Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:24])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([OH:19])[CH:13]=1)[CH:9]=[C:8]([C:20]([OH:22])=[O:21])[C:7]2=[O:23].[CH3:26][NH2:27]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:27][CH3:26])=[C:4]([F:24])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([OH:19])[CH:13]=1)[CH:9]=[C:8]([C:20]([OH:22])=[O:21])[C:7]2=[O:23]
Reactant: CN
Reactant: O=C(O)c1cn(-c2ccc(F)c(O)c2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(O)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 63 h
Yield: 98.7 %

Procedure:
8-Chloro-6,7-difluoro-1-(4-fluoro-3-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and an aqueous solution (about 40%; 600 mg) of methylamine were added to pyridine (1,500 mg), and the mixture was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (4 ml) was added to the resultant residue, and the mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (305 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([C:11]([O:13]C)=[O:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[OH-].[K+]>CS(C)=O.O>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C(=O)O)Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-methyl-2,3-dihydrobenzofuran-2-carboxylate (Step B, 0.22 g, 1.1 mmol) in 5 mL of dimethylsulfoxide was added potassium hydroxide (0.64 g, 11 mmol) in 0.5 mL of water. After stirring at room temperature for 1 h, the reaction mixture was partitioned between ether (50 mL) and 1 M hydrochloric acid (50 mL). The organic layer was separated and the aqueous layer extracted with ether (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.17 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.79 (d, 1H), 3.60 (d, 1H), 3.18 (d, 1H), 1.67 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[C:1]([C:5]1[CH:6]=[C:7]2[C:9]([C:15](=[O:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][NH:8]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)c1cccc(N)c1
Product: CCOC(=O)c1c[nH]c2cc(C(C)(C)C)ccc2c1=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
A mixture of 3-tert-butylaniline (5.30 g, 35.5 mmol) and diethyl ethoxymethylenemalonate (10.2 g, 47.30 mmol) were heated at 60° C. for 15 min. then 1 hour at 120° C. After the generated ethanol was evaporated in vacuo, the crude oil was added dropwise to boiling diphenylether (150 ml) at 200˜250° C. and the mixture was stirred at 250° C. for 90 min. After cooling to room temperature, the mixture was diluted with hexane (ca. 200 ml) and the precipitate solid was collected to give (4.55 g, 47%) of the title compound as a slightly yellow solid. The compound was used for the next step without the determination of NMR, MS for hard solids.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C(O)CCC>CS(C)=O>[CH2:12]([NH:16][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Solvent: CCCCO
Solvent: CS(C)=O
Product: CCCCNc1nc(N)c2nc[nH]c2n1
Temperature: 170 °C
Yield: 83 %

Procedure:
2-chloroadenine (1) (1.60 g, 9.44 mmol) was divided among three microwave vials (10-20 mL), each containing Butylamine (4 mL), 1-Butanol (10 mL,), and DMSO (1 mL). Each vial was heated to 170° C. for 90 minutes. After reaction completion the solvent was removed by rotary evaporation and the product was purified on flash column eluting 10% methanol in ethylacetate. Evaporation of solvent gave 1.62 g (83%) of 64 as an off white solid. 1H NMR (300 MHz, DMSO) δ 0.877 (t, 3H), 1.29 (m, 2H), 1.45 (m, 2H), 3.17 (t, 2H), 6.49 (s, 2H), 7.61 (s, 1H), 12.1 (s, 1H). LCMS: m/z for C9H14N6++H observed 207.2 at 1.40 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH:16]=[CH:17][CH2:18]Br.[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH:16]=[CH:17][CH2:18][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: BrCC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Product: C(=CCN(c1ccccc1)c1ccccc1)CN(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 39.3 %

Procedure:
A vigorously stirred mixture of diphenylamine (150 g, 0.9 mol), 1,4-dibromobut-2-ene (104 g, 0.49 mol), potassium iodide (8 g, 0.05 mol), tetrabutylammonium bromide (7 g, 0.025 mol), sodium hydroxide (43 g, 1.06 mol) and 150 ml of water is warmed to 60° C. for five hours. The mixture is allowed to cool to room temperature. The solids formed are collected and washed with water. The residue is recrystallized from ethanol to give 69 grams (36% yield) of the title compound as a tan solid melting at 105°-107° C.
Reaction SMILES: Cl[C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:21][S-:22].[Na+]>CN(C=O)C>[CH3:21][S:22][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: CCCc1c(OCc2ccccc2)ccc(C=O)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc(C=O)c1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-3-propyl-4-benzyloxybenzaldehyde (Step C; 0.683 grams) in dry DMF (7 mL) was treated with sodium methanethiolate (0.166 grams). The solution was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between isopropyl acetate and pH 7 buffer. The organic was washed 3 times with water, then dried over magnesium sulfate. Filtration and concentration afforded an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
A mixture of ethyl 7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.636 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture wax filtered and washed water (20 mL) and methanol (5 mL) to obtain a white solid, which after dried in vacuum at 50° C. afforded the title compound (34.6 mg, yield 15%). LC-MS (ESI) m/z: 362 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) 6 (ppm): 3.56 (s, 3H), 4.48-4.49 (d, J=6.0 Hz, 1H), 5.01-5.03 (m, 1H), 6.70-6.71 (m, 1H), 6.81-6.84 (m, 1H), 6.98-7.02 (m, 2H), 7.14-7.26 (m, 5H), 7.66-7.67 (m, 1H), 12.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[C:31]([CH3:45])[O:30][N:29]=1>ClCCl>[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([NH:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([CH:9]4[CH2:13][CH2:12][N:11]([CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:10]4)=[CH:5][CH:6]=3)(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[C:31]([CH3:45])[O:30][N:29]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 70.6 %

Procedure:
To a solution of 2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinamine (150 mg, 0.561 mmol) in dichloromethane (DCM) (4 mL) and pyridine (0.045 mL, 0.561 mmol) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol). The reaction vessel was sealed and heated at 65° C. for 2 hours. Additional 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol) and pyridine (0.045 mL, 0.561 mmol) were added and the reaction mixture was heated for a further 4 hours at 65° C. The reaction mixture was then cooled and separated between DCM (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The sample was purified by flash silica (Si) chromatography (0-25% methanol-dichloromethane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product (211 mg) as a brown gum (approx 71% pure). LCMS (2 min, formic) Rt 0.80 min, m/z (ES+) 533 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].O>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:31]([C:30]2[CH:34]=[CH:35][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)=[O:32])=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc2nccc(Cc3ccc(Br)cc3)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Cc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Reaction time: 15 h
Yield: 8.7 %

Procedure:
6,7-Dimethoxy-4-tri-n-butylstanniophenylmethyl)quinoline (82 mg) obtained in Example 162, commercially available 4-t-butylbenzoyl chloride (31 mg) and a catalytic amount of commercially available bis(triphenylphosphine)palladium(II) chloride were dissolved in chloroform (3 ml), and the admixture was stirred for 15 hours under reflux with heat. After the addition of water, the admixture was extracted with methylene chloride, and the organic layer was washed with brine and saturated aqueous potassium fluoride and then dried with anhydrous sodium sulfate. After removing the solvent by distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to obtain 6 mg of the title compound (yield: 10%).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28])[CH3:30]
Reactant: CCN(CC)CCCOc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCCOc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Yield: 38.8 %

Procedure:
N,N-Diethyl-N-[3-((6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolyl)oxy)propyl]amine (525 mg), iron powder (330 mg), ammonium chloride (660 mg), ethanol (20 ml) and water (5 ml) were stirred together at 80° C. for 80 minutes. After filtration with celite, NH type silica gel was added to the filtrate, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate, followed by ethyl acetate:methanol=3:1) to obtain 190 mg of a brown oil.
Reaction SMILES: C(OC(C=N[C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:18]([F:29])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=O)C.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:29][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:20][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:30]=[CH:31][C:32]([NH:30][CH2:31][CH2:32][OH:33])=[O:33])[CH:9]=2)=[N:16][CH:17]=1
Reactant: NCCO
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1)NCCO

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine, N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and 2-aminoethanol were reacted to prepare 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 13.28 min.; purity: 97.3%; MS (m/e): 413.04 (MH+).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH2:29](O)[CH3:30]>S(=O)(=O)(O)O>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:29][CH3:30])=[O:2]
Reactant: CCO
Reactant: COc1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(OC)cc3)cccc2o1

Procedure:
A mixture of 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-methoxy-phenoxypropane (10.0 g), ethyl alcohol (5 ml) benzene (100 ml) and concentrated sulphuric acid (5 drops) was heated under a Dean and Stark phase separator for 20 hours. The cooled solution was washed with saturated sodium bicarbonate solution and then with water. Removal of the benzene under reduced pressure afforded a solid which was recrystallized from aqueous dioxane to give 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-p-methoxyphenoxypropane, m.p. 135°-136.5° C as white needles.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50](=[N:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=4)=[O:54])[CH3:51])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([C:50](=[N:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=3)=[O:54])[CH3:51])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
3.2 ml of trifluoroacetic acid and 103 μl of trifluoromethanesulfonic acid were added to a solution of 430 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 636 μl of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. An the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was repeatedly washed with diethyl ether by decantation, to give 450 mg of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42](O)=[O:43])[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:79]([CH2:81][NH2:82])[OH:80]>CN(C=O)C>[OH:80][CH2:79][CH2:81][NH:82][C:42]([C:8]1[S:7][C:6]2[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=3[C:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:20]2)[CH2:14][CH2:15]1)=[O:43]
Reactant: NCCO
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCO)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 0.01 mL (0.15 mmol) of ethanol amine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of 2 N NH3 in MeOH/CH2Cl2) yielded 16 mg (76%) of a white solid. MS (electrospray): exact mass calculated for C33H37F4N5O4S2: 707.22; m/z found, 708.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.49 (dd, J=8.41, 2.35 Hz, 1H), 7.15 (dt, J=8.61, 2.54 Hz, 1H), 6.41 (t, J=5.67 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=7.04 Hz, 2H), 3.84 (dd, J=5.28, 4.70 Hz, 2H), 3.70 (t, J=5.67 Hz, 2H), 3.62 (m, 2H), 3.58 (br s, 1H), 3.05 (br m, 2H), 2.97 (t, J=5.67 Hz, 2H), 2.91 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.84 (br d, J=12.32 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37]>O>[NH2:33][C:31](=[O:32])[CH2:30][O:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:20][S:21](=[O:34])(=[O:35])[C:22]=2[CH:28]=1.[Na+:37]
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A suspension of the product of Example 28I (0.099 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.200 mL, 0.199 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.100 g, 85% two steps). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.75 (m, 7 H) 1.31 (m, 5 H) 1.64 (m, 2 H) 2.14 (m, 1 H) 4.45 (m, 2 H) 7.31 (m, 6 H) 8.05 (m, 1 H) 15.42 (m, 1 H). MS (ESI−) m/z 496 (M−H)−.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.[F:14][C:15]1[CH:26]=[CH:25][C:18]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:12]([CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1)[CH:19]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:26][CH:25]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:13]
Reactant: COC(=O)C=Cc1ccc(F)cc1
Reactant: N#CCc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1ccc(F)cc1)C(C#N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95 %

Procedure:
Sodium methoxide (3.0 g, 0.056 mol) is added in one portion to a stirred solution of m-fluorophenylacetonitrile (78.0 g, 0.577 mol) and methyl p-fluorocinnamate (100.0 g, 0.555 mol) in 700 mL of azeotropically dried toluene cooled in an ice bath under a nitrogen atmosphere. The reaction mixture is warmed to room temperature (18° C. to 24° C.) and stirred for five days. The mixture is concentrated under vacuum to yield a brown syrup which is partitioned between diethyl ether and water. The orange ether layer is washed three times with water, once with 1% aqueous hydrochloric acid, again with water and finally with a saturated aqueous sodium chloride solution. After stirring with magnesium sulfate, the filtrate is concentrated on a rotary evaporator using a water aspirator, followed by a vacuum pump at 0.5 mm Hg for eight hours. The title product is obtained in 95% yield (166.7 g) as a pinkish-orange semi-solid identified as an isomeric mixture of esters based on the proton and carbon magnetic resonance, infrared and chemical ionization mass spectra. The ratio of erythro/threo isomers is 62/38, respectively, based on the integrated areas of the CHCN doublets centered at δ4.38 (J=6 Hz) and 4.11 (J=7 Hz) ppm, respectively, in the proton nmr spectrum (CDCl3). Thin layer chromatography on Merck Silica Gel 60 F-254 plates (CH2Cl2) shows two major spots which are not completely resolved. Gas-liquid chromatography (10% SP 2100 programmed at 125°/five minutes to 250°/30 minutes at a rate of 10°/minute) indicates a 93 relative area percent purity for the isomeric esters.
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[F:34])(=O)C1C=CC=CC=1.C(N)CCC>CO>[F:34][C@@H:11]1[C@@H:10]([OH:9])[C@H:14]([CH2:15][OH:16])[O:13][C@@H:12]1[N:25]1[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: Cc1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2F)c(=O)[nH]c1=O
Solvent: CCCCN
Solvent: CO
Product: Cc1cn([C@H]2O[C@@H](CO)[C@H](O)[C@H]2F)c(=O)[nH]c1=O

Procedure:
A solution of 23 (47 mg, 0.1 mmol) and n-butylamine (0.74 g, 1.0 mL, 10 mmol) in methanol (2 mL) was heated at reflux for 3 hours. The solution was evaporated to dryness and triturated with ethyl ether to afford a solid that was filtered, washed with ether and dried to afford 24 (20 mg, 0.077 mmol, 77% as a white solid: mp 188° C. (lit. value: mp 185-187° C., 184-185° C., 187-188° C. for the D-isomer); [α]D20=−93 (c 0.25 MeOH); (lit. value: [α]D20=−111 (c 0.23 MeOH), [α]D20=−122 (c0.023 MeOH)); 1H-NMR (DMSO-d6) δ 11.0 (1H, bs, N—H, 7.58 (1H, s, C—H thymine), 6.09 (1H, dd, J=4.2 and J=15.6, H-1), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J−4.0, J−3.8 and J−52.8, H-2), 4.22 (1H, dt, J−3.8, J−4.0 and J=20.3, H-3), 3.76 (1H, q, J=4.0 and J−9.5, H-4), 3.69-3.57 (2H, m, H-5 and H-5′), 1.77 (3H, s, Thymine CH3).