Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][O:41][CH2:40]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][O:41][CH2:40]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCOC3)c2n1
Temperature: 60 °C

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (300 mg) in dry N,N-dimethylformamide (5.3 ml) was added potassium carbonate (474 mg). The reaction was stirred at 60° C. for ninety minutes. The reaction was cooled and 3-(tetrahydro-2H-pyran-3-yl)propyl methanesulfonate (209 mg) was added and the reaction heated at 90° C. for three hours. The reaction was cooled, diluted with ethyl acetate and washed with water (2×). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo. to afford a yellow oil. The product was purified by C18 reverse phase chromatography (43 g) (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (30-80%) to afford the title compound as a yellow oily residue (198 mg).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(F)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Fc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 20 °C
Yield: 107.6 %

Procedure:
A mixture 49.8 g (0.15 mole) of 1,2-diphenyl-4-p-fluorophenylbutane-1,4-dione, 100 ml of xylene, 30 g (0.0675 mole) of phosphorus pentasulfide and 130 g (3.81 moles) of hydrogen sulfide was heated and stirred in a 1-liter stainless steel autoclave for 4 hours at 157°-185° C. (620-1145 psig). After cooling the vessel to 20° C. and venting the hydrogen sulfide into a sodium hydroxide solution, the residue was stirred with 150 ml of absolute ethanol. Filtration gave 31.5 g (63.6%) of crude product, m.p. 108°-110° C. Recrystallization from 30 ml of dioxane and 90 ml of ethanol gave 24 g of pure 2,3-diphenyl-5-p-fluorophenylthiophene, m.p. 111°-113° C.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>C1COCC1>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH2:23])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and a solution of ammonia in THF.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:18]([F:20])[F:19])[N:13]([CH:15]2[CH2:17][CH2:16]2)[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:15]1([N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:21])[CH:11]=[C:12]2[CH:18]([F:20])[F:19])[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: O=c1cc(C(F)F)n(C2CC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)n(C2CC2)cc1O
Yield: 77.7 %

Procedure:
A mixture of 5-benzyloxy-1-cyclopropyl-2-difluoromethyl-1H-pyridin-4-one (3.0 g, 10.3 mmol) and 10% Pd/C (340 mg) in methanol (60 mL) was subjected to hydrogenation in a Parr apparatus under a 15 psi hydrogen pressure for 22 min. The mixture was diluted with 300 mL of methanol, sonicated for 20 min, and then filtered through a pad of CELITE™ (pre-treated with HCl and washed to neutral with deionized water). The volume of the filtrate was reduced in vacuo until a solid precipitated out. The solid was collected by suction filtration. The recrystallization was repeated on the filtrate to obtain a second crop of solid. The combined solids were dried to constant weight in a vacuum oven thereby affording the title product (1.61 g) in 77% yield. HPLC purity (peak area percent) of product is 99.5% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6+D2O) δ (ppm): 7.54 (s, 1H), 7.33 (t, J=53.0 Hz, 1H, CF2H), 6.51 (s, 1H), 3.53-3.57 (m, 1H, N—CH), 1.07-1.10 (m, 4H, 2CH2); MS-ESI (m/z): 202.5 [M+1]+, 142.3 (100%); Anal. Calcd. for C9H9F2NO2: C, 53.73; H, 4.51; N, 6.96%. Found: C, 53.75; H, 4.80; N, 6.89%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N+:16]([O-])=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:35][O+:36](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:35][OH:36])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2cc[n+]([O-])cc2)c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(CO)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]pyridine N-oxide (0.43 g, 1.0 mmol) in methylene chloride (10 mL) was added trimethyloxonium tetrafluoroborate (0.17 g, 1.2 mmol), and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and methanol (15 mL) was added to the residue. To the mixture was added a solution of ammonium persulfate (0.05 g, 0.22 mmol) in water (1 mL) under reflux, and the mixture was heated to reflux for 30 minutes. A solution of ammonium persulfate (0.03 g, 0.11 mmol) in water. (1 mL) was added to the reaction mixture, and the mixture was further heated to reflux for 13 hours. The reaction mixture was cooled to room temperature, then, concentrated under reduced pressure. To the residue was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and filtrated and concentrated under reduced pressure. The residued was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate) to obtain a title compound (0.26 g, yield 61%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([F:7])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(F)(Cc2ccccc2)CC1
Temperature: -71 °C
Reaction time: 0.83 h
Yield: 51.1 %

Procedure:
To a cooled (-71° C.) and stirred solution of diethylaminosulfur trifluoride (634 μl, 4.80 mmol) in anhydrous dichloromethane (15 ml) was added dropwise, via cannula, a solution of 1-tert-butyloxycarbonyl-4-benzyl-4-hydroxypiperidine (700 mg, 2.40 mmol) in anhydrous dichloromethane (15 ml) over 20 minutes, under nitrogen. After a further 50 minutes at -75° C., the mixture was warmed to -10° C. and stirred for a further 2 hours. Water (20 ml) and saturated aqueous potassium carbonate (7 ml) were added and products were extracted with diethyl ether (1×70 ml). The organic solution was washed with brine (1×25 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, hexane-diethyl ether, 86:14) gave 190 mg of 1-tert-butyloxycarbonyl-3,4-dehydro-4-benzylpiperidine and 360 mg (51%) of the title compound as pale yellow oils; δH (360 MHz, CDCl3) 1.44 (9H, s), 1.46-1.78 (4H, m), 2.90 (2H, d, J=22 Hz), 2.98-3.08 (2H, m), 3.86-3.94 (2H, m), 7.16-7.34 (5H, m); m/z (ES) 294 (M+ 1).
Reaction SMILES: [N+:1](=[C:3]([C:14]([CH3:16])=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26].[I-].[Na+]>C(#N)C>[N+:1](=[C:3]([C:14]([O:15][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH2:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccccc1
Yield: 84.3 %

Procedure:
To 1.5 ml of dry acetonitrile were added 83 mg (0.380 millimole) of benzyl 2-diazoacetoacetate, 64.8 μl (0.465 millimole) of triethylamine and 59 μl (0.465 millimole) of trimethylsilyl chloride. A solution obtained by dissolving 70 mg (0.467 millimole) of sodium iodide in 0.5 ml of dry acetonitrile was added dropwise thereto at a room temperature. After agitation for an hour, the reaction mixture was concentrated under a reduced pressure. After addition of 5 ml of hexane, insoluble materials were filtered off and the hexane was distilled off under a reduced pressure to give 93 mg (yield 84.1 %) of the desired compound in a yellow solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NC3CCCCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using cyclohexylamine (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 388 (M+1); Rt=4.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([CH2:25][CH3:26])=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([CH2:25][CH3:26])=[N:15][N:14]=1
Reactant: CCc1nnc(Cl)c2ccc(OC)cc12
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Yield: 35.2 %

Procedure:
Operating substantially as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (1.75 g, 10.77 mmoles), dry DMF (20 ml), 60% NaH in oil (0.26 g, 10.77 mmoles) and 1-chloro-4-ethyl-6-methoxy-phthalazine (1.2 g, 5.39 mmoles), prepared as described in example 10, in DMF (25 ml), 0.66 g of the title compound were obtained (yield: 36%). m.p.: 136-138° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1.Cl>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Reactant: ClCc1nnn[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (1R,3S,5R)-2-[2-(3-Acetyl-6-hydroxy-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]-hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 584 (80.0 mg, 0.165 mmol) in DMSO (2 mL) was treated with cesium carbonate (162 mg, 0.496 mmol). After stirring at RT for 5 min, 5-(chloromethyl)-1H-tetrazole (21.0 mg, 0.174 mmol) was added and stirring was continued at RT for 36 h. The mixture was neutralised by addition of 1N HCl, diluted with water extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine. The resulting suspension was filtered over phase separator and concentrated. The filtered solid was triturated with methanol, decanted and dried in vacuo to give the title compound. The filtrate was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions a second batch of the title compound as a white solid. MS (LC/MS): 566 [M+H]+; tR (HPLC conditions k): 3.22 min.
Reaction SMILES: [F:1][C:2]([F:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:1])[CH3:7])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(F)(F)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Treat a solution of 4,4-difluoropentan-1-ol (5 g, 40.3 mmol) and TsCl (8.4 g, 44.3 mmol) in DCM (80 mL) with TEA (6.1 g, 60 mmol) and DMAP (0.5 g, 4 mmol) and stir at RT overnight. Wash the mixture successively with 2M HCl, satd. NaHCO3, then brine, dry over Na2SO4, concentrate and purify by silica gel chromatography (EtOAc/Pet ether) to give the title compound (7.1 g, 63%). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.08 (t, J=5.6 Hz, 2H), 2.47 (s, 3H), 1.94-1.84 (m, 4H), 1.57 (t, J=18.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[N:4][C:5]2[N:6]([N:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[CH:38]=[CH:39][N:40]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]=2[C:24]1=[O:51]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[N:6]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:5]2[N:4]=[C:3]([CH3:21])[C:2]=1[C:27]1[C:26]2[CH:38]=[CH:39][N:40]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]=2[C:24](=[O:51])[N:23]([CH3:22])[CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Cc1cc2nc(C)c(Br)c(Oc3ccc(F)cc3F)n2n1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5cc(C)nn5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-bromo-7-(2,4-difluorophenoxy)-2,5-dimethylpyrazolo[1,5-a]pyrimidine and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C29H24F2N5O4S (M+H)+: m/z=576.1. found: 576.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:17][C:9]2[CH:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:27]1[N:32]=[N:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH2:36]([NH2:42])[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:27]3[N:32]=[N:31][C:30]([C:33]([NH:42][CH2:36][C:37]4[O:41][CH:40]=[CH:39][CH:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:8]3[C:15](=[O:16])[N:14]4[CH:10]([CH2:11][CH2:12][CH2:13]4)[C:9]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)nn1)C(=O)N1CCCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)nn1)C(=O)N1CCCC21
Reaction time: 2 h

Procedure:
The mixture of 6-[3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]-3-pyridazinecarboxylic acid (G, 33 mg, 0.07 mmol), furfurylamine (19.3 mmol, 0.14 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.7 mg, 0.14 mmol) and 1-hydroxybenzotriazole hydrate (18.8 mg, 0.14 mmol) in 2 ml dichloromethane was stirred for 2 hours. The mixture was then partitioned between water and ethyl acetate. The organic was washed with brine and dried over sodium sulfate. The residue upon the removal of the solvent was purified with flash chromatography. Twelve (12) mg white solid was obtained. NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 8.08 (d, 1H), 7.20 (t, 2H), 6.92 (t, 2H), 4.78 (m, 1H), 4.67 (d, 2H), 4.40 (dd, 2H), 3.90 (q, 2H), 3.64 (m, 1H), 3.39 (m, 1H), 2.48 (m, 1H), 2.35 (m, 2H), 1.40 (m, 1H), 0.90 (t, 3H) ppm. ESI-MS m/z 556 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[CH3:30][CH:31]([CH3:35])[C:32](O)=[O:33].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)C(=O)O
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Solvent: CC(=O)OC(C)=O
Product: CC(C)C(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
The title compound was prepared in analogy to Example 2-17 by using 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-methylpropanoic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[B:20]([OH:23])[OH:21]
Reactant: Brc1ccc2oc3ccccc3c2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -40 °C
Yield: 71.7 %

Procedure:
Under an argon atmosphere, 24.7 g of 2-bromodibenzofuran and 400 ml of anhydrous THF were loaded into a 1,000-ml three-necked flask, and then 63 ml of a solution of n-butyllithium in hexane having a concentration of 1.6 M were added to the mixture during the stirring of the mixture at −40° C. The reaction solution was stirred for 1 hour while being heated to 0° C. The reaction solution was cooled to −78° C. again, and then a solution of 26.0 g of trimethyl borate in 50 ml of dry THF was dropped to the solution. The reaction solution was stirred at room temperature for 5 hours. 200 milliliters of 1N hydrochloric acid were added to the solution, and then the mixture was stirred for 1 hour. After that, the aqueous layer was removed. The organic layer was dried with magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene. Thus, 15.2 g of dibenzofuran-2-boronic acid were obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:5]1=[O:12]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N3CCOCC3)cccc21
Temperature: 25 °C
Yield: 3.9 %

Procedure:
To a degassed solution of 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.00 g, 2.57 mmol), morpholine (0.34 mL, 3.9 mmol), sodium tert-butoxide (0.45 g, 4.7 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.30 g, 0.52 mmol) in toluene (40 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.24 g, 0.26 mmol). The mixture was stirred at reflux under nitrogen for 48 h, allowed to cool to ambient temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluted with ethyl acetate/hexanes (1/1) to afford 1′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.04 g, 4%): mp 246-249° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.29 (m, 1H), 6.94-6.87 (m, 2H), 6.42 (s, 1H), 6.17 (s, 1H), 4.75 (ABq, 2H), 4.14-4.02 (m, 4H), 3.30 (t, J=4.2 Hz, 4H), 3.12 (s, 3H), 2.52-2.27 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.8, 155.6, 149.9, 144.7, 144.3, 137.6, 130.3, 127.1, 121.6, 117.1, 111.3, 106.4, 98.6, 77.8, 66.7, 64.6, 64.0, 57.7, 53.0, 27.0; MS (ES+) m/z 395.0 (M+1).