Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[N:12]1([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C(=O)O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCOCC2)n1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (6.8 ml) was added morpholine (0.377 ml, 4.31 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 min when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred overnight. The crude reaction mixture was diluted with dichloromethane (10 ml) and methanol was added until a clear solution was observed. The mixture was loaded onto an aminopropyl cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane followed by methanol and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in sodium hydroxide solution (2M, 25 ml) and washed with dichloromethane (2×25 ml). The aqueous layer was acidified to pH7 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (129 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:24]=[C:25]([N+:27]([O-])=O)[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:24][CH:25]([NH2:27])[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=Cc1c[nH]c2c(OCc3ccccc3)cccc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(N)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (LAH, 24 g, 600 mmol) is added portionwise to dry tetrahydrofuran (1800 mL) at −5° C. to 5° C. A solution of the nitroolefin from above (61.6 g, 200 mmol) in tetrahydrofuran (1200 mL) is added to the LAH solution over 30 minutes while maintaining the temperature at −5° C. to 5° C. When the addition is complete, the reaction mixture is allowed to warm to 30° C. over 1.5 hours and is stirred at 25° C. to 35° C. for 2 hours. To complete the reaction, the mixture is heated to 60° C. for 30 minutes. After cooling to 0° C., the reaction is quenched by the sequential addition of water (30 mL), 5 N NaOH (30 mL), and water (100 mL) and the resulting mixture is stirred over the weekend. The aluminum salts are removed by filtration and the cake rinsed with tetrahydrofuran (500 mL). The combined filtrates are concentrated to give 47.6 g (55% purity corrected yield, approx 65% pure) of 7-benzyloxy-3-(2-aminopropyl)-1H-indole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Yield: 67.9 %

Procedure:
To a 150-mL sealed tube containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.72 g, 2.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.33 g, 2.2 mmol) in ethanol (20 mL) was added triethylamine (1.0 mL, 2.2 mmol). The mixture was heated with a heat gun until all solid material was dissolved, then mixture was allowed to cool, at which time a precipitate was formed. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a pale yellow solid (0.59 g, 68%). MS (ES+): 435.0 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 62 h
Yield: 75.6 %

Procedure:
To a solution of 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylic acid (68 mg) in dichloromethane (1.8 mL) were successively added methanesulfonamide (19 mg), 4-dimethylaminopyridine (49 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg). This mixture was stirred for 62 hours at room temperature. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (62 mg). 1H-NMR (DMSO-d6) δ ppm: 0.79 (3H, t, J=7.3 Hz), 1.19 (3H, d, J=6.9 Hz), 1.45-1.75 (2H, m), 2.80-2.95 (1H, m), 3.34 (3H, s), 3.83 (3H, s), 5.58 (2H, s), 6.32 (1H, s), 6.65-6.80 (1H, m), 7.20 (1H, s), 7.53 (1H, s), 7.85-7.95 (2H, m), 11.41 (1H, br s). ESI-MS (m/z): 450, 452 (M+H)+
Reaction SMILES: [CH3:1][O:2][N:3]([CH:14]1[C:30](=[O:31])[N:16]2[C:17]([C:22]([O:24]CC(Cl)(Cl)Cl)=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12)[C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.C(O)(=O)C.CN(C)C=O.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][N:3]([CH:14]1[C:30](=[O:31])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12)[C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CON(C(=O)COc1ccccc1)C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C(=O)COc1ccccc1)C1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
2,2,2-Trichloroethyl 7-(N-methoxy-2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate (490 mg) is dissolved in a mixture of methylene chloride (15 ml), acetic acid (4 ml) and dimethylformamide (4 ml), and under ice-cooling, zinc dust (400 mg) is added. The mixture is stirred at room temperature for 1.5 hours, at the end of which time acetic acid (10 ml), dimethylformamide (2 ml) and zinc dust (300 mg) are further added and stirred for another 1.5 hours. The reaction mixture is diluted with ethyl acetate and filtered. The filtrate is washed with 0.5 N-HCl and aqueous sodium chloride in that order, dried over magnesium sulfate and concentrated. The resultant crude crystals are washed with ether-ethyl acetate to give 7-(N-methoxy-2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (141 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH3:15][NH:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N+:16]([O-:17])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CNO
Reactant: O=C(Cn1ccnc1)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[N+]([O-])=C(Cn1ccnc1)c1cccs1
Temperature: 50 °C
Reaction time: 96 h
Yield: 89.7 %

Procedure:
Under a nitrogen, a mixture of 22.00 g (0.114 mol) of 2-(1H-imidazol-1-yl)-1-(2-thienyl)ethanone (3), 11.49 g (0.138 mol) of N-methylhydroxylamine hydrochloride, and 22.55 g (0.275 mol) of sodium acetate in 250 ml of ethanol is heated to 50° C. and stirred for 4 days. The reaction mixture is filtered while hot and the filtrate concentrated in vacuo. Crystallization from ethanol gives 22.62 g (89%) of compound 4, melting point 162°-164° C. Anal. Calcd. for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99. Found: C, 54.16; H, 5.06; N, 18.86.
Reaction SMILES: [CH2:1]([CH:8]([C:13](O)(O)[C:14]([F:17])([F:16])[F:15])[C:9]([O:11]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:23]([C:26]1[CH:27]=[N:28][C:29]([NH:32][NH2:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH3:21]>CO.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:11])[N:32]([C:29]2[N:28]=[CH:27][C:26]([S:23]([N:22]([CH2:20][CH3:21])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:25])=[O:24])=[CH:31][CH:30]=2)[NH:33][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)C(O)(O)C(F)(F)F
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C(F)(F)F)c(Cc3ccccc3)c2=O)nc1
Temperature: 90 °C
Yield: 12.4 %

Procedure:
A mixture of 1 g (3.59 mmol) of methyl 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate, 1.05 g (3.59 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 1 g of 4 Å molecular sieves in 8 mL of MeOH is heated for 12 hours at 90° C. At room temperature, the reaction medium is taken up in 30 mL of toluene, and refluxed for 12 hours in Dean-Stark apparatus. The reaction medium is then filtered and concentrated under reduced pressure, and the residue obtained is then taken up in 50 mL of DCM, washed with 1N HCl solution (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The solid thus obtained is recrystallized from EtOH. 224 mg of 6-(4-benzyl-5-oxo-3-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-sulfonamide are obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].[C:12](=S)=[S:13]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:12]([SH:13])=[N:9][N:8]=2)[N:7]=1
Reactant: S=C=S
Reactant: NNc1ccc(Cl)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a suspension of (6-chloro-pyridazin-3-yl)-hydrazine (1 g, 6.917 mmol) in ethanol (12 mL) was added a solution of KOH (390 mg, 6.917 mmol) in water (12 mL) dropwise. Carbon disulfide (0.84 mL, 13.84 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 48 h. Another 0.84 mL CS2 and 390 mg KOH were added, and the reaction mixture was further stirred for 24 h, before concentrating in vacuo. The residue was treated with 1 M aqueous NaOH and filtered. The filtrate was acidified to pH 3 with 1 N aqueous HCl, and the precipitate was filtered off. The resulting filtrate was extracted with ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, concentrated and dried in vacuo to provide 485 mg of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (38% yield): 1H NMR (DMSO-d6): δ 7.48 (d, 1H), 8.24 (d, 1H); MS (m/z) 187 [M+H+]+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[C:15]([I:16])=[CH:14][N:13]=[CH:12][N:11]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[I:16][C:15]1[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ncncc1I
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)COc1ncncc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.672 mL, 9.36 mmol) in THF (18.08 mL) was added, portion wise, at 0° C., NaH (0.424 g, 10.61 mmol). The reaction mixture was stirred at 0° C. for 30 min. Then 4-chloro-5-iodopyrimidine (1.5 g, 6.24 mmol) was added and the reaction mixture was refluxed for about 1 hr. The reaction mixture was allowed to cool to room temperature, then a saturated aqueous solution of NH4Cl was added. The mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (2×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a yellow solid. ESI MS (M+H)+=304.7.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:29]1[CH2:53][O:52][C:31]2([CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:47]([CH2:48][CH2:49][C@:32]23[CH3:33])[C@:45]2([CH3:46])[C@:40]([OH:51])([CH2:41][C:42](=O)[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[O:30]1>>[CH2:29]1[CH2:53][O:52][C:31]2([CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:47]([CH2:48][CH2:49][C@:32]23[CH3:33])[C@:45]2([CH3:46])[C@:40]([OH:51])([CH2:41][C:42](=[CH2:1])[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[O:30]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC21OCCO1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CCC45OCCO5)[C@@H]3CC[C@@]2(O)C1
Yield: 98 %

Procedure:
Following the procedure described above for the preparation 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 8) and starting from 17,17-(ethylendioxy)-5α-hydroxyandrostane-3-one, 17,17-(ethylendioxy)-3-methylene-androstane-5α-ol was obtained in 98% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (m, 1H), 4.50 (m, 1H), 3.78 (m, 4H), 3.42 (s, 1H), 2.36-1.03 (m, 21H), 0.93 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]1[CH2:26][CH2:25][C@:24]([CH3:31])([C:27]([O:29]C)=[O:28])[C:23]1([CH3:33])[CH3:32])(=[O:5])[NH2:4]>C(O)C.C(OCC)(=O)C>[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]1[CH2:26][CH2:25][C@:24]([CH3:31])([C:27]([OH:29])=[O:28])[C:23]1([CH3:33])[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)C(=O)O
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A 4.5 M aqueous potassium hydroxide (192 μl, 0.866 mmol) solution was added dropwise to a solution of (1S,3R)-methyl 3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethyl-cyclopentanecarboxylate (182 mg, 0.433 mmol) in ethanol (2885 μl). The reaction was heated at 75° C. for 24 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure, yielding an oil. The oil was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1.0 N HCl and was extracted with ethyl acetate (3×). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding (1S,3R)-3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylic acid (152.8 mg, 0.376 mmol, 87% yield) as a yellow solid. LC/MS found [M+H]+=407.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:5]([F:13])=[CH:4][C:3]=1[F:14].[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:17][CH:16]=[CH2:15])[CH2:9][N+:10]([O-:12])=[O:11])[C:5]([F:13])=[CH:4][C:3]=1[F:14]
Reactant: C=CC[Mg]Cl
Reactant: O=[N+]([O-])/C=C/c1cc(F)c(F)cc1F
Solvent: C1CCOC1
Product: C=CCC(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Temperature: -20 °C
Yield: 88.9 %

Procedure:
To a cooled (−40° C.) solution of (E)-1,2,4-trifluoro-5-(2-nitrovinyl)benzene (250 g, 1.23 mol) in THF (490 mL), allylmagnesium chloride (800 mL, 1.6 mol, 2 M in THF) was added at such a rate as to maintain the internal temperature below −20° C. The solution was stirred at −20° C. for thirty minutes and then carefully quenched by the addition of 2M HCl (1 L), while maintaining the temperature below −5° C. Methyl t-butyl ether (500 mL) was added, and the biphasic solution was allowed to warm to >10° C. The layers were separated, and the organic was washed with H2O (1×500 mL), saturated aqueous NaHCO3 (1×500 mL), and brine (1×500 mL). The organic layer was concentrated to dryness, and the crude product was filtered through a 450 g plug of silica gel (eluting with 5% ethyl acetate in hexane at a flow rate of 90 mL/min). The first 100 mL of eluent was discarded, and the subsequent 2 L were collected and concentrated to dryness to give the title compound as an oil (268 g, 89%). 1H NMR (300 MHz, CDCl3) δ ppm 7.05-6.90 (m, 2H), 5.65 (dddd, J=7.5, 7.5, 9.5, and 16.6, Hz, 1H), 5.12-5.06 (m, 2H), 4.63 (d, J=7.5 Hz, 2H), 3.75 (p, J=7.5 Hz, 1H), and 2.48 (t, J=7.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:56][O:57][CH:58]1[CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:60]4[CH2:61][CH:58]([O:57][CH3:56])[CH2:59]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC1CNC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a DMF (0.3 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 30 mg, 0.092 mmol) and HATU (42 mg, 0.11 mmol) was added 3-methoxyazetidine 2,2,2-trifluoroacetate (22 mg, 0.11 mmol), followed by dropwise addition of DIEA (0.048 mL, 0.27 mmol). After stirring for 30 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (25 mg, 69%). LCMS (apci) m/z=397.1 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([Se]C2C=CC=CC=2)[CH2:8][N:7]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:5].N1C=CC=CC=1.OO>ClCCl>[CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:5]
Reactant: CCOC(=O)[C@H]1C[C@H]([Se]c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: OO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C=CCN1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 7.35 g (0.016 mol) (2R,4S)-4-phenylselanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 80 ml dichloromethane were added at 0-5° C. 1.93 ml (0.024 mol) pyridine and 4.6 ml 30% hydrogen peroxide and stirring was continued for 1.5 hours. The mixture was extracted with 5% aqueous HCl, saturated aqueous sodium carbonate, and water. Chromatography on silicagel with ethylacetate/hexane 1:5 yielded 2.99 g (77%) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as colorless oil. MS m/e (%): 186 (11), 168 (48), 140 (32), 112 (100), 68 (85), 57 (58). [α]D=+242° (c=1% in chloroform).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38](C)[CH3:39])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(O[C:45]([CH2:47][CH2:48]C1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.C1(N)CCC1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:38][CH:39]3[CH2:48][CH2:47][CH2:45]3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: NC1CCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CCC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and cyclobutylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][N:14]=[CH:13]2)(=[O:9])=[O:8].CCCCP(CCCC)CCCC.O[C@H:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]2)[CH3:48]>C1COCC1>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]([C@@H:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]3[C:58]=1[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[CH2:55][CH2:54]3)[CH3:48])[N:14]=[CH:13]2)(=[O:8])=[O:9]
Reactant: C[C@H](O)c1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cn[nH]c3cc2C)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cnn([C@H](C)c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)c3cc2C)c(OC)c1
Reaction time: 0.83 h

Procedure:
To a 100 mL RB flask containing THF (4381 μl) at 0° C. was added sequentially N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-6-methyl-1H-indazole-5-sulfonamide (4-5, 200 mg, 0.438 mmol), TRI-N-BUTYLPHOSPHINE (216 μl, 0.876 mmol), DTBAD (202 mg, 0.876 mmol) and (S)-tert-butyl 8-(1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (243 mg, 0.876 mmol). After 50 min at 0° C., concentrated in vacuo. Purified by normal-phase ISCO (40 g column, 0-40% EtOAc:Hex) to give an off-white solid
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][SiH:4]([CH3:10])[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[CH2:13]([OH:17])[CH2:14][CH:15]=[CH2:16]>>[CH3:10][Si:4]([CH2:16][CH2:15][CH2:14][CH2:13][OH:17])([O:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[O:3][Si:2]([CH3:11])([CH3:12])[CH3:1]
Reactant: C=CCCO
Reactant: C[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Product: C[Si](C)(C)O[Si](C)(CCCCO)O[Si](C)(C)C
Yield: 83 %

Procedure:
The reaction of Example 2a was repeated using 1,1,1,3,5,5,5-heptamethyl trisiloxane instead of 1,1,3,3,3-pentamethyl disiloxane and 3-butenol instead of allylalcohol. After distillation at 78° C./0.1×102 Pa, 83% of a clear liquid product was obtained.