Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1.CO>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 21.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 4-Bromobenzoyl chloride (164.6 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (46.5 mg). Yield 21.2%.
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CC(N(C)C)=O>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])=[CH:31][CH:30]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Reactant: Nc1ccc(F)cc1
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.8 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.30 mmol) and 4-fluoroaniline (0.113 mL, 1.19 mmol) in DMA (1 mL) were stirred at RT for 4 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. A further purification was done by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford a oil which was triturated with pentane to give 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (80 mg, 59%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1)=[O:6])#[N:2]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1ccc(Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Under ice-cooling, to a mixture of 18.0 g of cyanoacetic acid and 25 mL of oxalyl chloride were added 0.07 mL of DMF and 10 mL of dichloromethane, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added toluene, followed by further concentrating under reduced pressure. This procedure was repeated and excess hydrogen chloride and oxalyl chloride were removed. A mixture of the obtained crude product and 50 mL of dichloromethane was added to a mixture of 80 mL of a 1 M aqueous sodium hydroxide solution, 300 mL of dichloromethane, and 14.3 g of 4-(pyridin-4-ylmethyl)aniline under ice-cooling. During mixing the reagent, a 1 M aqueous sodium hydroxide solution was added on time to adjust the reaction solution to be kept alkaline. After stirring at room temperature for 30 minutes, the organic layer was collected by separation and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 10.2 g of 2-cyano-N-[4-(pyridin-4-ylmethyl)phenyl]acetamide as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.[OH-].[Na+]>O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N2 until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H2O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[CH:10][CH:9]=2)[CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:23]=[CH:22][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(Oc2cccnc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl 4-(pyridin-3-yloxy)benzoate (18.0 g, 5.90 mmol) in ethanol (300 ml) was added 10% palladium/carbon (containing water by 50%, 2.0 g), and the mixture was stirred under a hydrogen stream at 80° C. overnight. The reaction solution was filtered with celite and the filtrate was concentrated. The residue was recrystallized from ethanol-hexane to give the objective substance (11.2 g, 88%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:15])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:15][C:16](=[O:18])[CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(OCc2cccs2)ncc1F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(OCc2cccs2)ncc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a 2 dram screw cap vial, a solution of 5-fluoro-2-(thiophen-2-ylmethoxy)-pyrimidin-4-ylamine (0.10 g, 0.4 mmol) in CH2Cl2 was treated with acetyl chloride (0.032 g, 0.4 mmol) and PS-NMM (0.42 g, 0.8 mmol), a resin-bound equivalent of N-methyl morpholine (NMM). The mixture was shaken at RT for 12 h. The reaction mixture was filtered and the solvent evaporated to yield 0.084 g (75%) of the title compound as white solid: mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.6 Hz, 1H), 7.86 (bs, 1H), 7.31 (m, 1H), 7.23 (m, 1H), 7.00 (m, 1H), 5.54 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:27]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:7]3[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:9][C:8]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:33][CH:32]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Brc1ccc(Cn2ccnc2)cc1
Reactant: CCCCc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1

Procedure:
5-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (300 mg, 1.27 mmol, see step (b) above), 1-(4-bromobenzyl)-1H-imidazole (606 mg, 1.90 mmol, see Example 1(d) above), toluene (15 mL), ethanol (4 mL), NaOH (1.0 M, 4.0 mL, 5.1 mmol) and Pd(PPh3)4 (43.9 mg, 0.038 mmol) were mixed under N2. The mixture was warmed to reflux for 2 hours, diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using chloroform:methanol (20:1) as eluent. The product was not completely pure but was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15](O)=[O:16])[CH:9]=[CH:10][CH:11]=1.C([N:26](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH2:26])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(N)=O)c1

Procedure:
To a solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D) in DMF, add triethylamine and BOP, after couple of hours of stirring, reaction mixture can be added to liquid ammonia at −40° C. and the resulting mixture can be warmed for 16 hours to give title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][OH:28]>>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[C:14]1[N:4]2[N:3]=[C:2]([O:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[C:11]3[C:6]([C:5]2=[N:12][N:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: OCc1ccccn1
Reactant: Clc1nn2c(-c3cnccn3)nnc2c2ccccc12
Product: c1ccc(COc2nn3c(-c4cnccn4)nnc3c3ccccc23)nc1

Procedure:
The title-compound was prepared from 6-chloro-3-(pyrazin-2-yl)-1,2,4-triazolo[3,4-a]phthalazine and 2-pyridylcarbinol using the procedure given for Example 98, 1H NMR (360 MHz, CDCl3) δ 5.77 (2H, s, CH2), 7.40 (1H, t, J=6.6 Hz, Ar—H), 7.71 (1H, d, J=7.8 Hz, Ar—H), 7.95-8.00 (2H, m, 2 of Ar—H), 8.08 (1H, t, J=7.6 Hz, Ar—H), 8.40 (1H, d, J=8.0 Hz, Ar—H), 8.70 (2H, m, 2 of Ar—H), 8.78 (1H, m, Ar—H), 8.88 (1H, s, Ar—H), 9.58 (1H, s, Ar—H); MS (ES30) m/e 356 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[N:20]([CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CBr)C2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CN1CC2(CCCC(C)(CN=[N+]=[N-])C2)OC1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 7-(bromomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (11.3 g, 34.1 mmol) in DMSO (171 mL) was added sodium azide (2.89 g, 44.4 mmol). The reaction flask was placed behind a blast shield and heated to 80° C. for 4 days. The temperature was increased to 100° C. After 16 h, additional sodium azide (0.665 g, 10.23 mmol) was added to the reaction. After 19 h, the reaction was cooled to rt and diluted with water (300 mL). The product was extracted into EtOAc (2×300 mL). The combined organics were washed with water (3×400 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (10.0 g, 95% crude yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.33 (q, J=8.53 Hz, 2H), 3.09 (s, 2H), 3.06 (d, J=14.00 Hz, 1H), 2.94 (d, J=14.05 Hz, 1H), 1.96-2.05 (m, 1H), 1.83-1.96 (m, 1H), 1.69 (dt, J=2.04, 14.24 Hz, 1H), 1.59-1.65 (m, 1H), 1.47 (d, J=14.05 Hz, 1H), 1.26-1.44 (m, 3H), 1.15 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7](=[O:12])[CH2:8][NH:9][CH:10]=[O:11])=[CH:5][CH:6]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:12])[CH:8]([NH:9][CH:10]=[O:11])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:6]=1
Reactant: O=CNCC(=O)c1ccc(Cl)s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(NC=O)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 2-chloro-5-(formylaminoacetyl)thiophene (20.1 g) in N,N-dimethylformamide (400 ml) was added sodium hydride (4.44 g, 60% mineral oil) under ice-cooling, and the mixture was stirred under argon atmosphere at room temperature for one hour. After ice-cooling, to the mixture was added dropwise ethyl bromoacetate (20.8 g), and the mixture was stirred at room temperature for 2 hours. After cooling, ice was added to the reaction mixture, and then water and ethyl acetate were also added to the mixture. The organic layer was collected washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=6:1) to obtain ethyl 4-(5-chlorothiophen-2-yl)-3-formylamino-4-oxobutyrate (17.8 g) as yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31]([OH:33])=O)[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([N:42]1[CH2:47][CH2:46][NH:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:42]1[CH2:47][CH2:46][N:45]([C:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]=23)=[O:33])[C:44]([CH3:49])([CH3:48])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCN1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(Cc4ccccc4)CC3(C)C)c12
Yield: 97.4 %

Procedure:
In analogy to Example 1 step (d) 300 mg 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was reacted with 160 mg 1-benzyl-3,3-dimethyl-piperazine to obtain 410 mg (94%) of the title compound.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[Cl:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([Cl:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1Cl
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 20 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:12](=[O:13])[CH:11](C(OC)=O)[CH:10]2[CH:6]1[CH2:7][C:8](=[O:18])[CH2:9]2)=[O:4]>CO.P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3]([CH:5]1[C:12](=[O:13])[CH2:11][CH:10]2[CH:6]1[CH2:7][C:8](=[O:18])[CH2:9]2)=[O:4]
Reactant: COC(=O)C1C(=O)C(C(=O)OC)C2CC(=O)CC12
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: COC(=O)C1C(=O)CC2CC(=O)CC21

Procedure:
One gram of 2,4-bismethoxycarbonylbicyclo[3.3.0]octane-3,7-dione is dissolved in 20 ml of methanol and combined with a solution of 2.5 g of α-chymotrypsin in 150 ml of 0.1-molar phosphate buffer pH 7. The solution is extracted with methyl isobutyl ketone after 22 hours of agitation at 28° C.; the extract is concentrated under vacuum, and the remaining residue is chromatographed over a silica gel column (gradient hexane/ethyl acetate), thus obtaining 610 mg of optically pure 2-methoxycarbonylbicyclo[3.3.0]octane-3,7-dione as an oily liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[C:13](OCC)([O:18]CC)([O:15][CH2:16][CH3:17])[CH3:14].C(O)(=O)CC>C(O)C>[CH3:10]/[C:9](=[CH:8]\[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)/[CH2:11][CH2:14][C:13]([O:15][CH2:16][CH3:17])=[O:18]
Reactant: C=C(C)C(O)c1ccc(C)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Solvent: CCO
Product: CCOC(=O)CC/C(C)=C/c1ccc(C)cc1
Yield: 23.1 %

Procedure:
1-(4-methylphenyl)-2-methyl-2-propen-1-ol (64.9 g, 0.4 mol) and triethyl orthoacetate (335 g, 2 mol) were heated in the presence of propionic acid (0.5 ml) in an oil bath at 150° C. (the ethanol formed during the reaction distills during this period) for 3 hours, then progressively to 200° C. (to distill off the excess orthoacetate). The product was then distilled under high vacuum (105° C./0.001 mbar) through a 20-cm Widmer column. 21.5 g of the desired product were obtained (94% purity, yield=24%).
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1COCO[CH2:13]1>ClC(Cl)C>[CH2:7]1[S:8](=[O:9])(=[O:10])[NH:11][CH2:13][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: C1OCOCO1
Reactant: NS(=O)(=O)Cc1ccccc1
Solvent: CC(Cl)Cl
Product: O=S1(=O)Cc2ccccc2CN1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the method described in Bravo, R. D. et al. Synth. Commun. 2002, 32, 3675. A flask was charged with alpha-toluenesulfonamide (1 g, 5.8 mmol) and 1,3,5-trioxane (0.175 g, 1.9 mmol) in anhydrous dichloroethane (23 mL) and amberlyst 15H+ resin (3.7 g). The mixture was stirred at 80° C. overnight, after which the resin was filtered off and washed with methylene chloride. The organic solution was concentrated to afford a white solid (0.848 g, 79%). 1H NMR (d6-DMSO, 300 MHz) δ 7.41-7.37 (t, 1H, J=6.8 Hz), 7.30-7.24 (m, 2H), 7.19-7.16 (m, 1H), 7.12-7.09 (m, 1H), 4.42-4.40 (d, 2H, J=6.6 Hz), 4.35 (s, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:46]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)([CH3:48])[CH3:47].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:51]3[CH:50]=[C:49]([CH:46]([CH3:48])[CH3:47])[S:53][CH:52]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: CC(C)c1cc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.55 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.32 g), 5-isopropylthiophene-3-carboxylic acid (0.19 g) and triethylamine (0.61 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.4 g.