Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[C:14]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)(=[O:32])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCCCCC=CCC=CC/C=C\CCCCC(=O)Cl
Product: CCCCCCCCCCCC=CC=CC=CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The same procedure as in Example 5 but 1.81 g (0.01 mole) of L-tyrosine was used as amino acid and EPA-Cl was replaced by 3.56 g (0.012 mole) of GLA-Cl.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:17][CH2:16]1.C([O-])(=O)C.[Na+]>O>[CH3:11][O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:19][CH2:20]1)=[O:9]
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: COC(=O)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1NCCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A mixture of 0.93 g of methyl anthranilate, 2 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine, 0.88 g of sodium acetate and 5 mL of H2O was stirred for 24 h at reflux. After cooling at room temperature, the mixture was extracted with EtOAc, the organic phase dried on Na2SO4, evaporated to dryness and the residue purified via flash chromatography (CH2Cl2-MeOH 98:2) giving 0.41 g (18%) of the title compound.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]([F:13])[F:12])=[CH:9][CH:10]=1)=O.[C:15]([NH:18][C:19]([NH2:21])=[NH:20])(=[O:17])[CH3:16].O>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:3]2[NH:21][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:20][C:2]=2[CH3:14])=[CH:10][CH:9]=1
Reactant: CC(=O)NC(=N)N
Reactant: CC(Br)C(=O)c1ccc(C(F)F)nc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(F)F)nc2)[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Dissolve 2-bromo-1-[6-(difluoromethyl)-3-pyridyl]propan-1-one (0.500 g, 1.89 mmol) and acetyl guanidine (0.514 g, 5.68 mmol) in DMF (12 mL). Heat the mixture to 50° C., and stir for 16 hours. Pour the mixture into water, and extract with EtOAc (3×20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the resulting residue by flash chromatography (silca gel) eluting with a 40:1 ratio of DCM/MeOH to give the title compound as a white solid (0.229 g, 46% yield). LCMS (m/z) 267 (M+1).
Reaction SMILES: [C:1]1(=[CH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:24])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.C(C(CC)=C[C@H]1CC[C@H](NC(=O)CC2C=CC(O)=C(OC)C=2)CC1)C>>[CH:1]1([CH2:5][C@H:6]2[CH2:7][CH2:8][C@H:9]([NH:12][C:13](=[O:24])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](C=C3CCC3)CC2)ccc1O
Agent: CCC(=C[C@H]1CC[C@H](NC(=O)Cc2ccc(O)c(OC)c2)CC1)CC
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](CC3CCC3)CC2)ccc1O

Procedure:
The above desired compound was prepared in a similar manner of Example 92 using the compound of Example 91 by which the compound of Example 90 in Example 92 was replaced.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>C(OCCCC)CCC>[C:11]1([C:2]2[O:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1coc(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: COC(=O)c1coc(-c2ccccc2)c1
Yield: 85 %

Procedure:
50 mmol of methyl 2-chlorofuran-4-carboxylate were heated with 52 mmol of phenylboronic acid, 50 mmol of potassium carbonate, 25 mmol of lithium chloride and 0.25 mmol of trans-di-μ-acetato-bis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium (1 mol %) in 150 ml of dibutylether at 80° C. for 8 hours. Aqueous work-up, filtration through a short silica gel column and distilling off the solvent leaves methyl 2-phenylfuran-4-carboxylate as a colorless residue. Yield: 85%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)([O:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:13][CH2:12][CH2:11][O:10][C@:8]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN2C(=O)c3ccccc3C2=O)c2cccc(Cl)c2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN)c2cccc(Cl)c2)C1
Temperature: 100 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)piperidine-1-carboxylate (0.6792 g, 1.32 mmol) and hydrazine monohydrate (2.350 g) in ethanol (20 mL) was heated at 100° C. for 19 h and then cooled to rt. The precipitates were filtered off and washed with CH2Cl2. After the filtrate was evaporated under reduced pressure, the crude (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate (0.410 g, 81%) was used in the next step without further purification. MS ESI +ve m/z 385 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[OH:6].[H][H].[ClH:16]>O>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:6])[OH:7].[ClH:16]
Reactant: [H][H]
Reactant: NCCCP(=O)(O)c1ccccc1
Agent: Cl
Solvent: O
Product: NCCCP(=O)(O)C1CCCCC1

Procedure:
A mixture of 1.5 g of 3-aminopropyl(phenyl)phosphinic acid in 10 ml of water and 7.9 ml of 1N hydrochloric acid is treated with hydrogen at 25° in the presence of 0.2 g of Nishimura-catalyst (Rh/PtO2). After 1.2 hours hydrogen up-take stops. The reaction mixture is filtered and the filtrate evaporated to dryness. The residue is recrystallized frommethanol/propylenoxide to give 1.2 g of 3-aminopropyl(cyclohexyl)phosphinicacid ×0,4 mol hydrochloric acid as a white solid, m.p. 202°-203°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCn1cc(C=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCn1cc(C=C[N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1-Ethyl-1H-indole-3-carbaldehyde (I-38b: 5.2 g, 29.885 mmol), nitromethane (46.81 mL, 866.66 mmol) and ammonium acetate (1.17 g, 15.241 mmol) were taken in a reaction flask. The flask was refluxed for 16 hours under nitrogen atmosphere. The reaction was monitored by TLC (25% ethylacetate in hexane). The reaction mixture was cooled to room temperature and the reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford 4.8 g of the product (75% yield).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:26])[CH:22]([CH2:23][CH2:24][OH:25])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1>N1C=CC=CC=1>[CH3:12][C:13]1([CH3:26])[CH:22]([CH2:23][CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)Oc2ccccc2CC1CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
38 g (0.2 mol) of 4-toluenesulfonyl chloride are added at room temperature, while stirring, to a solution of 37.1 g (0.18 mol) of 2,2-dimethyl-3-(2-hydroxyethyl)-chroman in 150 ml of pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The mixture is then stirred for 4 hours at room temperature. The reaction mixture is then poured onto ice-water and extracted with diethyl ether. The combined ethereal phases are washed three times using 150 ml of citric acid solution (5%) each time and three times using 150 ml of water each time, then dried over sodium sulfate and concentrated by evaporation, yielding 59.1 g (89% of the theoretical yield) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in the form of a yellow oil which is further used in that form.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:16])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[S:26])[NH2:16]
Reactant: COCCCCCCCCCCCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 127.3 %

Procedure:
To the title product from Example 12 (1.0 g, 5 mmol) in 70 mL of anhydrous tetrahydrofuran was added 2,4-bis (4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide [Lawesson's Reagent] (1.0 g, 2 mmol). After stirring at room temperature for 1 day, the solvent was removed by rotary evaporator and the resulting residue waspurified by chromatography on silica gel using 30-70 ethyl acetate-hexane as eluant to give the title compound (625 mg) as a white solid, m.p. 86.8°-89.2° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [OH-].[Na+:2].[NH:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[N:6][N:5]=[N:4]1.C(OCC)C>CO>[NH:6]1[C:7]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([O-:15])=[O:14])=[N:3][N:4]=[N:5]1.[Na+:2].[Na+:2].[NH:6]1[C:7]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([O-:15])=[O:14])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)C(=O)Nc1cccc(-c2nnn[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: O=C([O-])C(=O)Nc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sodium hydroxide (1.72 g; 43 mmol) was dissolved in methanol (100 ml), 3-(1H-tetrazol-5-yl)oxanilic acid (5 g; 21.5 mmol) was added thereto and the mixture was stirred for 1 hour at room temperature. The reaction solution was poured into 300 ml of ethyl ether at room temperature with stirring, the precipitated crystals were filtered off and were dried at 40° C. in vacuo in the presence of phosphorous pentoxide to obtain 5 g (yield 85%) of disodium 3-(1H-tetrazol-5-yl)oxanilate. Decomposition point: not less than 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1.[CH3:26][NH:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:27]([CH3:28])[CH3:26])=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1
Reactant: O=C(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1 dram vial was added 4-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-benzoyl chloride (300 mL, 0.3 mmol) as a 0.1M solution in Dichloromethane, Dimethyl-amine (27 mg, 0.6 mmol) and N,N-Diisopropylethylamine (77.4 mg, 0.6 mmol). The reaction was stirred at room temperature for 30 min and then placed directly on silica and purified using a gradient of Hexane to Ethyl Acetate 0-50% over 10 CV. The relevant fractions were combined and dried in vacuo to give 108.6 mg (92%) of an off white solid; MS (ES): 394 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J=7.8 Hz; 1.7 Hz 1H), 7.73-7.58 (m, 3H), 7.45-7.35 (m, 5H), 3.00 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.[CH:18]1(N=C=NC2CCCCC2)CCCCC1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1cc(Br)ccc1NC(=O)C1(C(=O)O)CC1
Solvent: CO
Product: COC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1

Procedure:
A 4.00 gram (0.01 mole) portion of 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylic acid prepared in Example VIII (Compound 111) was reacted in sequence with 80 milliliters of methanol (excess as solvent) and 2.77 grams (0.01 mole) of 1,3-dicyclohexylcarbodiimide, employing a 16-hour reaction period, in a manner similar to that described in Example XL to give 1.54 grams (0.005 mole) of methyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate as a white powder having a melting point of 106° C.-108° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH3:12])[CH:5]=1.CO.[OH-].[Na+].Cl>O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13]([C@@H:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:24])=[O:2])[CH3:12])=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Oc1cccc(C(=O)O)c1)C(=O)Nc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Heat a suspension of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester (0.42 g, 1.30 mmol) in a 1:1 mixture of MeOH:water (10 mL) to 50° C. and add sodium hydroxide (1.0 mL, 2.5 mmol) as a 10% aqueous solution. Stir the mixture at 50° C. for 1 h during which time all of the solids dissolve. Cool the reaction mixture to room temperature and adjust the pH of the mixture to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. Dilute the mixture with water and extract with methylene chloride. Dry the combined organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.38 g of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid as a foam.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5].CC#[N:12]>>[NH2:12][CH2:9][CH:7]1[CH2:8][CH2:6][CH2:4][N:3]1[CH2:2][CH3:1].[CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5]
Reactant: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCC1CN
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A stock solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.08 M) and DIEA (1.19 M) in CH3CN was prepared and 0.5 mL (containing 69 mg/79 μL, 0.542 mmol amine and 77 mg/104 μL, 0.596 mmol DIEA) was dispensed into each of the 40 mL from the second step. The vials were then shaken on the J-KEM block at about 80° C. for about 15 h. The solutions were cooled to room temperature and taken to dryness in vacuo. The residues were then extracted with ethyl acetate and the extract was washed with brine. The aqueous layers were extracted a second time with ethyl acetate and the combined organic layers were dried over Na2SO4 and passed through a plug of Celite™ into barcoded, tared vials. After concentration in vacuo, masses were determined and yields were calculated, and the compounds were sampled for LC/MS analysis.
Reaction SMILES: [F:1][CH:2]1[C:6](=[O:7])[O:5][CH:4]2[CH2:8][CH2:9][CH:10]([CH:11]=[CH:12][CH:13]([OH:20])[CH:14]([F:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]12.[O:21]1[C:25](=O)[CH:24]=[C:23]2[CH:27]=[CH:28]C=C12>>[F:1][CH:2]1[C:6](=[O:7])[O:5][CH:4]2[CH2:8][CH2:9][CH:10]([CH:11]=[CH:12][CH:13]([O:20][CH:25]3[CH2:24][CH2:23][CH2:27][CH2:28][O:21]3)[CH:14]([F:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]12
Reactant: CCCCC(F)C(O)C=CC1CCC2OC(=O)C(F)C12
Reactant: O=C1C=C2C=CC=C2O1
Product: CCCCC(F)C(C=CC1CCC2OC(=O)C(F)C12)OC1CCCCO1

Procedure:
By the procedure of Example 5 [3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one was converted to [3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4[3-(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[CH2:8]2)=[O:4].O.[OH-].[Li+].[Li+].COC1C=C(OC)C=CC=1CN1CC2C(=CC=C(C([O-])=O)C=2)C1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C1COCC1.CO.O>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:14][N:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:4])[CH:6]=2)[CH2:10]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1OC)C2
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(CN2Cc3ccc(C(=O)[O-])cc3C2)c(OC)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2Cc3ccc(C(=O)N4CCOCC4)cc3C2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (4.65 g; 14.2 mmol) and lithium hydroxide monohydrate (660 mg; 1.1 equiv.) in 4:1:1 THF-MeOH—H2O (60 ml) was stirred at room temperature overnight. A further 170 mg of base were added and stirring continued for 7 hours. The reaction was evaporated then re-evaporated with MeOH/toluene (×2). A mixture of the crude 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid lithium salt (1.5 g; 4.7 mmol), morpholine (820 μl; 2 equiv.), EDAC (1.1 g; 1.2 equiv.) and HOBt (760 mg; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, the EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (2% then 5% MeOH/DCM as eluant) gave 1.1 g of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindol-5-yl]-morpholin-4-yl-methanone as a red/brown gum. 1H NMR (DMSO-d6) 7.30-7.18 (4H, m), 6.56 (1H, d), 6.52 (1H, dd), 3.85 (4H, s), 3.78 (5H, m), 3.73 (3H, s).
Reaction SMILES: C([BH-](CC)CC)C.[Li+].C1COCC1.[CH3:14][CH2:15][O:16][C:17]([C@@H:19]1[CH2:23][CH2:22][C:21](=O)[N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18].CCN(C(C)C)C(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[CH3:14][CH2:15][O:16][C:17]([C@@H:19]1[CH2:23][CH:22]=[CH:21][N:20]1[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[O:18]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
At −50° C. a solution of lithium triethylborohydride in THF (1.0 M, 107 mL, 1.07 eq) is added dropwise to a solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (100 mmol, 1.0 eq) in toluene (170 mL). After 45 min DIPEA (450 mmol, 4.5 eq) and powdered DMAP (1.31 mmol) are added slowly at −50° C. The mixture is treated with trifluoroacetic anhydride (120 mmol, 1.20 eq) while keeping the internal temperature below −45° C., allowed to reach RT within 90 min and stirred for additional 17 h. At 0° C. water (250 mL) is added slowly and the layers are separated. The organic layer is washed with ice-cold water (3×250 mL) and concentrated in vacuo to give the desired product as an orange liquid. LC-MS (acidic): tR=0.93 min; [M+H]+=242.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Agent: [Pd]
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from [5-(isobutyl-methyl-amino)-4-methyl-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C35) (1.48 g, 4.39 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a white solid (1.08 g, 80%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[F:14][C:15]1[C:20]([C:21](Cl)=O)=[C:19]([F:24])[C:18]([F:25])=[C:17]([F:26])[C:16]=1[F:27].[OH-].[K+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:13][C:21]([C:20]3[C:19]([F:24])=[C:18]([F:25])[C:17]([F:26])=[C:16]([F:27])[C:15]=3[F:14])=[CH:11][C:10](=[O:12])[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: C=CCc1cccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: C=CCc1cccc2c(=O)cc(-c3c(F)c(F)c(F)c(F)c3F)oc12
Temperature: 80 °C

Procedure:
A mixture of 19 g (mmol) 3'-allyl-2'-hydroxyacetophenone, 25 g (110 mmol) pentafluorobenzoyl chloride, 36 g (110 mmol) tetra-n-butylammonium bisulfate, 750 ml 10% aqueous KOH, and 750 ml benzene was heated at 80° C. for 6 hours, cooled and the phases separated. The organic phase was concentrated in vacuo and flash chromatographed over 100 g silica gel with success, 2 liter portions of hexane, diethyl ether and CHCl3. The diethyl ether eluate was evaporated in vacuo. The residue was dissolved in 250 ml methanol and cooled at -20° C. for 24 hours. The mixture was filtered and yielded 8-allyl-2-(pentafluorophenyl)-4H-benzopyran-4-one as 10.141 g (27%) solid: TLC Rf 0.35 in 49:25:25:1 CHCl3 :toluene:hexane:methanol.