Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH:9]=[CH2:10])(C)(C)C.Cl>CO>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([C@H:8]([NH2:7])[CH:9]=[CH2:10])[CH:16]=[CH:15][CH:14]=1
Reactant: C=C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1F
Agent: Cl
Solvent: CO
Product: C=C[C@@H](N)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl(1-(3-chloro-2-fluorophenyl)allyl)carbamate: To a solution of crude Intermediate 6B (1.44 g, 4.97 mmol) in MeOH (10 mL) was added HCl (7 mL, 28.0 mmol) and stirred at rt for 1 h. Aliquot LCMS indicates that the starting material had been consumed. The reaction mixture was concentrated and coevaporated with toluene (2×). The crude product was then triturated with ether, filtered and then washed with ether to give (R)-1-(3-chloro-2-fluorophenyl)prop-2-en-1-amine as beige solid. The solid was dissolved in ACN (25 mL) and TEA (3.46 mL, 24.85 mmol) and to this solution was added Boc2O (1.50 mL, 6.46 mmol). The reaction was then stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water followed by brine. The crude product was then purified using silica gel chromatography to give (R)-tert-butyl(1-(3-chloro-2-fluorophenyl)allyl)carbamate (835 mg, 59%) as a white solid. MS (ESI) m/z: 271.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.17 (td, J=7.0, 1.5 Hz, 1H), 7.09-7.03 (m, 1H), 6.03-5.92 (m, 1H), 5.48 (br. s., 1H), 5.26-5.11 (m, 2H), 1.49-1.35 (m, 9H) ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:37])=[N:34][CH:35]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[N:34][CH:35]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1

Procedure:
Neat TFA (0.09 mL, 1.15 mmol) was added to a DCM solution (1 mL) of tert-butyl 3-(5-(2-(((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (44 mg, 0.08 mmol). After 16 h the resulting mixture was concentrated in vacuo, dissolved in DCM and 1 N HCl in diethyl ether was added. The resulting solution was concentrated in vacuo and the DCM/HCl process was repeated 2×. The resulting solid was characterized as the corresponding HCl salt of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ncc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ncc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=420.83.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O[Li].O>C1COCC1.O>[C:12]([O:11][C:9]([NH:8][C:7]([CH3:17])([CH3:16])[C:6]([NH:5][C:4]([CH3:20])([CH3:19])[C:3]([OH:21])=[O:2])=[O:18])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 3 (20.42 g, 67.53 mmol) was dissolved in THF (530 mL) and a solution of LiOH.H2O (8.50 g, 0.203 mol) in de-ionized H2O (270 mL) added in one portion. The reaction mixture was stirred for 4 h 30 min at room temperature. The solvents were evaporated and the residue redissolved in H2O (800 mL). The solution was washed with Et2O (2×500 mL) and acidified to pH 1-2 by addition of concentrated hydrochloric acid. This resulted in the precipitation of a white solid, which was collected by filtration, washed with H2O (4×100 mL) and dried under vacuum overnight (16.18 g, 83%). The compound has been prepared before,4 but as far as we have been able to establish has not been appropriately characterised; 1H NMR (200 MHz, DMSO-d6) δ 12.33 (br s, 1H, COOH), 7.43 (s, 1H, NH(Aib2)), 6.84 (br s, 1H, NH(Aib1)), 1.36 (s, 15H, (CH3)3/CH3), 1.27 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 175.9, 173.7, 154.2, 78.2, 55.8, 55.1, 28.1, 25.0, 24.4; HRMS (m/z): [M+Na]+ calcd. for C13H24N2O5Na, 311.1582. found, 311.1590; Anal. Calcd. for C13H24N2O5: C, 54.15; H, 8.39; N, 9.72. Found: C, 54.5; H, 8.4; N, 9.6.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](O)/[CH:7]=[CH:8]/[C@@H:9]1[C@H:13]2[CH2:14]/[C:15](/O[C@H:12]2[CH2:11][C@H:10]1[OH:24])=[CH:16]/[CH2:17][CH2:18][CH2:19][C:20](O)=O.C(O)C.C(O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC.CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(O)=O>C(Cl)(Cl)Cl.CS(C)=O>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:24][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)O[C@H]2C[C@H]1O
Agent: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCO
Product: CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC

Procedure:
After addition of prostacyclin, human thrombocytes were isolated from platelet-rich plasma and suspended in Tyrode-Hepes buffer of pH 7.4 at 2×108 cells/ml. One ml aliquots of cells were incubated either with a compound according to the invention (0.1 to 100 μM) or a solvent (ethanol and/or dimethyl sulfoxide) at 37° C. for 3 minutes and thereafter with radioactively labelled arachidonic acid (3.5 μM) for 5 minutes. The reaction was stopped and the metabolites of arachidonic acid were extracted by adding methanol, chloroform and formic acid. After evaporation of the chloroform-containing layer to dryness under nitrogen, the residue obtained was resuspended in 50 μl chloroform and analyzed by thin layer chromatography. The distribution of the radioactivity of the different metabolites of arachidonic acid was measured using a TLC linear analyzer. By correlating the percentages of the amount of TXB2 formed under the action of thromboxane synthase in the presence of solvent and in the presence of different concentrations of compounds according to the invention, the following IC50 -values were determined graphically from semilogarithmic diagrams.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.N>C(O)(C)C>[CH3:21][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Cc1cc(N)ccc1O
Agent: N
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Temperature: 25 °C
Yield: 82 %

Procedure:
4-Chloro-5-fluoroquinazoline (6.76 g) was dissolved in iso-propanol (200 ml) and 4-amino-2-methylphenol (5.00 g) was added. The mixture was heated under reflux for 2 hours, causing a yellow solid to precipitate. The mixture was cooled to ambient temperature and the solid was collected by filtration. The solid was dissolved in a boiling mixture of methanol (500 ml) and water (100 ml) to give a brown solution. With vigorous stirring, the solution was basified with aqueous ammonia (0.880, 10 ml), causing a light brown solid to precipitate. The mixture was concentrated in vacuo to such a volume that all of the methanol had been removed, leaving the product as a suspension in aqueous solution. The suspension was cooled; the solid was collected by filtration, triturated with ethyl acetate and dried over P2O5 in a vacuum oven to give 2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol as a light brown solid (8.18 g, 82%); NMR spectrum (DMSO-d6) 3.30 (s, 3H), 6.78 (d, 1H), 7.28 (m, 2H), 7.38 (dd, 1H), 7.57 (d, 1H), 7.78 (m, 1H), 8.43 (s, 1H), 8.88 (d, 1H), 9.22 (s, 1H); Mass spectrum MH+ 270.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[N:42][C:41]=1[CH3:50]>>[CH3:38][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH:43]=[N:42][C:41]=4[CH3:50])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: Cc1ncc2ccccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Product: Cc1ncc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 4-bromo-3-methylisoquinoline were reacted to give 228. LCMS m/z: 503.7 (MH+)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[Cl:27][C:28]1[CH:33]=[C:32](O)[CH:31]=[CH:30][N:29]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:28]1[CH:33]=[C:32]([O:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:31]=[CH:30][N:29]=1
Reactant: OC1CCOCC1
Reactant: Oc1ccnc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cc(OC2CCOCC2)ccn1
Temperature: 55 °C
Yield: 82.9 %

Procedure:
Triphenylphosphine (6.88 g, 26.2 mmol) was added to a mixture of tetrahydro-2H-pyran-4-ol (2.68 g, 26.2 mmol) and 2-chloropyridin-4-ol (2.72 g, 21.00 mmol) in THF (70 mL) under argon. Diisopropyl azodicarboxylate (DIAD) (5.28 mL, 26.9 mmol) was added dropwise over 5 mins and then the mixture was heated to 55° C. overnight. The mixture was cooled to RT and the solvent was removed in vacuo to give an oil. The oil was purified by silica gel chromatography to give crude 2-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyridine as an oil. This material was dissolved in ethyl acetate and then washed with 1N aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyridine (3.71 g, 17.4 mmol, 83% yield) as a light yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>N1CCCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1ccc2cc(I)ccc21
Solvent: C1CCNC1
Product: Cn1ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 50 °C
Yield: 84794 %

Procedure:
To a solution of 5-iodo-1-methyl-1H-indole (200 mg, 0.778 mmol) in pyrrolidine (5 mL) was added ethynyl-trimethyl-silane (92 mg, 0.932 mmol), followed by tetrakis-triphenyl-phosphine palladium (61 mg, 0.233 mmol) after which the reaction mixture was heated at 50° C. for 12 h. The reaction mixture was filtered and the filtrate evaporated in vacuo to obtain a residue, which was purified by column chromatography (ethyl acetate:hexane; 5:95) to give a product (150 g, 84%). 1H NMR (CDCl3, 400 MHz) 0.25 (s, 9H), 3.76 (s, 3H), 6.44 (d, J=3.0 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.30 (dd, J=1.4 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 0.18, 32.8, 90.9, 101.2, 107.0, 109.0, 113.6, 125.3, 125.4, 128.1, 129.6, 136.4.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:23])[CH:3]=1.C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:23])[CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(O)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 120 °C
Yield: 90 %

Procedure:
A mixture of ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (325 mg, 1.005 mmol), acetic acid (3 ml) and concentrated hydrochloric acid (1.5 ml) was heated under reflux for 2 hours in an oil bath at 120° C. After then adding water (30 ml) and cooling with ice, the crystals formed were filtered out and then washed with water, 5% aqueous ethanol solution, and diethyl ether to obtain 267 mg (90%) of the title compound as a pale-yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([NH2:28])[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([NH:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:27]
Reactant: CCN
Reactant: BrCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCNCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 24 h

Procedure:
1Bromo-4-[[2-phenyl-6-(phenylmethylene)-1-cyclohexen-1-yl]oxy]butane is dissolved in toluene, treated with two equivalents of ethyl amine and allowed to stand at room temperature for 1 day, and washed with potassium carbonate solution. Evaporation of the toluene yields the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:16]=[C:17]([CH:21]=2)[C:18]([OH:20])=[O:19])[CH:7]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CC(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:19][C:18](=[O:20])[C:17]2[CH:21]=[C:13]([C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:27][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH:14]=[C:15]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:16]=2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(=O)Nc1cc(C(=O)O)cc(C2=C(c3cc(F)ccc3O)CCC2)c1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)OCc2ccc(F)cc2)cc(C2=C(c3cc(F)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure 5 but using 5-[2-(5-fluoro-2-hydroxyphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid instead of 6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2 carboxylic acid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide and acetone instead of 2-butanone.
Reaction SMILES: [N:1]1([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7](OCC)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[NH3:16]>>[N:1]1([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([NH2:16])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N
Reactant: CCCCC(C(=O)OCC)n1cncn1
Product: CCCCC(C(N)=O)n1cncn1
Reaction time: 8 h

Procedure:
Ethyl α-1,2,4-triazol-1-ylcaproate (3.0 g) was added to liquid ammonia (0.880, 15 ml) and the mixture was shaken well for a few minutes and then left overnight at room temperature. The white solid was filtered and washed with water to give, after recrystallisation from water, the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC(F)(F)F)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:10]1([C:7]2[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: CC(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (3 g, 9.8 mmol) in dichloromethane (30 mL) was added trifluoroethyl acetate (15 mL), and the mixture was stirred at RT for 30 min. LCMS showed the reaction was completed. The reaction mixture was neutralized with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound as a light yellow solid (2 g, 100%), which was directly used in the next step without further purification. MS (ES+) C10H14N4O requires: 206. found: 207 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[N:5]=1)=[O:3]
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 3-acetyl-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.39 g, 4.45 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in AcOEt. The organic solution was washed with half-saturated brine, and the aqueous solution was extracted with AcOEt four times. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (1.46 g, 89% yield) as orange crystals: mp 176-178° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, J=13.2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, br s), 7.84-7.90 (2H, m), 7.96 (1H, s). Anal. Calcd for C17H16F3N3O3: C, 55.59;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71](O)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]>CN(C=O)C.ClCCl>[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71]([NH:14][CH2:13][CH2:12][C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=4)[NH:8][CH:7]=3)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CC(=O)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 1-(4-acetylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.213 g; 0.865 mmol) in DMF (3 mL). Dichloromethane was added to the crude mixture to precipitate 1-(4-acetylphenyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxopyrrolidine-3-carboxamide 0.105 g (29%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]([OH:7])[OH:6])[C@H:3]1[C:8](O)=O.[CH:12]([O:15][C:16]([CH2:18]P1(=O)OC(C)C(C)O1)=[O:17])([CH3:14])[CH3:13]>>[CH3:11][C:2]1([CH3:1])[CH:3]([CH:8]=[CH:18][C:16](=[O:17])[O:15][CH:12]([CH3:14])[CH3:13])[CH:4]1[C:5]([OH:7])=[O:6]
Reactant: CC(C)OC(=O)CP1(=O)OC(C)C(C)O1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)O
Product: CC(C)OC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Using the procedure of Example 6, 0.76 g of the lactone of (1R,cis) 2,2-dimethyl-3-dihydroxymethyl-cyclopropane-carboxylic acid and 1.9 g of 2-isopropoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane were reacted to obtain 1 of (1R,cis,ΔZ) 2,2-dimethyl-3-[3-oxo-3-isopropoxy-1-propenyl]-cyclopropane-carboxylic acid melting at 100° C. and having a specific rotation of [α]D20 =+71°±2° (c=1% in chloroform) and 0.09 g of the corresponding E isomer.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (2.475 g, 5.74 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.687 mL, 5.74 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (29.5 mL, 177.28 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (1.41 g, 61.4%) was isolated. MS m/z 401 (M+H)+