Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.Cl.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:17]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.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]>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[CH2:17]2)[CH:11]=1
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2nc(N[C@H]3CCN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C3)cc(C)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a mixture of 2-chloro-4,6-dimethylquinoline (0.20 g), Pd2(dba)3 (0.048 g), (±)-BINAP (0.10 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.75 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.45 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain colorless amorphous (S)-1-(3-(4,6-dimethylquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.30 g).
Reaction SMILES: C(O)C.[NH2:4][OH:5].C[O:7][C:8](=O)[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]>C1COCC1>[OH:5][NH:4][C:8](=[O:7])[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Ethanol (1.0 mL) and a 50% aqueous solution (1.0 mL) of hydroxylamine were added to a THF (1.0 mL) solution of 4-{3-[(4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]propyl}morpholine (0.11 g) as obtained in Example 4-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=90/10), and then recrystallized from ethyl acetate/hexane to obtain N-hydroxy-N′-methyl-2-[methyl({4′-[3-(morpholin-4-yl)propoxy]biphenyl-4-yl}carbonyl)amino]propanediamide (Compound 7, light brown solid) (43 mg, 39%).
Reaction SMILES: CC1CCCN(C)C1(C)C.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][OH:25].CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[Br:16][C:17]1[C:18]([CH2:24][OH:25])=[CH:19][C:20]([F:23])=[C:21]([CH:22]=1)[CH:28]=[O:29]
Reactant: OCc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(CO)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 106.7 %

Procedure:
Tetramethylpiperidine (0.68 g, 4.87 mmol) was dissolved in tetrahydrofuran (4.5 mL). To the resultant solution was added n-butyllithium (1.0 M n-hexane solution, 4.88 mL) at 0° C., and the solution was then stirred for 15 minutes. The solution was cooled to −78° C., and a solution of (2-bromo-5-fluorophenyl)-methanol (0.50 g, 2.43 mmol) in tetrahydrofuran (2.5 mL) was added dropwise. The temperature of the solution was raised over 2 hours to −40° C. The solution was again cooled to −78° C., and N,N-dimethylformamide (0.47 mL, 6.07 mmol) was added thereto. The temperature of the solution was raised to room temperature, and the solution was then stirred for 30 minutes. Saturated aqueous ammonium chloride was added, and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to thereby obtain the titled compound (604.3 mg, quantitative).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([O:19]CC)=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:27][CH2:26]1>C(O)C.O>[F:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([OH:19])=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cn(C)c2cnc3c(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)c(F)ccc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2c3ccc(F)c(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)c3ncc21
Temperature: 80 °C
Yield: 50.4 %

Procedure:
1.02 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.46 g of ethyl 8-fluoro-7-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 5 cm3 of ethanol and 4 cm3 of water. The mixture was heated at about 80° C. for 2 hours and then evaporated to dryness. The residue was dissolved in 20 cm3 of water, the aqueous phase was washed with 20 cm3 of dichloromethane, acidified with 0.06 cm3 of acetic acid and then extracted 3 times with 50 cm3 of dichloromethane. The organic phase was dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa). The residue obtained was washed twice with 5 cm3 of diisopropyl ether and dried. 0.22 g of 8-fluoro-7-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted at 245° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1.Br[CH2:37][CH2:38][OH:39].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][N:33]([CH2:37][CH2:38][OH:39])[CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCNCC6)cn5)C4)c3n2)cn1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCN(CCO)CC6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (71 mg, 0.14 mmol) was dissolved in DMF (2 ml), and then 2-bromoethanol (16 μl, 0.22 mmol), K2CO3 (100 mg, 0.72 mmol), and Et3N (100 ul, 0.72 mmol) were added, followed by stirring at room temperature overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give 2-(4-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (10 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.[ClH:8].[C:9](=[NH:15])(OCC)[CH2:10][CH3:11]>C(#N)C>[ClH:8].[CH3:7][C:6]1[C:2]([NH:1][C:9](=[NH:15])[CH2:10][CH3:11])=[N:3][NH:4][CH:5]=1
Reactant: CCOC(=N)CC
Reactant: Cc1c[nH]nc1N
Agent: Cl
Solvent: CC#N
Product: CCC(=N)Nc1n[nH]cc1C
Reaction time: 1 h

Procedure:
A 8.06 g portion of 3-amino-4-methyl-1H-pyrazole was dissolved in 30 ml of acetonitrile and, with cooling on an ice bath, 12.9 g of ethyl propionimidate hydrochloride was added to the solution. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature. After removing insoluble materials by filtration, the resulting filtrate was concentrated under a reduced pressure, and the thus obtained residue was subjected to silica gel column chromatography. Elution with methanol-chloroform (1:9-3:7, v/v) gave 8.40 g of N-(4-methyl-1H-pyrazol-3-yl)propionamidine hydrochloride.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][C:8]1[N:9]([CH2:19][CH2:20][CH3:21])[C:10]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:2][CH3:3].[OH-].[Na+]>[Ni].C(O)C>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][N:4]([CH2:22][CH2:23][CH3:24])[CH2:1][CH2:2][CH3:3])[N:9]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH:16]=1
Reactant: CCCN(CCC)CCCc1nc2ccc(C#N)cc2n1CCC
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCc1nc2ccc(CN)cc2n1CCC
Reaction time: 6 h
Yield: 66.4 %

Procedure:
An ethanol solution (12 ml) containing the compound (0.363 g) obtained in Example 46-5 was added with a 1 mol/l sodium hydroxide aqueous solution (3.6 ml) and added with Raney nickel (120 mg). The whole was stirred for 6 hours under a hydrogen atmosphere. The catalyst was removed by filtration through Celite and the solvent was distilled off. After that, the resultant was partitioned into chloroform and water. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (0.244 g) as a colorless liquid.
Reaction SMILES: [C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.O.C(=O)([O-])[O-].[Li+].[Li+].[Cl-].[Li+]>CN(C=O)C>[C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Temperature: 120 °C

Procedure:
A mixture of (S)-(+)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.397 g, 1.31 mmol), cupric chloride dihydrate (0.513 g, 3.01 mmol), and acetic acid/water (1:1, 4 mL) is heated at 120° C. for 6 h. After cooling, the mixture is partitioned between dichloromethane, water, and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate, concentrated, and stored over the weekend in the freezer. The mixture is then stirred at 130-140° C. with lithium carbonate (0.106 g, 1.44 mmol), lithium chloride (0.061 g, 1.44 mmol), and DMF (3 mL). After cooling, the mixture is partitioned between dichloromethane and sat'd aq. ammonium chloride. The organic layers are dried over sodium sulfate, concentrated, and the residue is chromatographed on silica gel gel (60 mL) using ethyl acetate/hexane (10/90) to give 0.184 g (47% for both steps) of (S)-(+)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol. [α]D=+98°(MeOH).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:52])[CH2:14][C:15]1([CH2:44][C:45](=[O:51])[O:46]C(C)(C)C)[O:19][N:18]=[C:17]([C:20]2[CH:25]=[C:24]([O:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=3)[CH:23]=[CH:22][C:21]=2[CH2:39][CH2:40][C:41]([OH:43])=O)[CH2:16]1)(C)(C)C.[NH2:53][CH2:54][CH2:55][S:56]([OH:59])(=[O:58])=[O:57].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>O.C(#N)C.CN(C=O)C>[NH:34]([C:31]1[CH:30]=[CH:29][C:28]([C:27]([O:26][C:24]2[CH:23]=[CH:22][C:21]([CH2:39][CH2:40][C:41](=[O:43])[NH:53][CH2:54][CH2:55][S:56]([OH:59])(=[O:58])=[O:57])=[C:20]([C:17]3[CH2:16][C:15]([CH2:14][C:13]([OH:12])=[O:52])([CH2:44][C:45]([OH:46])=[O:51])[O:19][N:18]=3)[CH:25]=2)=[O:38])=[CH:33][CH:32]=1)[C:35]([NH2:37])=[NH:36]
Reactant: NCCS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2CCC(=O)O)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(CCC(=O)NCCS(=O)(=O)O)c(C3=NOC(CC(=O)O)(CC(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-((4-carbamimidamidobenzoyl)oxy)phenyl)propanoic acid trifluoroacetate (160 mg), taurine (32.5 mg), WSC (50.4 mg), HOBt (43.9 mg), N,N-diisopropylethylamine (0.057 mL), and DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). The obtained fraction was concentrated under reduced pressure. To the obtained residue, TFA (4 mL) was added, and the obtained mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then, the pH of the residue was adjusted to about 4 by the addition of an aqueous ammonium acetate solution. The mixture was stirred at room temperature for 2 hours, and then, the obtained solid was collected by filtration and washed with water and acetone to obtain the title compound (40.3 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:15]([O:17]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:16].Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([C:15](=[O:17])[CH3:16])=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) (1.78 g, 7 mmol), 1-ethoxyvinyltributyltin (EVTB) (3.3 g, 9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23 mmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. To the reaction, additional EVTB (1.5 g, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) were added and the mixture was and refluxed for an additional 24 h. The reaction mixture was cooled to room temeperature and 10% hydrochloric acid (10 ml) was added. After 10 min, the mixture was extracted with ether (3×50 mL), the combined organic layer was washed with water (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesium sulfate. Solvent was removed under reduced pressure, and after purification by flash chromatography the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:8]=3[NH:7][C:6](=O)[C:5]=2[CH:4]=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>C1COCC1>[CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)C(=O)N2
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 3,6-dimethyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E2.3 (2.35 g, 10.3 mmol) in anhydrous THF (100 ml) at 0° C. was added lithium aluminium hydride (1.56 g, 41.2 mmol), and the resulting suspension was heated at reflux for 18 h then allowed to cool to room temperature. A further portion of lithium aluminium hydride (781 mg, 20.6 mmol) was added, and the mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (1.60 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH:23]=[O:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(C=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxaldehyde (Example 18) (1.4 g, 3.9 mmol) in EtOH (30 ml), sodium borohydride (297 mg, 7.84 mmol) was added. After heating at reflux for 3 hours, the reaction mixture was cooled to room temperature and quenched with acetic acid. The solvent was removed under reduced pressure and the residue was redissolved in methylene chloride. After washing with 1N HCl and brine, the organic fractions were filtered, concentrated and purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-methanol (1.4 g, 100%) as a white solid: mp (DSC) 148° C. Anal Calc'd. for C19H18NSFO3 ·0.4 H2O: C, 62.25; H, 5.17; N, 3.82; S, 8.75. Found: C, 62.29; H, 4.87; N, 3.86; S, 8.86.
Reaction SMILES: [C:1]([C:4]1([C:29]([OH:31])=[O:30])[CH2:7][CH:6]([C:8]2([CH2:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12]C(=O)N[C:9]2=[O:14])[CH2:5]1)([OH:3])=[O:2].[OH-:32].[Na+]>>[NH2:12][C:8]([CH:6]1[CH2:7][C:4]([C:1]([OH:3])=[O:2])([C:29]([OH:31])=[O:30])[CH2:5]1)([CH2:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]([OH:32])=[O:14]
Reactant: O=C1NC(=O)C(CC(c2ccccc2)c2ccccc2)(C2CC(C(=O)O)(C(=O)O)C2)N1
Reactant: [OH-]
Agent: [Na+]
Product: NC(CC(c1ccccc1)c1ccccc1)(C(=O)O)C1CC(C(=O)O)(C(=O)O)C1

Procedure:
A solution of 5-(3,3-dicarboxycyclobutyl)-5-(2,2-diphenylethyl)imidazolidine-2,4-dione (0.21 g, 0.5 mmol) in 2M sodium hydroxide (4 ml) was heated to 150° C. for 4 days in a PTFE lined stainless steel pressure vessel. After cooling, the mixture was filtered and the filtrate acidified with 5M hydrochloric acid (2 ml). The precipitate was cooled and filtered, washed with water and dried to give the title product (m.p. 182-185° C. with effervescence). 1H NMR (D2O/NaOH) δ 7.21-7.50 (10H, m)), 4.06 (1H, dd), 2.44-2.63 (2H, m), 2.11-2.38 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CCOCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of a solution of 4-fluorophenyl-magnesium bromide in ether (2 M, 12.5 mL, 25 mmol) and anhydrous tetrahydrofuran (25 mL) was stirred at ambient temperature under a nitrogen atmosphere. A solution of 1-benzyl-4-formylmethylpiperidine (3.6 g, 16.6 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise. The reaction mixture was stirred for 19 hours, then it was poured onto a saturated ammonium chloride solution, mixed and extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate:hexanes:1:1) gave the product, a pale yellow solid (Rf =0.08, 2.7 g):mp=84°-86° C.; 1H-NMR:7.4-7.25(m,7H), 7.0(t,2H,J=8), 4.7(dd,1H,J=8,6), 3.45(s,2H), 2.9-2.75(m,2H), 2.1-1.2(m,10H); HR-MS:Calcd for C20H24FNO:313.1842; Found:313.1862.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[OH:12])[CH2:3]1)[CH2:9]2.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>CS(C)=O.O>[Cl:19][C:20]1[C:21]([O:12][CH:5]2[CH:4]3[CH2:10][CH:8]4[CH2:9][C:2]([Cl:1])([CH2:11][CH:6]2[CH2:7]4)[CH2:3]3)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: OC1C2CC3CC1CC(Cl)(C3)C2
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OC2C3CC4CC2CC(Cl)(C4)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 5-chloroadamantan-2-ol (2.00 g, 10.70 mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide (3.01 g, 26.80 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (2.06 g, 10.70 mmol) was added to the reaction mixture, stirring was continued for 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueous hydrochloric acid solution and diluted with water (100 mL), the white precipitate was filtered, washed with water and dried to afforded the title compound as colorless solid (3.30 g, 86%), containing o-substituted regioisomer, which was used for next step without further purification: MS (ES+) m/z 359.2, 361.2 (M+1), MS (ES−) m/z 357.1, 359.1 (M−1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1.CCOCC>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:36](=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)CCC(=O)O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 108.5 %

Procedure:
To a solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (25 mg, 0.05 mmol) in dichloromethane (4 mL) was added succinic anhydride (6 mg, 0.6 mmol). The resultant solution was stirred overnight and then ether was added. The precipitated solids were recovered by filtration to give 4-[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoic acid (31 mg, 99%) as a white solid. 1H NMR (CDCl3/CD3OD): δ 7.71 (m, 2 H), 7.47 (d, 2 H), 7.32 (m, 1 H), 6.97 (d, 2 H), 6.15 (d, 1 H), 6.04 (d, 1 H), 4.30 (m, 1 H), 3.88 (s, 3 H), 3.38–3.27 (m, 4 H), 2.62 (m, 2 H), 2.45 (m, 2 H), 2.10–2.00 (m, 2 H), 1.84–1.55 (m, 10 H); MS m/z 572 (M+1).