Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CN.C(N(CC)CC)C.C1C[O:23]CC1>>[C:3]([NH2:2])(=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(CN)c1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
After cooling N,N-dimethyl-1-phenylethane-1,2-diamine represented by Formula 101 (292 mg, 1.78 mmol, purchased from Alfa Aesar Co.) and triethylamine (0.55 mL, 3.95 mmol) in THF (8 mL) at 0° C. under a nitrogen atmosphere, 4-n-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (606 mg, 1.98 mmol) prepared in Preparative Example 1 in THF (12 mL) was slowly added to the cooled solution. After agitating the above solution at the same temperature for 30 minutes, this was left alone at room temperature for 18 hours. A precipitate generated during the reaction was filtered and discarded, the remaining solution was diluted using chloroform and washed with a potassium carbonate solution, followed by separation and drying with sodium sulfate. The solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 19 as a desired product (VVZ-020; 451.3 mg, 52% yield).
Reaction SMILES: C[Si]([N:5]=[N+]=[N-])(C)C.[C:8]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[C:9]1[CH3:10].C(Cl)(Cl)Cl>C(O)C>[CH3:10][C:9]1[NH:5][C:8](=[O:15])[O:14][C:12](=[O:13])[CH:11]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc(=O)oc(=O)[nH]1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
At room temperature, 50.0 g of trimethylsilylazide was added to a mixture of 44.8 g of citraconic anhydride and 60 ml of chloroform. The mixture was stirred at 50-60° C. for 5 hours. After cooling the reaction mixture with an ice, 25.0 g of ethanol was added, followed by stirring for additional 30 minutes. The resulting solid was collected by filtration, and washed with a mixed solvent of chloroform and ethanol to obtain crude 4-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([N+:17]([O-])=O)=[CH:10][C:11]=1[CH2:12]2.O.O.Cl[Sn]Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:17])=[CH:10][C:11]=1[CH2:12]2
Reactant: COc1cccc2c1Sc1ccc([N+](=O)[O-])cc1C2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2c1Sc1ccc(N)cc1C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-Methoxy-2-nitro 9H-thioxanthene (11.59 g, 42.40 mmol) was suspended in ethyl acetate (250 ml). SnCl2.2H2O (47.84 g, 212 mmol) was added and the clear yellow solution was stirred at 50° C. overnight. The reaction was the quenched with NaOH (2M) and then extracted with ethyl acetate (3×300 ml). The organics were washed with saturated brine (100 ml), dried over magnesium sulphate and the solvents were removed in vacuo to give the title compound (10.32 g, 100%) as viscous yellow oil. The oil was used without further purification. 1HNMR (300 MHz, DMSO-d6): δH=3.83 (3H, s), 3.67 (2H, s), 5.14 (2H, bs), 6.43 (1H, dd), 6.61 (1H, d), 6.89 (1H, d), 6.99 (1H, d), 7.06 (1H, d), 7.18 (1H, t). m/z (LC-MS, ESP), RT=3.88 min, (M++1)=244.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:30]=[C:29]([O:28][CH3:27])[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Product: COc1cc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1
Yield: 66 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3,5-dimethoxycinnamic acid under the conditions described in example 86 to yield 66% of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[BH4-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH:10]([OH:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: O=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccccc1C=CC(O)CCc1ccccc1O
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 1,5-bis(2-hydroxyphenyl)penta-1,4-dien-3-one (EF1) (109 mg, 0.41 mmol) in THF/methanol (10/1) (2.5 mL) was added NaBH4 (40 mg, 1.30 mmol) in one portion at 0° C. After stirring for 30 min at this temperature the reaction was quenched with H2O dist and cold brine, diluted with Et2O (10 mL) and neutralized by bubbling CO2 through the dark-red solution (color change to pale yellow). The aqueous phase was extracted with ether, the combined ether layers washed with brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel using 30% EtOAc/hexanes. The product was obtained as a white solid (66%).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].O[Li].O.Cl>CO.O1CCCC1.O>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
A solution of 684 mg (2.0 mmoles) of methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylbenzoate in 9 ml MeOH, 9 ml tetrahydrofuran and 3 ml water was treated with 420 mg (10 mmoles) LiOH.H2O and stirred at room temperature for 4 hours. The reaction mixture was diluted with water, acidified by addition of concentrated HCl and extracted with dichloromethane. The combined extracts were washed with water, dried with MgSO4 and evaporated to give a white solid. Recrystallization of this material from ether gave 416 mg (63% yield) of the title compound as fine white needles mp 188°-188.5° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH2:29]([O:36][C:37]([C@@H:39]([NH:45]C(OC(C)(C)C)=O)[CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>ClCCl.C(N(CC)CC)C>[NH2:45][C@H:39]([C:37]([O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38])[CH2:40][CH2:41][C:42]([NH:28][CH2:27][CH2:26][O:25][CH2:24][C:7]1[NH:8][C:9]([CH3:23])=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:6]=1[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](N)C(=O)OCc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 17.2 %

Procedure:
The title compound (0.29 g) was prepared as an oil by the reaction of amlodipine (1.1 g), (S)-4-benzyloxycarbonyl-4-t-butoxycarbonylaminobutanoic acid (1.0 g) (commercially available), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.57 g), 1-hydroxybenzotriazole (0.40 g) and triethylamine (0.30 g) according to method of part (a) of Example 5 followed by treatment of the resulting intermediate in dichloromethane with gaseous hydrogen chloride according to the method of part (b).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[NH:16]C(=O)C.Cl>CO>[CH3:4][O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[NH2:16]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
Sodium methoxide (1.50 g, 27.7 mmol) was added to a solution of methyl-2-(acetylamino)-3-nitrobenzoate (1.0 g, 4.2 mmol) in MeOH (30 ml) and the mixture stirred at ambient temperature under nitrogen for 16 h. The reaction was cautiously acidified with concentrated hydrochloric acid then heated at reflux overnight, followed by evaporation and re-evaporation by toluene (2×30 ml). The residue was treated with CH2Cl2 (50 ml), the insoluble material removed through filtration and the filtrate reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:4, 1:0)] affording methyl-2-amino-3-nitrobenzoate (535 mg) as a bright yellow solid.
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][N:43]=[C:35]4[C:34]4(OCCC[O:46]4)[C:33]=3[CH:32]=2)(=[O:30])=[O:29])(=O)=O)=CC=1.CN(C=O)C>C1COCC1>[Br:1][C:2]1[C:7]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:44])([CH3:45])[CH2:42][N:43]=[C:35]4[C:34](=[O:46])[C:33]=3[CH:32]=2)(=[O:29])=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Reactant: OC1(Br)C=CC=CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4cccnc4Br)ccc3N2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-bromo pyridinol (0.089 g, 0.510 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.020 g, 0.085 mmol) and the reaction was stirred at rt for 1 hr. {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.100 g, 0.170 mmol) in THF (2 mL)/DMF (2 mL) was added and the reaction was heated overnight at 100° C. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70). The resulting product was dissolved in CH2Cl2 (3 mL) and methanesulfonic acid (2 mL) was added and the solution stirred at 35° C. overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70) to give the title compound as a yellow foam (0.058 g, 56%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 533.1 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>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>[NH:37]1[CH:36]=[C:35]([C:22]2[CH:21]=[CH:20][C:19]([C:13]3([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:26])=[CH:12][CH:11]=4)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:24][CH:23]=2)[CH:39]=[N:38]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)COc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)COc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 80 °C
Yield: 5 %

Procedure:
{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst and heating at 80° C. for 30 minutes, to yield a mixture of the title compounds. On work up the basic aqueous extract was neutralised with hydrochloric acid and extracted with ethyl acetate (×2), then these organic extracts were combined and washed with brine, dried (MgSO4), filtered and concentrated to give a crude product that was recrystallised from water to afford (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid (12 mg, 5%); LCMS (PS-A3) Rt 5.33 min [M+H]+ 378. 1H NMR (DMSO-d6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br.s).
Reaction SMILES: CO.[CH2:3]([O:6][C:7]([CH2:9][N:10]1[C@H:13]([S:14]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:12]([CH:34]([OH:36])[CH3:35])[C:11]1=[O:37])=[O:8])[CH:4]=[CH2:5].[N+]([O-])([O-])=O.[Ag+:42]>N1C=CC=CC=1>[OH:36][CH:34]([C@@H:12]1[C@@H:13]([S-:14])[N:10]([CH2:9][C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[O:8])[C:11]1=[O:37])[CH3:35].[Ag+:42]
Reactant: C=CCOC(=O)CN1C(=O)[C@H](C(C)O)[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: c1ccncc1
Product: C=CCOC(=O)CN1C(=O)[C@H](C(C)O)[C@H]1[S-]
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a 50 ml flask equipped with a nitrogen atmosphere add 10 ml of methanol and 460 mg of (3S,4R)-1-(allyloxycarbonylmethyl)-3-(1-hydroxyethyl)-4-(triphenylmethylthio)azetidin-2-one. To this system add 160 mg silver nitrate and 0.15 ml of pyridine. Stir the system at 20° C. for 1 hour. Stop the reaction and remove the methanol by stripping to give the title compound.
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].CCCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19][CH:18]([C:17]([O:21][CH3:22])=[O:20])[O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccccc2)N(Cc2ccccc2)O1
Yield: 71 %

Procedure:
A solution of 8.0 g (37.9 mmol) of N-benzylidenebenzylamine N-oxide and 6.69 g (77.7 mmol) of methyl acrylate in 20 ml of toluene is heated under reflux for 12 hours. The reaction mixture is evaporated under reduced pressure to give a pale yellow oil. Flash chromatography (silica gel, 2:1 heptane:ethyl acetate) affords 8.0 g of the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:18][C:17]2[C:16]3[O:19][C@@:20]45[CH2:30][CH2:29][C@H:28]([OH:31])[C:27]([CH3:33])([CH3:32])[C@@H:26]4[CH2:25][CH2:24][C@H:23]([CH3:34])[C@@:21]5([CH3:35])[CH2:22][C:15]=3[C:14]([OH:36])=[CH:13][C:12]=2[C:11]1=[O:37])=[O:9])([CH3:6])([CH3:5])[CH3:4].[P:38](Cl)(=[O:53])([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:18][C:17]2[C:16]3[O:19][C@@:20]45[CH2:30][CH2:29][C@H:28]([OH:31])[C:27]([CH3:33])([CH3:32])[C@@H:26]4[CH2:25][CH2:24][C@H:23]([CH3:34])[C@@:21]5([CH3:35])[CH2:22][C:15]=3[C:14]([O:36][P:38]([O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([O:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:53])=[CH:13][C:12]=2[C:11]1=[O:37])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OP(=O)(Oc4ccccc4)Oc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
Under nitrogen, 40 mg (1.0 mmol) of sodium hydride (ca. 60% in oil) was added to a solution of the above Compound (55a) (234 mg, 0.48 mmol) in 2 ml of dry dimethylformamide, and the mixture stirred for 15 min. To the reaction mixture was added dropwise 120 μl (0.58 mmol) of diphenyl phosphorochloridate, and the mixture stirred for another 1.5 hours at the same temperature. After addition of ice-water under ice-cooling, the reaction 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 a column chromatography (silica gel 15 g; n-hexane:ethyl acetate=2:1) to give 277 mg (80%) of Compound (56a) as an oily material.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:21][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:28][C:26]2[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C(C)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1C(C)C(N)=O
Yield: 59 %

Procedure:
A mixture of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)propanamide A49 (0.250 g, 0.823 mmol), 1-methyl-1H-pyrazol-4-amine (0.096 g, 0.99 mmol), and p-toluenesulfonic acid monohydrate (0.016 g, 0.082 mmol) in 1,4-dioxane (5 mL) was irradiated in the microwave at 120° C. for 3 hours. The volatiles were removed in vacuo and the residue was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 50-100% EtOAc in petroleum benzine 40-60° C., then 0-10% MeOH in EtOAc). The fractions containing suspected product were combined and the solvent removed in vacuo to give a green solid. The solid was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-10% MeOH in CHCl3) to give the title compound 51 as a white solid (0.178 g, 59%); 1H NMR (400 MHz, d6-DMSO) δ ppm 9.16 (s, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.46 (s, 1H), 7.41-7.35 (m, 1H), 7.24 (s, 1H), 7.20-7.10 (m, 3H), 6.87 (s, 1H), 3.86 (q, J=7.1, 7.0, 7.0 Hz, 1H), 3.78 (s, 3H), 3.23-3.11 (m, 1H), 3.08-2.97 (m, 1H), 2.96-2.78 (m, 2H), 2.05 (s, 3H), 1.33 (d, J=6.9 Hz, 3H). LCMS-D: rt 2.99 min; m/z 365 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:31]3[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=3[F:36])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3F)c(-c3ccc(OC)cc3)c12
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Dissolve 150 mg (0.34 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 106 mg (0.70 mmol) (2,6-difluorophenyl)boronic acid in 3.5 ml toluene and 1.0 ml ethanol, and add 0.34 ml of 2 M aqueous sodium carbonate solution and 25 mg (0.03 mmol) 1,1′-bis(diphenylphosphano)ferrocene palladium(II) chloride. Next, stir for 15 h at 70° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 13 mg (8% of theor.) of the desired product is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:4].Cl.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[C:8]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10](=[O:15])[CH2:9]4)=[O:4])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)CC(=O)N2
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2c(c1)CC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide (Example 143a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 178-180° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[F:13][C:14]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15]1>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:16]1[CH2:17][CH2:18][C:14]([F:19])([F:13])[CH2:15]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1Br)N1CCC(F)(F)C1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (0.300 g, 1.17 mmol) and 3,3-difluoropyrrolidine hydrochloride (0.169 g, 1.17 mmol) in pyridine (5 mL) was stirred for 16 hours at 60° Celsius. The reaction was then cooled to rt, diluted with EtOAc (25 mL), washed with 1 N HCl (2×25 mL), and brine (50 mL). The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to yield the title compound (0.335 g, 86%), The product was used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.13-8.09 (m, 1H), 7.80-7.76 (m, 1H), 7.50-7.41 (m, 2H), 3.74 (t, J=12.8, 2H), 3.67 (t, J=7.2, 2H), 2.44-2.35 (m, 2H).
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].Cl[C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([NH2:17])[N:9]=1>O>[CH2:2]([O:6][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([NH2:17])[N:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCO
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: O
Product: CCCCOc1nc(N)c2[nH]cnc2n1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Sodium (13.6 g, 0.59 mol) was added to butanol (480 ml), the temperature of the mixture was raised to 90° C. to completely dissolve sodium therein. Subsequently, 2-chloroadenine (4.0 g, 23.6 mmol) was added, and the resultant was heated under reflux for 9 hours. After the reaction solution was cooled to 4° C., water (400 ml) was added thereto, and the resultant was vigorously stirred for 30 minutes. The separated layer of butanol was concentrated under reduced pressure, water (400 ml) was added to the residue, and concentrated hydrochloric acid was added dropwide under ice cooling to neutralize the product. The precipitated solid was collected by filtration, the resulting solid was added to ethanol (70 ml), and the resultant was heated under reflux for 30 minutes. The product was cooled to room temperature, and the precipitated solid was then collected by filtration. Thus, 3.72 g of the title compound was obtained (yield: 76%).