Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 50 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of amine (S)-N1,N1-dimethyl-3-phenylpropane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM) to afford 23 mg of biphenyl amide 51. Yield 45%.
Reaction SMILES: O[Li].O.[CH3:4][CH:5]([CH3:24])[CH2:6][S:7]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)(=[O:9])=[O:8]>O.CO.C1COCC1>[CH3:4][CH:5]([CH3:24])[CH2:6][S:7]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)(=[O:8])=[O:9]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)CC(C)C)CC2
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CS(=O)(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Reaction time: 6 h

Procedure:
LiOH.H2O (200 mg, 4.8 mmol, 3 eq) in water (3 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(2-methylpropylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-03) (500 mg, 1.6 mmol, 1 eq) in MeOH:THF (1:1, 12 ml), and stirring was carried out for 6 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 2 with 2M HCl solution and extracted with dichloromethane (2×80 ml). The combined organic phases were washed with sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated and dried under reduced pressure. Yield: 450 mg
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
53 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(4-methoxyphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [O:1]=[C:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:27](N(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2](=[O:1])[C:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:27][N:28]([CH3:30])[CH3:29])[CH3:8]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)C(C(=O)Cc1ccccc1)c1ccccc1
Product: CCOC(=O)C(C(=O)C(=CN(C)C)c1ccccc1)c1ccccc1

Procedure:
Ethyl 3-oxo-2,4-diphenyl-butyrate (76 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (102 mg) as a red oil which was used directly in the next step.
Reaction SMILES: OC1C=C(C=CC=1)C=O.N1CCSCC1.[BH4-].[Na+].[S:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1.Cl.Cl[CH2:34][CH2:35][CH2:36][NH2:37].[H-].[Na+]>>[S:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:20][CH2:19]1
Reactant: Oc1cccc(CN2CCSCC2)c1
Reactant: NCCCCl
Agent: C1CSCCN1
Agent: Cl
Agent: O=Cc1cccc(O)c1
Product: NCCCOc1cccc(CN2CCSCC2)c1

Procedure:
By operating as described hereinabove, by reacting 0.2 mol of 3-hydroxybenzaldehyde with 0.4 mol of thiomorpholine in the presence of 0.2 mol of sodium borohydride (as in PREPARATION 1(a) 3-thiomorpholinomethylphenol is obtained, which, treated with an excess of 3-chloropropylamine hydrochloride in the presence of sodium hydride (as in PREPARATION 1(b), gives 3-(3-thiomorpholinomethylphenoxy)propylamine, in the form of an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[C:7](Cl)(=O)[CH2:8][CH3:9].C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([CH2:8][CH3:9])[O:6][N:5]=1
Reactant: N=C(CCl)NO
Reactant: CCC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 1.80 g of propionyl chloride were dissolved in 50 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. The mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.62 g of 3-(chloromethyl)-5-ethyl-1,2,4-oxadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.Br.[H][H]>CCOC(C)=O.CC(O)=O.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)CCC=Cc1cccc(Br)c1
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCc1cccc(Br)c1
Yield: 77.8 %

Procedure:
To a solution of 5-(3-Bromo-phenyl)-pent-4-enoic acid (4 g, 16 mmol) in EtOAc (150 mL) was added Pd/C (400 mg) and a solution of 40% HBr in AcOH (0.5 mL). The mixture was stirred at rt under 1 atm of hydrogen for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a solvent system of 5:1 petroleum ether/EtOAc to give 5-(3-Bromo-phenyl)-pentanoic acid (3.2 g, 80%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.3-7.4 (m, 2H), 7.05-7.15 (m, 2H), 2.55 (s, 2H), 2.35 (s, 2H), 1.7 (m, 4H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C(OC)(OC)OC.[NH2:15][C:16]1[C:17]2[C:24]([C:25]#[C:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)=[CH:23][N:22]([C@@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]([NH:51][NH2:52])=[O:50])[CH2:38]3)[C:18]=2[N:19]=[CH:20][N:21]=1.C(O)(=O)C>O.C(OCC)(=O)C>[NH2:15][C:16]1[C:17]2[C:24]([C:25]#[C:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)=[CH:23][N:22]([C@@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@H:39]([C:49]4[O:50][CH:1]=[N:52][N:51]=4)[CH2:38]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Cc1ccccc1
Reactant: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Solvent: O
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: COc1cc(C#Cc2cn([C@H]3C[C@@H](c4nnco4)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Toluene (3 ml) and trimethyl orthoformate (79 μl) were added to the (2S,4S)-tert-butyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydrazine carbonyl)pyrrolidine-1-carboxylate (93.6 mg) obtained in Step 2, and the resulting mixture was stirred at 110° C. overnight. Acetic acid (400 μl) was added to the reaction mixture, and stirred at 110° C. for 6 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a light-yellow, amorphous substance (50 mg). Physical properties: m/z [M+H]+ 532.2
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:10]([C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([NH:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:37][C:2]2[N:7]3[N:8]=[C:9]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)[C:10]([C:11]4[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([NH:19][CH:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCC1
Reactant: Cc1cccc(-c2nn3c(Cl)cccc3c2-c2nc(NC3CCCC3)nc(C)c2C)c1
Product: Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2nc(NC3CCCC3)nc(C)c2C)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
A mixture of 4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine (80 mg, 0.19 mmol) and cyclopentylamine (2 mL, 20 mmol) was heated in a sealed tube at 90° C. for 3 hours followed by 125° C. for 24 hours. The reaction mixture was cooled to room temperature and excess cyclopentylamine was removed in vacuo. The crude residue was washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (5:1 hexanes:ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-5,6-dimethyl-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine (40 mg, 44%) as a clear oil. Rf 0.32 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 7.57 (s, 1H), 7.33 (d, 1H), 7.19–7.11 (m, 3H), 6.91 (d, 1H), 6.03 (d, 1H), 6.93 (d, 1H), 4.91 (d, 1H), 4.29 (m, 1H), 4.01 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.15 (m, 2H), 1.99 (broad, 2H), 1.87–1.40 (m, 15H); MS m/z 481 (M+1). To a solution of the product (20 mg) in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].CCCCCC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].[Cl-].[NH4+]>O1CCCC1>[OH:31][CH:30]([C:29]1[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:33][CH:32]=1)[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
Ethyl acetate (3.55 g, 40.3 mmol) was dissolved in tetrahydrofuran (100 mL), and a 1 M lithium bis(trimethylsilyl)amide hexane solution (40.0 mL, 40.0 mmol) was added thereto at −78° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at −78° C. for 20 minutes. Thereafter, a tetrahydrofuran solution of 4-nitrobenzaldehyde (5.08 g, 33.6 mmol) was added thereto at −78° C., and the resulting mixture was stirred under a nitrogen atmosphere at −78° C. for 30 minutes. To the reaction solution, a saturated aqueous solution of ammonium chloride was added at −78° C., and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 20:80 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (4.31 g, yield: 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][N:27]4[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]4)[NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.O.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([N:21]1[CH2:20][CH:19]([C:16]2[S:17][CH:18]=[C:14]([C:11]3[CH2:10][CH:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[O:13][N:12]=3)[N:15]=2)[CH2:24][CH2:23][N:22]1[C:25](=[O:37])[CH2:26][N:27]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:35])([F:36])[F:34])=[N:28]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1
Solvent: O
Product: CC(=O)N1CC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CCN1C(=O)Cn1nc(C(F)(F)F)cc1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3 isoxazolyl]-2-thiazolyl]tetrahydrol(2H)-pyridazinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (i.e. the product of Example 1) (0.24 g, 0.44 mmol) in acetic anhydride (2 mL) was heated at 100° C. overnight. The reaction mixture was cooled, water (30 mL) was added and the mixture was stirred for 30 min and then extracted with ethyl acetate. The ethyl acetate extract was washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfatate, filtered, and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0-100% gradient of ethyl acetate in hexane as eluant) to provide the title compound (150 mg), a compound of the present invention, as a dark foam.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[CH3:16][N:17](C=O)C.S(Cl)(Cl)=O.CN>ClCCCl.C(O)C>[CH3:16][NH:17][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Agent: CN
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CNC(=O)c1c(C)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6.0 g (29.6 mmol) of 3-methyl-5-phenyl-isoxazole-4-carboxylic acid in 150 ml DCE is added 0.3 ml of DMF and 2.6 ml (35.5 mmol, 1.2 eq.) of thionyl chloride. The mixture is stirred for 2 h at reflux until a brown solution is formed. The solution is cooled to room temperature and then slowly added to a 8M solution of methylamine in ethanol (18 ml) at 5° C. The suspension is poured onto methylene chloride, washed with sat. NaHCO3-solution, dried over Na2SO4 and concentrated. This yields 6.7 g (quant.) of the title compound as brown solid, which is used for further reactions without purification. Mass spectrum: m/z (M+H)+: 217.2
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:22][CH:23]([N:37]=C(C4C=CC=CC=4)C4C=CC=CC=4)[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:25])[CH:15]=[C:16]([Cl:21])[C:17]=3[O:19][CH3:20])[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CCOCC>[ClH:21].[NH2:37][CH:23]([CH2:22][C:14]1[CH:15]=[C:16]([Cl:21])[C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:9])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25]
Reactant: COc1c(Cl)cc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cnn(S(=O)(=O)c3ccccc3)c12
Agent: Cl
Solvent: CCOCC
Product: COc1c(Cl)cc(CC(N)C(=O)NCCCCc2ccccc2)c2cnn(S(=O)(=O)c3ccccc3)c12

Procedure:
3-(1-Benzenesulfonyl-6-chloro-7-methoxy-1H-indazol-4-yl)-2-(diphenylmethylenamino)-N-(4-phenyl-butyl)-propionamide (0.46 g, 0.65 mmol) is dissolved in Et2O (15 mL) and rapidly stirred with 2N HCl for 14 hours. The ether layer was decanted and the remaining aqueous layer was washed with Et2O. The aqueous layer was then concentrated and azeotroped to dryness with PhMe to provide 2-amino-3-(1-benzenesulfonyl-6-chloro-7-methoxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide hydrochloride which was used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].O[NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1)=[NH:9].C([O-])([O-])=O.[K+].[K+]>O>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([C:8]3[N:7]=[C:3]([CH2:2][Br:1])[O:4][N:9]=3)=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: O=C(Br)CBr
Reactant: N=C(NO)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: BrCc1nc(-c2ccc3c(c2)OCO3)no1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
Bromoacetyl bromide (0.22 g, 1.10 mmol) was added to N-Hydroxy-benzo[1,3]dioxole-5-carboxamidine (0.40 g, 0.55 mmol) and K2CO3 (0.38 g, 0.78 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 5% EtOAc-Hexane) to get the desired product (0.05 g, 31%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:35])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.49 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.37 g, 78%). MS (ISP) 474.0 [(M+H)+]; mp 208° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]3[N:20]=[C:21]([CH2:23][O:24]C(=O)C)[CH:22]=[C:16]3[C:15]2=[O:28])=[N:12][CH:13]=1>CO>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]3[N:20]=[C:21]([CH2:23][OH:24])[CH:22]=[C:16]3[C:15]2=[O:28])=[N:12][CH:13]=1
Reactant: CC(=O)OCc1cc2n(n1)CCN(c1ccc(F)cn1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1c2cc(CO)nn2CCN1c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
Potassium carbonate (63 mg, 0.46 mmol) was added to a stirred suspension of acetic acid 5-(5-fluoro-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (70 mg, 0.23 mmol) in MeOH (1 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(5-fluoro-pyridin-2-yl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 50% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)cc2)o1

Procedure:
The title compound was prepared analogous to Example 4, Step 4 starting from methyl 2-(4-(4′-(5-tert-butyl-1,3,4-oxadiazol-2-ylamino)biphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (82 mg, 0.17 mmol) and NaOH (0.52 ml, 0.52 mmol). After acidification with 1N HCl, the slurry was filtered and washed with water to afford the title compound as white solid after drying (75 mg, 95% yield). HR/MS (M+H)+ found 462.2396. calc. 462.2392. RT: 2.75 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (s, 1H) 10.51 (s, 1H) 7.62 (s, 4H) 7.58 (d, J=8.34 Hz, 2H) 7.38 (d, J=8.59 Hz, 2H) 3.90 (s, 2H) 2.33 (s, 2H) 1.82-2.07 (m, 8H) 1.36 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]3[CH:36]=[C:35]([NH2:37])[N:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([NH:37][C:35]1[CH:36]=[C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][N:18]([CH2:16][CH3:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)[N:32]=[CH:33][N:34]=1)=[O:15]
Reactant: CCN1CCN(c2ccc(Nc3cc(N)ncn3)cc2)CC1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2ccc(Nc3cc(NC(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.2 eq.) is added to a solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (350 mg, 1.18 mmol) in NMP (2 ml), at 70° C. and under an argon atmosphere. The resulting mixture is stirred at 70° C. for 2 h, allowed to cool to RT and concentrated. The residue is diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by trituration in MeOH followed by silica gel column chromatography (DCM/MeOH+1% NH3aq, 97:3) affords the title compound as a white solid: