nitrogen. The solution was cooled with an ice-water bath and trimethylaluminum (2M in toluene, 2.2 mL, 4.4 mmol) was added. The resulting solution was transferred to a pressure tube and heated to 110° C. for 18 h. The reaction mixture was cooled to room temperature and water was added (10 mL). The mixture was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as a colorless oil (317 mg, 43.8%). MS (ES+) (M+H) 294.2; LCMS retention time: 1.03 minutes (Method M).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH2:17]([OH:19])C.[C:20]1([CH3:26])C=CC=CC=1.Cl>>[C:2]1([NH:1][C:17](=[O:19])[O:9][CH2:20][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCO
Reactant: Cc1ccccc1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml capacity SUS 316 stainless autoclave were fed the above catalyst (61.9 mg) (0.020 mmol in terms of Pd), aniline (0.931 g, 0.010 mol), nitrobenzene (1.23 g, 0.010 mol), ethanol (4.61 g, 0.10 mol), toluene (10.6 g, 0.11 mol) and 35% hydrochloric acid aqueous solution (0.071 g, HCl=0.68 mmol, H2O=0.067 mmol), followed by introducing CO gas up to 28 Kg/cm2 at room temperature without purging the air inside the system, reacting them at a reaction temperature of 190° C. for 3 hours, cooling the reaction mixture down to room temperature after the reaction, returning the pressure inside the system to the atmospheric pressure and analyzing the reaction product according to gas chromatography. As a result, ethyl N-phenylcarbamate (NPU) (2.97 g) was formed (NPU yield: 90%), and aniline (0.093 g, 0.001 mol) and nitrobenzene (0.123 g, 0.001 mol) remained unreacted.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Br)ccc12)C1CC1
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1H-indazol-3-amine (4.24 g, 20 mmol) in pyridine (100 mL) was added cyclopropanecarbonyl chloride (1.83 mL, 20 mmol) dropwise at 0° C. The reaction mixture was stirred at this temperature for 4 hours. Once the reaction was completed, the solvent was removed in vacuo. The residue was dissolved in DMF, and water was added dropwise. The precipitated solid was filtered off and washed three times with hexanes (15 ml each). The product was dried in vacuo and used without further purification (4.3 g).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:24]1([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccccc1CCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCc2ccccc2OC[C@H]2CCCN2)cc1
Reaction time: 1 h
Yield: 68 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 630 mg of (R)-1-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting oily residue was cooled, which resulted in its solidification. The solid was triturated in pentane, and the resulting powder was collected by filtration to give 360 mg (yield 68%) of the title compound as a colorless solid, melting 73°-88° C. [α]D25 -7.5° (c=3.76, ethanol).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:16]([S:18][CH2:19][C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=1[Cl:33])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][S:18][C:16](=[O:17])[C:15]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=1
Reactant: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.082 g, 0.100 mmol) in DCM (4 ml), HCl 4M in dioxane was added, and the reaction was stirred at RT for 3 days. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel column (DCM:MeOH=95:5) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoylthio)acetoxy)ethyl)pyridine 1-oxide (0.042 g, 0.058 mmol, 58.3% yield, MS/ESI+ 721.32 [MH]+, [αD]=−31.40, c=0.5, MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4](C(=O)C)[CH2:3]1.Cl>CCO>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: 70 °C

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g, Step C) was dissolved in EtOH (50 mL), 12N HCl (50 mL) was added and the resulting mixture was heated at 70° C. overnight. After the mixture was concentrated in vacuo, it was partitioned between saturated NaHCO3 solution and EtOAc, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. MS:193 (M+1). Calc'd. for C10H12N2O2—192.21.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Br.[NH2:7][C:8]1[NH:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:5][O:4][C:2]([NH:7][C:8]1[NH:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:3]
Reactant: NC1=NC(c2ccccc2)CN1
Reactant: COC(=O)Cl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)NC1=NC(c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This example illustrates another process embodiment of the invention wherein an alkyl chloroformate is used as one of the reagents. In this example, 0.8 g. of methyl chloroformate is added over a five minute period to a stirring mixture of 2 g. 2-amino-4-phenyl-2-imidazoline hydrobromide, 1.4 g. sodium bicarbonate, and 20 ml. acetone held at 0° C. After addition is complete, the mixture is allowed to warm to room temperature and then stirred for 16 hours at room temperature. The mixture is distilled to a low volume and 50 ml. of water is then added. The mixture is filtered and the precipitate collected and washed with water and then dried affording 4,5-dihydro-2-methoxycarbonylamino-4-phenylimidazole which is then further purified by recrystallizaton from chloroform.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:7][CH2:8][CH:9]1[S:14](=[O:16])(=[O:15])[C:13]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=2[CH:11]([NH2:24])[CH2:10]1)[CH:5]=[CH2:6].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:4]([O:7][CH2:8][CH:9]1[S:14](=[O:16])(=[O:15])[C:13]2[S:17][C:18]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:19][C:12]=2[CH:11]([NH:24][CH2:1][CH3:2])[CH2:10]1)[CH:5]=[CH2:6]
Reactant: C=CCOCC1CC(N)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: CC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOCC1CC(NCC)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Acetaldehyde, 1.5 ml. (1.19 g, 0.027 m), was added to a solution of 5,6-dihydro-6-allyloxymethyl-4-amino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, 10.0 g. (0.028 m.), in dry tetrahydrofuran, 150 ml., and the mixture was stirred at ambient temperature for 0.75 h. under nitrogen. The solution was added over 15 min. to a stirred suspension of sodium borohydride, 5.3 g. (0.14 m.) in absolute ethanol, 150 ml., at 0° C. After stirring for an additional 15 min. at 0° C., the mixture was treated dropwise with 10% hydrochloric acid, 35 ml., until gas evolution ceased. After concentration in vacuo, the residue was distributed between 200 ml. of water containing 10 ml. of 3N hydrochloric acid and 75 ml. of ethyl acetate. The ethyl acetate layer was washed with 100 ml. of water, the combined aqueous wash and acidic water layer were basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (300 ml. and 2×200 ml.). After washing twice with brine and drying over sodium sulfate, ethyl acetate was evaporated in vacuo to yield 6.6 g. (63%) of the mixture of isomers as a yellow foam.
Reaction SMILES: [Cl-].[Na+].C(CC[CH:8]([CH:14]([C:19]#[N:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(O)=O.CS(C)=O>O.C(OC)(C)(C)C>[C:19]([CH:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:20]
Reactant: CCOC(=O)C(CCC(=O)O)C(C#N)CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)CC(C#N)CC(C)C
Reaction time: 0.38 h
Yield: 89.4 %

Procedure:
An 800 L still was charged with sodium chloride (21 kg, 359 mol), 2-carboxyethyl-3-cyano-5-methylhexanoic acid, ethyl ester (80.0 kg, 313 mol), dimethylsulfoxide (238 kg), and water (10.8 kg, 600 mol). The mixture was heated to 137°-148° C. for 8.5 hours. The mixture was cooled to below 50° C., and treated with methyl tert-butyl ether (125 kg). The mixture was cooled to 0°-10° C., and treated with water (160 L) in portions to maintain the temperature below 40° C. After stirring for 15-30 minutes, the phases were separated. The aqueous phase was extracted with methyl tert-butyl ether (125 kg). The organic extracts were combined with a vessel rinse (25 kg methyl tert-butyl ether) and was extracted with water (110 L). The water phase was discarded. The methyl tert-butyl ether phase was concentrated by atmospheric pressure distillation to a batch temperature of about 65° C. The batch was cooled to 30°-40° C. and further concentrated by vacuum distillation until the solvent content was acceptable (<5% methyl tert-butyl ether by area %GC analysis). The product was obtained as a brown oil (51.3 kg, 85.7%).
Reaction SMILES: [Mg].[CH3:2][Si:3]([CH3:6])(Cl)[Cl:4].II.Cl[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>O1CCCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([Si:3]([CH3:6])([CH3:2])[Cl:4])=[CH:11][CH:12]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)Cl)cc1
Reaction time: 5 h
Yield: 61 %

Procedure:
The following were placed in a dry four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer under a nitrogen blanket: 23.3 g (1.0 mol) powdered magnesium, 129.1 g (1.0 mol) dimethyldichlorosilane, and 200 mL tetrahydrofuran. A small quantity of iodine was added in order to activate the magnesium. Then, while cooling the flask to below 10 degrees Centigrade, a mixture of 142.6 g (1.0 mol) p-chloroanisole and 300 mL tetrahydrofuran was dripped in from the addition funnel with stirring over 5 hours. The reaction mixture was aged by heating under reflux for 2 hours, the precipitate was removed by suction filtration, and the filtrate was distilled to give 122 g (0.61 mol) product. The yield was 61%. The properties of this product are reported below.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].P([CH2:15]N[C@H](C(O)=O)C)(O)(O)=O>>[CH3:15][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: C[C@H](NCP(=O)(O)O)C(=O)O
Reactant: O=C(O)CNCP(=O)(O)O
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
Liquid chromatography analysis of the recrystallized product showed that N-phosphonomethylglycine was present along with a sister compound whose peak on the chromatogram was of an intensity equal to that exhibited by glyphosate. The sister compound was understood to be N-phosphonomethylalanine. No N-methylglyphosate was formed, but a measurable trace of N-formylglyphosate was observed.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:52][CH2:53][CH:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[OH:59]>ClCCl.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:4]2[C:9]([C:10]([NH:52][CH2:53][CH:54]3[CH2:58][CH2:57][CH2:56][CH:55]3[OH:59])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: NCC1CCCC1O
Reactant: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)NCC1CCCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example X1) (0.50 g, 1.91 mmol) in dichloromethane (20 ml) are added N-ethyl-diisopropylamine (0.81 ml, 4.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.29 mmol), and 1-hydroxybenzotriazole hydrate (0.05 g, 0.38 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0° C., before 2-(aminomethyl)cyclopentanol (0.22 g, 1.91 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness affording example X4 as crude product. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield the first eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X4a) (0.34 g, 0.95 mmol, [M+H]+360.2) and the second eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X4b) (0.27 g, 0.75 mmol, [M+H]+360.2) as white solids.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:17]1[CH2:22][CH2:21]OC[CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCC1>CN(C=O)C>[N:17]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]2[CH2:15][CH2:14]2)[CH2:18][CH2:21][CH2:22]1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CC1
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC1)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-2-cyclopropylacetic acid (2.0 g, 9.30 mmol), which is commercially available, and NMM (3.07 mL, 27.9 mmol) was mixed in DMF (20 mL). The mixture was cooled to 0° C. and TBTU (3.34 g, 10.42 mmol) was added. After 10 min at rt was azetidine (1.6 mL, 23.7 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (300 mL). The organic phase was washed with NaHCO3 (saturated, 150 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (2.04 g, 86%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.39, 0.44-0.63, 1.09, 1.43, 2.31, 3.84, 3.93-4.46, 5.30. Total no of protons: 22.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=O.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:16]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12][C:4]1[C:3]([CH2:2][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:8]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=1)[CH2:17][CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C
Agent: [Na]
Solvent: CCO
Product: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)C(=O)OCC
Yield: 23.5 %

Procedure:
To a solution of 2.38 g (0.103 gram atoms) of sodium metal in 52 cc of absolute ethanol at room temperature was added 18.51 g (0.07 mole) of the nitro compound in one portion, with stirring, followed by 15.42 g (0.103 mole) of diethyl oxalate. The reaction was refluxed under nitrogen for about 20 minutes, cooled, quenched on 700 cc of ice-water and acidified with 3N hydrochloric acid. This aqueous solution was washed with a small volume of ether, basified to pH 8.5 with solid sodium carbonate and extracted with 3 portions of ether. The combined ether extract was washed with saturated brine, dried over anhydrous magnesium sulfate, clarified with charcoal and concentrated in vacuo. The residue was triturated with cold petroleum ether, filtered and air-dried to give 6.0 g of ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate as a yellow powder. The triturate was concentrated in vacuo and distilled to give 7.3 g of recovered starting material which was recycled. In the same manner, a total of three recycles provided 11.0 g of ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.CC(O)=O>[Si:1]([O:8][C@H:9]1[CH2:10][NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CN=C(c2cccc(F)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Temperature: -78 °C
Yield: 76.9 %

Procedure:
(R)-3-(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.21 g, 21.2 mmol) was dissolved in methanol (100 mL) and AcOH (10 mL). The reaction was cooled to −78° C. and the sodium borohydride (2.00 g, 52.9 mmol) was slowly added in small portions. The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and the residue was diluted with EtOAc and 1N NaOH. Additional NaOH pellets were added to basify the aqueous layer. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. The residual oil was purified by silica chromatography eluting with 5% MeOH/EtOAc to afford (2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine (4.82 g, 77.1%) as a brown oil. MS (apci) m/z=296.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C@@H:4]([C:6]([NH:8][C@@H:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1)=[O:7])[NH2:5].F[C:33](F)(F)[C:34]1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=C[CH:39]=1.C(=O)C(C)(C)C>CC(C)=O>[CH:34]([NH:5][C@H:4]([C:6]([NH:8][C@@H:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1)=[O:7])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])([CH3:39])[CH3:33]
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C[C@H](N)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: CC(C)(C)C=O
Solvent: CC(C)=O
Product: CC(C)N[C@@H](CC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 4-methyl-N1-(3aR,4S,6aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide from Example 419 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and acetone for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26-8.29 (m, 1H), 8.13-8.16 (m, 2H), 7.89-7.91 (m, 2H), 4.21-4.26 (m, 1H), 3.85 (dd, J=9.9, 2.3 Hz, 1H), 3.36 (dd, J=7.5, 4.1 Hz, 1H), 3.15-3.20 (m, 2H), 2.98 (dd, J=9.6, 6.7 Hz, 1H), 2.83 (hept, J=6.2 Hz, 1H), 2.51-2.62 (m, 2H), 1.91-1.97 (m, 1H), 1.79-1.88 (m, 2H), 1.63-1.81 (m, 1H), 1.51-1.59 (m, 1H), 1.47 (dd, J=14.1, 7.5 Hz, 1H), 1.31 (ddt, J=9.6, 12.8, 6.4 Hz, 1H), 1.03 (dd, J=6.2, 2.7 Hz, 6H), 0.98 (s, 9H); MS (ESI+) m/z 504 (M+H)+.