Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[CH3:28][N:29]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30]1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Reactant: Cn1cc(B(O)O)cn1
Product: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN(C(=O)C(F)(F)F)[C@H]2C3)cn1
Yield: 32 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and 1-methyl-pyrazol-4-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 32% of theory; LC (method 1): tR=3.88 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(=O)CCC=C1>C1CCCCC1>[C:11]1([C@H:9]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:17]3([CH2:22][CH2:21][CH:20]=[CH:27]3)[O:10]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O[C@@H](c1ccccc1)[C@@H](O)c1ccccc1
Agent: O=C1C=CCC1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Product: C1=CC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Yield: 676.8 %

Procedure:
A solution of (S,S)-hydrobenzoin (10.0 g, 46.7 mmol), pyridinium p-toluene sulfonate (1.4 g, 5.6 mmol), 2-cyclopentene-1-one (20 mL, 238.7 mmol) and cyclohexane (200 mL) was heated under reflux for 4 h with a Dean-Stark trap to remove water formed during the reaction. The mixture was then cooled in an ice bath for 20 min, and the insolubles were filtered off through filter aid. The resulting solution was washed with a 10% aqueous potassium bicarbonate solution (2×25 mL) and water (2×25 mL), and then dried over anhydrous sodium sulfate. The dried solution was passed through a pad of silica gel 60 (26 g of 230–400 mesh). The pad was further eluted with additional hexanes (475 mL). The resulting solution was concentrated in vacuo to afford 2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]non-6-ene (10.55 g, 81%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1N=C[N:12]([C:15](N2C=NC=C2)=[S:16])C=1.N>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:15](=[S:16])[NH2:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
To a suspension of 1-isopropylpiperazine (1.5 g, 11.70 mmol) in THF (24 mL) was added 1,1-thiocarbonyldiimidazole (2.398 g, 13.45 mmol). The reaction mixture was stirred at ambient temperature for about 8 h. Upon addition of the 1,1-thiocarbonyldiimidazole, the reaction mixture slightly warmed. A solution of ammonia (7.0 M in MeOH, 20 mL) was added and the reaction mixture was stirred overnight at ambient temperature. Additional ammonia (7.0 M in MeOH, 20 mL) was added and the reaction mixture was stirred overnight at about 40° C. The reaction mixture was cooled to ambient temperature and solvent was removed under reduced pressure. The residue was triturated with Et2O (15 mL) and filtered to give the title compound (2.5 g, 97%) as a yellow solid: LC/MS (Table 1, Method a) Rt=0.74 min; MS m/z: 188.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:37][C:36]6([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]6)[CH2:35][N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[C:67](Cl)(=[O:69])[CH3:68].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:67]([N:40]1[CH2:39][CH2:38][C:36]2([CH2:35][N:34]([C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])[CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:2]([CH3:59])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[CH2:37]2)[CH2:42][CH2:41]1)(=[O:69])[CH3:68]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(C)=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec-3-yl}-1H-imidazol-4-yl]-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 20) (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was added triethylamine (0.016 mL, 0.12 mmol) followed by acetyl chloride (0.01 mL, 0.14 mmol) and the reaction stirred at room temperature for 1 h. The reaction is concentrated in vacuo and dissolved in methanol (0.7 mL) to which was added potassium carbonate (30 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and partitioned between CH2Cl2 and water (3 mL each) and the aqueous layer extracted with CH2Cl2 (3 mL) and the organic layers combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (18 mg, 90% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.88 (m, 10H) 7.32 (br. s., 2H) 5.05-5.23 (m, 2H) 4.03-4.34 (m, 2H) 3.71-4.03 (m, 3H) 3.56-3.71 (m, 8H) 3.34-3.56 (m, 2H) 2.14-2.46 (m, 4H) 1.89-2.14 (m, 6H) 1.46-1.83 (m, 4H) 1.19-1.32 (m, 2H) 0.78-1.07 (m, 14H). HRMS for C46H60N9O7 (M+H)+ calc: 850.4616. found: 850.4617. Purity (LC-MS): 94%.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:24])[C:8](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:9]([C:8]1[C:7](=[O:24])[C:3]2[O:4][CH:5]=[CH:6][C:2]=2[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:12]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c2ccoc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
A suspension of 1-(3-bromofuran-2-yl)-2-{[3-(trifluoromethyl)phenyl]hydrazono}butane-1,3-dione (1.59 g) and potassium carbonate (0.817 g) in DMF (10 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (683 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[NH2:13])=[O:7].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:31]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:10]3[N:11]=[CH:12][C:8]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[C:9]3[N:13]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([CH3:30])(=[O:29])=[O:28])[C:32]#[CH:33]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: C#CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(C)(=O)=O
Yield: 77.1 %

Procedure:
0.1 g (0.33 mmol) of 4-thiophene-2-carbonyl-2H-pyrazol-3-ylamine and 0.063 g (0.33 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynyl-methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 8 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporate to dryness to yield an oil which, in the presence of ethyl acetate gave a yellow solid, 111 mg (yield=78%) N-2-propynyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.CC1(C)C(C)(C)[O:20][B:19](B2OC(C)(C)C(C)(C)O2)[O:18]1.CC([O-])=O.[K+].Cl>CCOC(C)=O.O1CCOCC1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][C:4]=2[F:15])=[CH:9][CH:10]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(B(O)O)cc2F)cn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (2.0 g, 9.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.9 g, 11.0 mmol), chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.14 g, 0.18 mmol), and KOAc (2.7 g, 27 mmol) were combined in a sealable reaction vessel under nitrogen, and then treated with anhydrous 1,4-dioxane (100 mL, sparged with nitrogen). The vessel was sealed and then heated at 80° Celsius for 16 hours. The mixture was cooled to rt, HCl (1 m, 50 mL) was added and the mixture stirred for 20 min. The mixture was then diluted with EtOAc (200 mL) and the aqueous phase was collected. The organic phase was extracted with 1 M HCl (2×75 mL). The combined aqueous phases were cooled in an icebath and the pH was adjusted to ca. 7 using solid sodium bicarbonate. The resulting precipitate was collected by filtration, washed well with water, and dried to provide the title compound (2.1 g, 98%). MS (CI): mass calcd. for C11H10BFN2O2, 232.08; m/z found, 233.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.29-8.20 (s, 2H), 8.18-8.13 (s, 1H), 7.80-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.51-7.44 (m, 1H), 6.84-6.57 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH3:21])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(2-chloro-5-fluoro-phenyl)quinolin-3-yl)ethanamine (0.072 g, 0.215 mmol), 6-chloropurine (0.040 g, 0.26 mmol, 1.2 eq) and DIEA (0.42 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.68 (s, 1 H), 8.60 (s, 1 H), 8.02-8.10 (m, 2 H), 7.92-7.99 (m, 1 H), 7.85-7.93 (m, 1 H), 7.54-7.63 (m, 1 H), 7.50 (dd, J=8.80, 4.89 Hz, 1 H), 7.07 (td, J=8.61, 3.13 Hz, 1 H), 5.48-5.65 (m, 1H), 1.71 (d, J=7.04 Hz, 3H), Mass Spectrum (ESI) m/e=454 (M+1).
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:12]1=[O:13].BrCCCCC.Br[CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][N:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:12]1=[O:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: BrCCCOCc1ccccc1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: O=C1C(=O)N(CCCOCc2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with isatin, and 1-bromopentane with benzyl 3-bromopropyl ether, the title compound was obtained (95%) as a pale yellow syrup: 1H NMR (300 MHz, CDCl3) δ 7.57-6.92 (m, 9H), 4.50 (s, 2H), 3.84 (t, 2H), 3.54 (t, 2H), 2.03-1.94 (m, 2H); MS (ES+) m/z 296.3 (M+1), 318.3 (M+23).
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@@:34]3([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:38](=[CH2:40])[C@@H:37]4[C@H:35]3[C@H:36]4[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:25]1[C:26]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@@:34]3([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:38]4([CH2:2][CH2:40]4)[C@@H:37]4[C@H:35]3[C@H:36]4[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:32])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OCC1c3ccccc3-c3ccccc31)(C(=O)OCC)CC21CC1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
Add a solution of trifluoroacetic acid (2.66 g, 23.3 mmol) in dichloromethane (11.7 mL) dropwise over 5 minutes to a stirred solution of diethyl zinc 1M in heptanes (23.3 mL, 23.3 mmol) in dichloromethane (11.7 mL) cooled to 0-5° C. under nitrogen (exothermic reaction). After 10 minutes, add a solution of diiodomethane (6.25 g, 23.3 mmol) in dichloromethane (11.7 mL). After 10 minutes, add a solution of diethyl (1S,2S,5R,6S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (3.70 g, 7.8 mmol) in dichloromethane (11.7 mL). After 2 hours at 0° C., allow to warm to room temperature and stir for 16 hours. Quench the reaction mixture with cold 0.5M hydrochloric acid (50 mL) and dichloromethane (20 mL) and stir vigorously. Separate the dichloromethane layer via a hydrophobic frit and then evaporate to a pale yellow oil. Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a colorless oil (3.49 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) taking the centre cut fractions to give a colorless foam of title compound (2.12 g, 56%). MS (m/z): 490 (M+1). A second lot of product from the less pure fractions is obtained by repeated chromatography (363 mg, additional 9%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.O>[Cl:17][C:16]1[C:11]([N:4]2[C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:6][C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)=[N:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COC(=O)c1cc(N)nn1-c1ncccc1Cl
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
1.90 g (7.52 mmol) of methyl 3-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate 1.50 g (8.27 mmol) of 2-chloro-5-trifluoromethylpyridine, 0.275 g (0.3 mmol) of tris(dibenzylacetone)dipalladium, 0.286 g (0.60 mmol) of 2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl and 3.12 g (22.5 mmol) of potassium carbonate were initially charged in 190 ml of tert-butanol, and the reaction mixture was stirred at 100° C. for 24 hours. After cooling, the mixture was poured into water and extracted repeatedly with ethyl acetate, and the extracts were dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 950 mg (29% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylate. (logP: 3.14; MH+: 398.0); 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.74 (s, 3H), 7.26 (m, 1H), 7.37 (s, 1H), 7.66 (m, 1H), 7.95 (m, 1H), 8.25 (d, 1H), 8.56 (m, 2H).)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.OO.S([O-])([O-])=[O:25].[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:25])([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: Brc1ccc(P(c2ccccc2)c2ccc(Br)cc2)cc1
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=P(c1ccccc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
10.05 g (24 mmol) of bis(4-bromophenyl)phenylphosphine were dissolved in 200 ml of ethyl acetate in a 500 ml four-necked flask with internal thermometer, mechanical stirrer, reflux condenser and dropping funnel and cooled to an internal temperature of 5° C. A solution of 2.25 ml (26.4 mmol) of H2O2 (35%) in 17.5 ml of water was added dropwise over the course of 30 min., and the mixture was stirred at room temperature for a further 12 h. 25 ml of saturated sodium sulfite solution were subsequently added, the organic phase was separated off, washed twice with saturated sodium sulfite solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The purification was carried out firstly by column chromatography on silica using a solvent mixture of initially hexane:ethyl acetate 2:1 to hexane:ethyl acetate 1:1. Further purification was carried out by recrystallisation from heptane/toluene, giving 6.5 g of product in a purity of 99.7% (according to HPLC). 1H-NMR (500 MHz, CDCl3): [ppm] 7.46-7.66 (m). 31P-NMR (CDCl3): [ppm] 28.40.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 39.6 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (36 mg, 0.35 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.114 g, 0.35 mmol) and N,N-diisopropylethylamine (208 mg, 1.6 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (50 mg, 40%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[F:14][C:2]([F:1])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([N:23]([O:24][CH3:25])[CH3:22])=[O:5]
Reactant: O=C(O)C(F)(F)Oc1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)C(F)(F)Oc1ccc(F)cc1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (2.2 g, 10.6 mmol) in DCM (20 ml), were added oxalyl chloride (1.02 ml, 12 mmol) and a couple of drops of DMF and the reaction mixture was stirred for 2 h. The reaction mixture was evaporated to dryness and the yellowish residue was dissolved in DCM. The solvent was evaporated again and the residue was left under light vacuum (30 mm Hg) for 1 h. After dissolving the residue in DCM (20 ml), N,O-dimethyl hydroxylamine hydrochloride (1.24 g, 12.7 mmol) and TEA (25.4 mmol) were added. After stirring the reaction mixture overnight at rt, the heterogeneous mixture was washed with water and brine. After drying over sodium sulfate, the solvent was removed under vacuum to yield 2,2-difluoro-2-(4-fluorophenoxy)-N-methoxy-N-methylacetamide as an oil (2.05 g, 77%).
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([OH:22])=[O:21])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:20]([C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:22])=[O:21]
Reactant: O=C(O)C1=C(C(=O)CC(=O)c2ccccc2)CCCC1
Reactant: NN
Agent: Cl
Agent: [Na][Na]
Solvent: CO
Solvent: O
Product: O=C(O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1

Procedure:
To a slurry of 31.6 g of the disodium salt of 2-benzoylacetyl-1-cyclohexenecarboxylic acid in 150 ml of methanol is added 12 g of concentrated hydrochloric acid, followed by 12 g of hydrazine hydrate. The reaction mixture is refluxed for 2 hours, cooled to 5°, acidified to pH 3, and diluted with 150 ml of water. The solid is collected and recrystallized from acetic acid-water to give 11.4 g of 3-(2-carboxy-1-cyclohexen-1-yl)-5-phenylpyrazole, m.p. 207-209°.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>O.O1CCCC1>[OH:4][CH2:3][C@@H:2]([NH:1][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH3:5]
Reactant: C[C@H](N)CO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 39 h
Yield: 87.3 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (2.6 kg, 35 mol) in purified water (10.5 L) was added sodium bicarbonate (4.4 kg, 52 mol). To the resulting mixture was added a solution of 2-nitrobenzenesulfonyl chloride (7.3 kg, 33 mol) in tetrahydrofuran (10.2 L) at an internal temperature of −8° C. to −6° C. Subsequently, the resulting reaction mixture was stirred at room temperature for 39 hours. After confirming the disappearance of 2-nitrobenzenesulfonyl chloride by TLC, the mixture was filtered. The filtrate was then extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether/ethyl acetate to give the target product as a white solid (7.5 kg, yield 82.4%).