Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2].C(OC(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[CH:46][C:39]=1[N+:36]([O-:38])=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cc1ccc(CN2CCOCC2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (25 g, 130 mmol) and diethylcarbonate (33.79 g, 286 mmol) in tetrahydrofuran (62.5 ml) under nitrogen at −10° C. was added lithium diisopropylamide in tetrahydrofuran (158.9 ml, 1.8M, 286 mmol) dropwise over 1 hr 10 min. After stirring for an additional 30 mins at −10° C. a solution of 4-nitrobenzonitrile (29.78 g, 195 mmol) in tetrahydrofuran (175 ml) is added dropwise and stirring continued for 3 hrs. The reaction mixture was poured into a cold aqueous hydrochloric solution (375 ml, 2M) at 0° C.; after warming to room temperature the acidic aqueous layer was separated and washed with tert-butyl methyl ether (200 ml). The acidic aqueous layer was cooled in an ice bath and tert-butyl methyl ether (500 ml) was added. The mixture was then made basic (pH 9) by addition of sodium carbonate solution (55 ml, 25 w/w %). The mixture was then warmed to room temperature and the organic phase separated; the basic aqueous phase was extracted with tert-butyl methyl ether (250 ml). The combined organic layer was treated with Celite® (12.5 g), then filtered and the filtrate concentrated in vacuo to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester crude (28.58 g, 51% w/w %). The crude material was dissolved in ethanol (300 ml) then heated to 40° C. and a solution of hydrochloric acid in isopropanol (8 ml, 4.95M, 20.7 mmol) was added followed by addition of seeds (90 mg) and the solution cooled to −10° C. over 10 hrs. The crystals were filtered and washed with tert-butyl methyl ether. After drying at 40° C. under vacuum gave 14.51 g, 25% yield of (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt as red wine crystals. Characterisation data were in accordance with example 7.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23].Cl.[OH-].[Na+]>CCO.O>[CH2:7]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Aminodiphenylmethane (5.00 g, 27 mmol) was added in portions to acetic anhydride (26 mL, 273 mmol) with rapid stirring. A solid mass formed which was liberated by the addition of 15 mL additional acetic anhydride. The reaction was allowed to cool to ambient temp, and nitric acid (2.0 mL, 41 mmol) was added slowly dropwise via addition funnel over 30 min. The homogeneous red mixture was allowed to stir overnight and poured into a rapidly stirring solution of 30 mL water, 7 mL conc. HCl, and 24 mL EtOH (exothermic!). The reaction was allowed to cool and was then heated to reflux for ˜4 h, cooled and poured onto ice and neutralized with 10N NaOH to pH 8-9. The aqueous layer was extracted 3×DCM and dried over sodium sulfate, filtered, and concentrated. The resulting dark red oil was purified by silica gel chromatography, ISCO 120 g, 0-20% EtOAc/hexanes, to give 4-benzyl-2-nitrobenzenamine as a red oil. MS (ESI) m/z: Calculated: 228.1; Observed: 229.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=2)OCC[O:3]1.Cl.CC(C)=O.C(=O)([O-])O.[Na+]>O>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:2](=[O:3])[CH3:1])=[CH:12][CH:11]=1)[CH:14]=[C:15]([CH3:17])[CH3:16]
Reactant: CC(C)=CCc1ccc(C2(C)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(CC=C(C)C)cc1
Yield: 97.6 %

Procedure:
A solution of 69.0 g of 2-methyl-2-(p-prenylphenyl)-1,3-dioxolane, 8 ml of 6 N hydrochloric acid and 400 ml of acetone was stirred at room temperature for 3 hours. A solution of 5.0 g of sodium hydrogen carbonate and 200 ml of water was added to the solution, which was extracted with ethyl ether after removal of the acetone. The ethereal solution was washed with water, dried, concentrated and distilled to give 54.6 g of p-prenylacetophenone, b.p. 110-112 °C/0.05 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][SH:43])=[CH:38][CH:37]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]([S:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)CC=C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSC(CC(C)C)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-(2-tert-butoxycarbonyl-5-methyl-hex-2-enyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.24 mmol) in DMF (5 mL) was added to a mixture of potassium carbonate (0.54 g, 3.93 mmol) and 4-methoxy-α-toluenethiol (1.17 g, 10.48 mmol) in DMF (50 mL) under nitrogen. The mixture was refluxed for 5 h and allowed to cool to room temperature. The reaction mixture was then poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered and concentrated under reduced pressure to give 3.76 g of crude material. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:10) to give 4-[2-tert-butoxycarbonyl-3-(4-methoxy-benzylsulfanyl)-5-methyl-hexyl]-piperidine-1-carboxylic acid tert-butyl ester (1.77 g, 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[C:3]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
4-chloro-3-nitro-2-pyridone (5 g, 28.65 mmol) was suspended in 150 mL of acetonitrile then benzylamine (3.15 mL, 28.65 mmol) was added followed by potassium carbonate (4 g, 28.65 mmol) and the mixture was stirred at 60° C. overnight. The solvent was removed in vacuo and the residue was suspended in water (200 mL). A solution of HCl 2M was added until pH˜6. The precipitate was filtered and dried in vacuo to give 4.75g of the title compound as a beige solid. A second crop from the mother liquids provided 1.4 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:13]1([NH:19][C:20](C2C=CC=CC=2C(O)=O)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: C1COCCN1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)N1CCOCC1
Yield: 32.8 %

Procedure:
A solution of 0.9 g morpholine with 5 ml aceton was added dropwise during 5 minutes to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml acetone, under stirring. The reaction mixture was stirred for a further 30 minutes at ambient temperature, then diluted with 150 ml water. Acetone was distilled off, the mixture was cooled, and 0.35 g phenylcarbamoyl-morpholine was isolated by filtration. The white crystalline material melted at 160°-162° C.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].CO[C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11](OC)[C:12]=1OC.[Cl:21]C1C=C(C=CC=1)N.N#CN.[N+]([O-])(O)=O>O>[N+:1]([O-:4])([O-:3])=[O:2].[Cl:21][C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Reactant: Nc1cccc(Cl)c1
Agent: N#CN
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NC(=[NH2+])Nc1cccc(Cl)c1

Procedure:
The 3-chlorophenylguanidinium nitrate starting material was prepared by the method described for 3,4,5-trimethoxyphenylguanidinium nitrate in Example 1 from 3-chloroaniline (10.35 g, 81.2 mmol), cyanamide (10.2 ml of a 50% w/v solution in water) and concentrated nitric acid (6 ml, 85.3 mmol) to give the desired product as a pale brown solid (12.5 g) m.p. 172-174°. δH (d6 DMSO) 9.75 (1H, br s), 7.52 (4H, br s), 7.45 (1H, t, J 7.8 Hz), 7.35-7.29 (2H, m) and 7.21 (1H, d, , 8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([F:14])[CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:14])[CH:3]=1
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1N
Temperature: 50 °C
Yield: 99.4 %

Procedure:
Methyl 4-amino-2-fluoro-5-methoxybenzoate (100 mg; 0.50 mmol; 1 eq.) was dissolved in MeOH (2 mL). NaOH (0.50 mL; 5 M; 2.51 mmol; 5 eq.) was added and the mixture was heated at 50° C. overnight. The solvents were evaporated. EtOAc was added and the resulting solution was washed with NH4Cl sat. The aqueous phase was extracted with EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording the title compound (92 mg; 99%). HPLC (Method A) Rt 1.92 min (Purity: 96.4%).
Reaction SMILES: [SH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>C(O)(=O)C>[C:13]([S:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:15])[CH3:14]
Reactant: COc1cccc(C(=O)O)c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cccc(C(=O)O)c1SC(C)=O

Procedure:
A solution of 2-mercapto-3-methoxybenzoic acid (14.6 g, 79 mmol), acetic anhydride (9.7 g, 95 mmol) and glacial acetic acid (35 ml) was refluxed 15 minutes, then cooled and poured into dilute hydrochloric acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.[CH3:19][S-:20].[Na+].O>CN(C)C=O>[CH3:17][O:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[O:13][C:14]1[CH:15]=[C:2]([S:20][CH3:19])[CH:3]=[CH:4][C:5]=1[C:6]2=[O:18]
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)c3ccc(SC)cc3oc12

Procedure:
A suspension of 3-chloro-5-methoxyxanthone (5 g.) in dimethylformamide is added to a solution of excess sodium thiomethoxide in dimethylformamide (prepared from methyl mercaptan and sodium hydride). After 1 hour the reaction mixture is poured into water and extracted with ether, giving on evaporation 5-methoxy-3-(methylthio)xanthone, m.p. 201°-203° C. on recrystallisation from methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:16]=[C:15]([Cl:20])[N:14]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: Oc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1Oc1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,6-Difluorophenol (10.0 mmol) is added to a mixture of sodium hydride (240 mg, 10 mmol) in DMF (6 mL). The reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture is cooled to 0° C., and 2,4,6-trichloropyridine is added. The reaction mixture is stirred at 0° C. for 1 hour, then at room temperature for 4 hours. The reaction mixture is partitioned between ethyl acetate and water, the organic layer is washed with 2N NaOH, water, brine, dried, and concentrated. The residue is purified via chromatography eluting with 5:1 hexane:ethyl acetate to afford 2,6-dichloro-4-(2,6-difluorophenoxy)pyridine.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCCCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A solution of 180 mg of 17e in 2 ml of dioxane was mixed with a solution of 120 mg of KOH in 1 ml of water. The mixture was stirred for 1 hr at 50° C. The reaction mixture was cooled and diluted with 10 ml of water, acidified to pH 3 with 1N HCl and the product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to provide 175 mg of 17f as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C(=O)C>[CH2:18]([N:8]([CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:21])[F:20])(=[O:11])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccccc1C(F)(F)F)N(Cc1ccccc1)Cc1ccc(Br)s1
Reaction time: 0.08 h
Yield: 152.5 %

Procedure:
To a stirred solution of N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (0.594 g) in N,N-dimethylacetamide (4 mL) was added NaH (dispersion, ca 55% in oil, 0.039 g) at 0° C. After stirring for 5 min, the ice bath was removed and the mixture was stirred for 50 min. Benzyl bromide (0.28 g) was added and the mixture was stirred overnight at r.t. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane to cyclohexane/ethyl acetate 2:1) to give N-benzyl-N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (0.555 g) as a colorless solid. MS: 490 ([M+H]+)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:15])=O>>[N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([Cl:15])=[O:2])=[CH:5][CH:6]=1)=[C:11]=[S:12]
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(N=C=S)cc1
Yield: 93 %

Procedure:
A mixture of 500 mg (2.79 mmol) of 4-carboxyphenylisothiocyanate and 5 ml of thionyl chloride was refluxed for 6 hours. The reaction mixture was concentrated at reduced pressure and the resulting tan solid was pumped at high vacuum overnight. The solid was triturated with a small amount of hexane and collected by suction filtration to yield 516 mg (93%) of product as an off-white solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4]Br.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][N:17]=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl bromide (1.5 g, 5.26 mmol) and sodium azide (0.68 g, 10.5 mmol) in DMF (20 mL) was stirred at room temperature for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was washed with brine, dried, filtered and evaporated to yield a residue. Purification of the residue by flash chromatography on a silica gel column, using hexane as the eluant, afforded the title compound as an oil (1.2 g, 4.85 mmol, 92%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:29])[CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10].Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:29])[CH:12]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether. (100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.84 g, 98%) as a colorless oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH:18]=[CH2:19]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([C:4]1([CH2:19][CH2:18][C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1CCCCC1=O
Reactant: C=CC(=O)OCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)C1(CCC(=O)OCc2ccccc2)CCCCC1=O
Temperature: 40 °C
Yield: 100.7 %

Procedure:
To a solution of 2-acetylcyclohexanone (9.6 g, 0.068 mol), potassium carbonate (11.3 g, 0.082 mol) and benzyltriethylammonium chloride (0.3 g, 0.0013 mol) in toluene (26 ml), was added benzyl acrylate (16.72 g, 0.103 mol) at room temperature. The mixture was heated at 40° C. for 20 hours, cooled, partitioned between water (200 ml) and toluene (200 ml) and toluene (200 ml) and the layers separated. The aqueous layer was extracted with toluene (2×200 ml), the combined organic extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound as a pale yellow oil, (20.7 g), Rf. 0.2 (silica, hexane/diethyl ether, 2:1). The crude product was used without further purification.
Reaction SMILES: [C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])(=[O:5])[C:2]([CH3:4])=O.Cl.[NH2:15]O.C([O-])(=O)C.[Na+].Cl>O.[Pd].C(O)C.O>[NH2:15][C@H:2]([C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:4]
Reactant: NO
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 17 h
Yield: 99.5 %

Procedure:
N-pyruvyl-L-proline (0.085 g., 0.46 mmoles, 1.0 eq.), hydroxylamine hydrochloride (0.048 g., 0.69 mmoles, 1.5 eq.), sodium acetate (0.056 g., 0.69 mmoles, 1.5 eq.), and 2 mL water and 10 mL ethanol were added to a 25 mL flask. The suspension was heated to reflux for 2 h. The imine was transferred under nitrogen gas with 100 mL ethanol to a 250 mL Parr flask. Palladium hydroxide-on-carbon (0.02 g., 0.18 mmoles, 0.4 eq.) and hydrochloric acid (6 mL, 0.2 moles, 430 eq.) were added and nitrogen was bubbled through for 3 minutes (pH=0.1). The material was hydrogenated for 17 hours as described in Example 1, Part A, to produce a>99.5% diastereomeric L-alanyl-L-proline. Isolation of the product from the reaction mixture can be accomplished by filtering the latter through Celite, adjusting the pH to 4, and concentrating the resultant solution to one-half volume. The solid which forms is collected by filtration, and held under vacuum to remove any residue solvent.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]>>[OH:16][CH2:5][C:38]1([C:29]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=2[OH:27])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]
Reactant: CCCCCN1C(=O)C(c2cc(C(F)(F)F)ccc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(C(F)(F)F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 376 (M−17), 416 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:26]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:28]=3)[C:22](OC)=[O:23])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[C:21]([CH2:22][OH:23])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(CO)cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-[(methylamino)carbonyl]benzoate (intermediate 31) (0.206 g, 0.43 mmol) in THF (5 mL), was added a 1M solution of LiAlH4 in THF (0.65 mL, 1.5 eq.). The reaction was stirred at RT for one night. Water was added and the compound was extracted with AcOEt, dried over sodium sulfate and concentrated in vacuo. After trituration from hot methanol, filtration and dry, the title compound was obtained as a white solid (0.03 g, 15.8%). HRMS calculated for C20H19Cl2N5O3 (M+H)+448.0943. found: 448.0910, Rt: 2.66 min. MP: 223-225° C.