Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])([CH3:4])([CH3:3])[CH3:2].C(OC(NCCCCCCCCCCC[O:49][S:50]([CH3:53])(=O)=[O:51])=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][S:50]([CH3:53])(=[O:51])=[O:49])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCOCCOCCOCCO
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCOCCOCCOCCOS(C)(=O)=O

Procedure:
Compound 16 was prepared from compound 4 using methods analogous to the preparation of compound 3 (Example 1, step C). 1H NMR (DMSO-d6) δ 6.95 (t, 1H, J=5.5 Hz), 4.50 (m, 2H), 3.86 (m, 2H), 3.75–3.62 (m, 8H), 3.57 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 3.07 (q, 2H, J=6.0 Hz), 1.70–1.58 (m, 27H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO.Cl>O>[Br:8][C:6]1[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:2]([O:22][CH3:21])[CH:7]=1
Reactant: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Yield: 95.3 %

Procedure:
A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800 mL), and the pH adjusted to 2 by the addition of conc. HCl. The resulting mixture was extracted with CH2Cl2 (3×150 mL). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated to give a nearly colorless oil (20.5 g) which slowly solidified upon standing. This was recrystallized from methanol (125 mL)/water (40 mL) to give the desired acid 16 (11.6 g), m.p. 134-135° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(C1C=CC([O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH+:25](C)[CH2:24][CH2:23]2)=CC=1C)=O.O1C2(CCNCC2)OCC1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[Na]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CC(O)C.CO>[NH:25]1[CH2:26][CH2:27][CH:22]([O:21][CH2:20][CH2:19][OH:18])[CH2:23][CH2:24]1
Reactant: Cc1cc(OCCOC2CC[NH+](C)CC2)ccc1C=O
Agent: C1CC2(CCN1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: OCCOC1CCNCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium toluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassiuim tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][C:15]#[N:16].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:17]1[C:18]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([Br:1])=[C:3]([O:13][CH2:14][C:15]#[N:16])[CH:4]=[CH:5]3)=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: N#CCOc1ccc2cc(Br)ccc2c1Br
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Temperature: 70 °C
Yield: 63.9 %

Procedure:
A mixture of (1,6-dibromo-naphthalen-2-yloxy)-acetonitrile (9.2 g, 27 mmol), benzothiophene-2-boronic acid (7.2 g, 40 mmol) in two portions, tetrabutylammonium bromide (8.7 g, 27 mmol), potassium carbonate (9.4 g 68 mmol) and palladium (II) acetate (0.079 g, 0.35 mmol) in THF (25 mL) and water (41 mL) was heated at 70° C. for seven hours. After cooling to ambient temperature, the reaction mixture was poured into 2N hydrochloric acid. This was extracted with hot chloroform (due to limited solubility). The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtrered and solvent evaporated. The residue was stirred in acetonitrile for ten minutes. It was then filtered and rinsed with acetonitrile. The precipitate was dried for 12 hours in vacuo at 76° C. to yield 6.8 g of title compound as a taupe-colored solid. The filtrate was concentrated and purified by flash chromatography with 10–45% chloroform in hexane. After drying for 20 minutes in vacuo at 60° C., 1.33 g more of the title compound was obtained as a light buff-colored solid. The total yield of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile was 8.1 g (86%): MP: 179–81° C.; Mass spectrum (+EI, M+) m/z 393/395. 1H NMR (500 MHz, DMSO-d6): δ8.37 (d, 1H,J=1.83 Hz), 8.20 (d, 2H, J=7.94 Hz), 8.15 (dd, 1H, J=8.86 and 1.87 Hz), 8.01–4 (m, 2H), 7.88–7.90 (m, 1H), 7.67 (d, 1H, J=9.16 Hz), 7.37–7.43 (m, 2H), 5.44 ppm (s, 2H). Elemental Analysis for C20H12BrNOS: Calcd: C, 60.92; H, 3.07; N, 3.55; Found: C, 60.75; H, 2.91; N, 3.34.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH:30]=[CH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:20][CH2:19]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1COCC1>[C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH:30]=[CH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:20][CH2:19]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(P(=O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.06 ml (5.55 mmol) diphenylphosphinic acid chloride are dissolved in 20 ml abs. THF and cooled to ca. 0° C. under moisture exclusion. 2.0 g (5.55 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) and 2.3 ml (16.6 mmol) TEA are suspended in 90 ml abs. THF and added dropwise under ice cooling. The mixture is stirred for four days at RT without further cooling. Subsequently the solvent is removed under vacuum and the residue is taken up in 70 ml 10% sodium hydroxide solution and extracted twice, each with 100 ml CHCl3. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is pre-purified over silica gel with CHCl3/CH3OH (90/10), subsequently further purified by flash-chromatography with CHCl3/CH3OH (90/10) and crystallized from 30 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 154–155° C.; yield: 1.04 g (30%).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH2:7]=[C:8]([CH3:10])[CH3:9].Cl>ClCCl>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C=C(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Reaction time: 20 h
Yield: 95.2 %

Procedure:
To the optically-active catalyst of Example 1 (a) (total product) under nitrogen was added a solution of chloral (3.3 ml, 33.8 mmole) in dichloromethane (dried over calcium hydride) (30 ml). After cooling the solution to 0°-5° C., isobutene gas (2.84 g, 50 mmole) was bubbled through the mixture over about 1 min. At this stage the temperature of the mixture was not allowed to rise above 20° C. After stirring the mixture at 10°-15° C. for up to 20 h, it was poured into 10% hydrochloric acid (30 ml). After shaking the phases, the aqueous layer was separated and extracted with fresh dichloromethane (2×30 ml). The combined organic extracts were washed with water (30 ml) and dried (MgSO4). Concentration of the extract gave a red oil (6.55 g, 95%) which was distilled to give the product as a colourless oil, with physical characteristics identical to those reported in the literature.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[C:28](N=C(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH2:29][CH:28]([CH3:31])[CH3:30])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(C)nc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (100 mg, 0.257 mmol) in acetonitrile (5 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.054 mL, 0.257 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.056 mL, 0.515 mmol) added. The reaction was then heated by microwaves to 150° C., for 25 minutes. After cooling the solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (formic acid modifier). The solvent was removed under a stream of nitrogen to give the title product (11.7 mg) as a yellow oil which solidified. LCMS (2 min, formic) Rt 1.31 min, m/z (ES+) 445 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@:32]1([CH3:39])[C:36](O)=[O:37])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:36]([C@@:32]3([CH3:39])[CH2:33][CH2:34][CH2:35][N:31]3[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:37])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (22 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 68% acetonitrile/water to yield the N-Boc-protected product, (R)-tert-butyl 2-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2-methylpyrrolidine-1-carboxylate, as a beige solid (32 mg, 73% yield). The de-protection was carried out by adding 1 mL 4 N HCl solution in dioxane to the above protected product. After 1 hour at ambient temperature, the reaction mixture was concentrated, treated with ether (1 mL), and filtered, giving the final product as an off-white solid. MS (apci) m/z=427.2 (M+H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:8]3[CH2:15][CH2:16][CH:5]([CH2:6][CH2:7]3)[C:4]=2[C:3]1=[O:17].N1C=CC=CC=1.[C:24]12([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(Cl)Cl.CCOC(C)=O>[C:24]12([CH2:34][C:35]([NH:1][N:2]3[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]4[CH:8]5[CH2:15][CH2:16][CH:5]([CH2:6][CH2:7]5)[C:4]=4[C:3]3=[O:17])=[O:36])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1nn(N)c(=O)c2c1C1CCC2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)c2c1C1CCC2CC1
Yield: 54.8 %

Procedure:
A mixture of Example 8C (18.3 mg), pyridine (0.008 mL, 0.10 mmol), and (adamantan-1-yl)acetyl chloride (18.7 mg, 0.088 mmol) in CH2Cl2 (0.35 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (20% EtOAc/CH2Cl2) to give the title compound (17.6 mg, 0.043 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 3.40-3.35 (m, 1H), 3.21-3.07 (m, 2H), 1.99 (s, 2H), 1.93 (s, 3H), 1.83-1.72 (m, 4H), 1.72-1.54 (m, 12H), 1.33-1.17 (m, 4H), 1.14 (d, 6H); MS (ESI+) M/Z 410.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[N:6]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>ClCCl>[CH:1]1([CH2:4][NH:5][C:7](=[O:8])[NH:6][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)NCC2CC2)cc1
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To cyclopropylmethanamine (57.5 mmol, 4.99 mL, 4.09 g) in dichloromethane (40 mL) was added to ethyl 4-isocyanatobenzoate (52.3 mmol, 10 g) in dichloromethane (45 mL) and the reaction stirred overnight. The reaction was then concentrated under reduced pressure to give the title compound (14.7 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH:2]([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[C:14](I)([F:19])[C:15]([F:18])([F:17])[F:16].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.COC(C)(C)C.O>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:14]([F:19])([C:15]([F:18])([F:17])[F:16])[C:13]([F:22])([F:21])[F:12])[NH2:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccc(N)c1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CC(C)Cc1cc(N)ccc1C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
3-Isobutylaniline (14.9 g, 0.1 mol) was diluted in a 300 ml mixed solvent of tert-butyl methyl ether-water (1:1), followed by sequentially adding heptafluoroisopropyl iodide (29.6 g, 0.1 mol), tetrabutylammonium hydrogensulfate (3.4 g, 0.01 mol), sodium hydrogen carbonate (8.4 g, 0.1 mol) and sodium dithionite (17 g, 0.1 mol) and stirring overnight at room temperature. The reaction solution was diluted with hexane, followed by washing twice with a 3N HCl solution, and with aqueous sodium bicarbonate and a saturated brine. The solution was dried over magnesium sulfate and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=6:1) to obtain 14.9 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: C=C1C[C@@H](C(=O)OCC)[C@H](C(=O)OCC)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C1C[C@@H](C(=O)O)[C@H](C(=O)OCC)C1
Yield: 49.1 %

Procedure:
A suspension of 20.0 g of trans-(1SR,2SR)-4-methylene-cyclopentane-1,2-dicarboxylic acid diethyl ester and 36.6 g of potassium carbonate in 200 ml of MeOH was heated at reflux temperature for 2 h. The mixture was cooled to 22°, diluted with 200 ml of water, the pH was adjusted to 2 using 80 ml of 25% HCl and the mixture was evaporated to half of the volume. The aqueous layer was extracted with AcOEt, the organic layer was washed with water, dried and evaporated to give 16.7 g of a crude mixture of mono and diacid. Optionally this mixture can be purified on silica using CH2Cl2/MeOH (19:1) to give 8.60 g of the pure title compound 1a. MS: 183.3 (M−H)−.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:14])[F:15])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-azido-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-benzo[e][1,4]diazepine-2-one (crude from above) in 1.3 L THF was added triphenylphosphine (109 g, 0.417 mol) and water (150 mL). This was stirred overnight at ambient temperature The reaction was then concentrated under reduced pressure, taken up in 1N HCl (1500 mL), and extracted with ethyl ether (2×500 mL). The combined organics were back extracted with 1N HCl (1×300 mL). The combined aqueous layers were back extracted with ethyl acetate (100 mL) and then basefied with sat. NaHCO3 (100 mL) and 50% NaOH until pH=10. This was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate fractions were dried over Na2SO4, evaporated under reduced pressure and crystallized from ethyl ether to give the title compound as a powder. MP=141-143° C.;
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[C:10]=[O:11].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[C:10](=[O:11])[NH:7][N:6]=[N:5]1
Reactant: Cc1ccccc1N=C=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nn[nH]c1=O
Temperature: 0 °C
Yield: 104.3 %

Procedure:
Under ice-cooling, to N,N-dimethylformamide 500 mL was added anhydrous aluminum chloride 55.1 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 26.9 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-isocyanato-2-methylbenzene 50.6 g and the resulting mixtures were heated at 70° C. for four hours. After cooling, to a mixture of sodium nitrite 51.8 g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methylphenyl)-1,4-dihydrotetrazole-5-one 69.8 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:23])[C:14]3[N:15]([N:17]=[C:18](C(O)=O)[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:23])[C:14]3[N:15]([N:17]=[CH:18][CH:19]=3)[CH:16]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn3nc(C(=O)O)cc3c(=O)[nH]2)cc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)c1ccc(-c2cn3nccc3c(=O)[nH]2)cc1
Temperature: 190 °C
Reaction time: 20 h

Procedure:
28.9 mg (0.454 mmol) Copper powder is added to a solution of 70.7 mg (0.227 mmol) 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid in 2 ml quinoline. The mixture is stirred at 190° C. for 20 hours. Quinoline is distilled off under vacuum and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 6-(4-tert-butyl-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one as colourless crystals; HPLC/MS: 1.88 (C), [M+H] 268; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.49 (s, 1H), 8.03 (s, 1H), 7.92 (d, J=2.2, 1H), 7.69 (d, J=8.5, 2H), 7.49 (d, J=8.6, 2H), 7.01 (d, J=1.6, 1H), 1.32 (s, 9H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.O>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([NH2:27])=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To 100 mg of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid in 5 ml of dry tetrahydrofuran were added 0.2 g of oxalyl chloride and a drop of dimethylformamide, and the mixture was stirred with ice cooling under a dry atmosphere for 3 hours. To the mixture was added 5 ml of tetrahydrofuran containing 1% ammonia, and the mixture was stirred under a dry atmosphere at room temperature for 14 hours. After the addition of water, the mixture was extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate, thereby obtaining 66 mg (yield: 66%) of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetamide as colorless crystals having a melting point of 188°-189° C.