Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:40])[N:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[C:24]([CH2:30]Cl)=[N:25]2>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:30][C:24]3[N:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])[C:22](=[O:40])[C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[Cl:19])[N:25]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(Cn2ccc(=O)c3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one (0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 100° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of :MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as yellow solid (0.1707 g, 60%). The yellow solid was triturated with MeOH and filtered to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=13 nM] as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.20 (1 H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1 H, d, J=7.8 Hz), 7.65-7.72 (1 H, m), 7.49-7.59 (3 H, m), 7.37 (1 H, dd, J=8.2, 1.2 Hz), 7.31 (1 H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1 H, m), 6.20 (1 H, d, J=8.2 Hz), 4.91-5.13 (2 H, m), 3.85 (3 H, s). Mass Spectrum (ESI) m/e=461.0 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[C:16]1[N:17]2[N:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]([O:28]CC)=[O:27])=[C:18]2[S:19][CH:20]=1.Cl>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[C:16]1[N:17]2[N:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]([OH:28])=[O:27])=[C:18]2[S:19][CH:20]=1
Reactant: CCOC(=O)c1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(OC)c(-c2csc3c(C(=O)O)c(OC)nn23)c(OC)c1
Yield: 96.7 %

Procedure:
After adding ethanol (124 mL) and aqueous 5N sodium hydroxide (11 mL, 55 mmol) in that order to ethyl 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazole-7-carboxylate (2.8 g, 6.89 mmol), the mixture was heated to reflux for 2 hours. Aqueous 5N hydrochloric acid (11 mL) was then added to the mixture while cooling on ice, and the solvent in the mixture was distilled off under reduced pressure. Water was added to the residue, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (2.52 g, 6.66 mmol).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1([NH:11][N:12]=[CH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:16][C:14]1[C:13]([C:1](=[O:2])[CH3:3])=[N:12][N:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:15]=1
Reactant: CC(=O)C=NNC1CCCCC1
Reactant: O=CC=O
Solvent: O
Product: CC(=O)c1nn(C2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
A 40% aqueous solution of glyoxal (1.73 mL, 15.1 mmol) was added to 2-oxopropanal cyclohexyl-hydrazone (2.54 g, 15.1 mmol) in H2O (125 mL). The mixture was then heated at reflux. After 1 hour, the mixture was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 3.22 g of 1-(4-hydroxy-1-cyclohexyl-1H-pyrazol-3-yl)ethanone as a yellow oil. The crude product was then used in the next step without further purification.
Reaction SMILES: C(Cl)(Cl)Cl.Cl.[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([OH:12])=O)[CH2:8]1.ClC(OCC(C)C)=O.[CH:24]1([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([NH:33][CH2:32][CH:24]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:12])[CH2:8]1
Reactant: NCC1CCCCCCC1
Reactant: CN1CCCC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCCC(C(=O)NCC2CCCCCCC2)C1
Yield: 62 %

Procedure:
To 80 ml of chloroform were added 3.59 g of 1-methylnipecotic acid hydrochloride and 6.26 ml of triethylamine. Thereto was added 3.0 g of isobutyl chloroformate under ice cooling and stirring. The mixture was stirred for 30 minutes. Thereto was added 3.1 g of cyclooctylmethylamine, and the mixture was subjected to a reaction for 2 hours at room temperature. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was purified by a Silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 3.3 g of 1-methyl-3-cyclooctylmethylaminocarbonylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[N:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([C:10]#[N:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1C#N

Procedure:
Using 2-chloro-4-fluoroisophthalonitrile (503 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (629 mg) and lithium carbonate (259 mg), the title compound was obtained as a pale-yellow solid (yield: 540 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]#[N:28])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])C(C#N)=[N:16]3)=[CH:11][C:10]=2[O:25][CH3:26])=[CH:4][CH:3]=1.Cl.[C:30]([OH:33])(=[O:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]#[N:28])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[C:31]([C:30]([OH:33])=[O:32])=[N:16]3)=[CH:11][C:10]=2[O:25][CH3:26])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(-n2nc(C#N)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Agent: Cl
Product: COc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of 4 parts of 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile, 24 parts of concentrated hydrochloric acid and 40 parts of acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated in vacuo and the residue is stirred in water. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is dried, filtered and evaporated, yielding 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:9][N:10]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:12]([CH3:19])[C:11]1=[O:20]>Cl.C(O)C>[CH3:19][N:12]1[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:14][N:10]([N:9]=[CH:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[C:11]1=[O:20]
Reactant: O=Cc1cccnc1
Reactant: Cn1c(C(C)(C)C)cn(N)c1=O
Agent: Cl
Solvent: CCO
Product: Cn1c(C(C)(C)C)cn(N=Cc2cccnc2)c1=O

Procedure:
4.3 g of 3-formylpyridine and two drops of concentrated hydrochloric acid are added to a solution of 6.8 g of 1-amino-2,3-dihydro-3-methyl-2-oxo-4-tert-butyl-1H-imidazole in 50 ml of ethanol. The reaction mixture is refluxed for 30 minutes with stirring and then substantially concentrated. The liquid residue is dissolved in a small amount of diethyl ether, and the solution is cooled to 0°. The crystals which have separated out are filtered off with suction and dried. This gives the title compound which melts at 116°-121°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]#[N:22]>>[C:21]([CH:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:23]([CH3:26])([CH3:25])[CH3:24])#[N:22]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)C(N)C#N
Product: CC(C)(C)C(C#N)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3,3-dimethyl-butyronitrile (CAN 77425-86-6) as starting materials and isolated (782 mg, 90%); MS (ESI, m/z): 356.2 (M+H+).
Reaction SMILES: [C:1]([CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([OH:12])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=[O:3])[NH2:2].[H-].[Na+].Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:5]([OH:12])([CH2:4][C:1](=[O:3])[N:2]([C:24]([O:26][CH3:27])=[O:25])[C:24]([O:26][CH3:27])=[O:25])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)C(=O)OC
Reaction time: 1 h
Yield: 4.8 %

Procedure:
3-Carbamoyl-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.94 g., 3 mmole) was added to a suspension of oil-free sodium hydride (0.14 g., 5.8 mmole) in dry tetrahydrofuran (10 ml). The suspension was stirred for one hour and then a solution of methyl chloroformate (0.6 g., 6.3 mmole) in dry tetrahydrofuran (10 ml) was added dropwise over 15 minutes. The mixture was stirred at room temperature for three hours and then the solvent was evaporated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and ethyl acetate (40 ml), and the organic phase was separated, washed with brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methanol 95:5 (v:v), and the fractions containing the product were combined and evaporated and recrystallized from ethyl acetate-hexane to give the title compound, (62 mg, 5%), m.p. 155°-156° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1>CCO.CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc(C)c1O
Reaction time: 72 h

Procedure:
A suspension of 222 mg (0.30 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 10.3) and 60 mg 10% Pd/C in 10 mL EtOH and 6 mL MeOH was hydrogenated at 60 psi and RT for 72 h. The catalyst was filtered off and the crude product was purified by HPLC-MS.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[CH:3]2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc2cc(Br)ccc2c1F
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3c2)cc1

Procedure:
Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-boronobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.04 (b, 1H), 10.23 (b, 1H), 8.29 (s, 1H), 7.91-8.01 (m, 7H), 7.74 (d, 1H). MS (ESI): m/z=281.26 [M−1]−.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])C.C1COCC1.O.O[Li].O>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH.H2O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50° C. overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39]O)=[CH:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cn1cc(CO)c2ccccc21
Product: Cn1cc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (1-methyl-1H-indol-3-yl)-methanol according to the procedure of Example 69. MS (ES) m/z 523.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH2:26])[N:20]=1)C1C=CC=CC=1>C(O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:20]=2)[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1ccccc1)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1)c1cccc(-c2cccc(C(C)(C)C)c2O)n1
Reaction time: 3 h
Yield: 36 %

Procedure:
Compound 13 (1.0 g, 2.38 mmol, 1.0 equiv) was dissolved in ethanol (30 mL) and 10% palladium (50% aqueous) on carbon (0.2 g) was added. The material was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 3 hr. The reaction was filtered through a bed of Celite and rinsed with dichloromethane (100 mL). The product was absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (50 g) by eluting with ethyl acetate (0.5%) in heptanes (800 mL). The desired product was isolated pure in 36% yield (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH:27]([C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][C:31]1[CH:41]=[CH:42][CH:43]=[C:29]([C:27]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Br:26])[C:6]([N:11]4[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:19])[NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)[CH2:13][CH2:12]4)=[C:7]3[N:8]=2)[CH:30]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 5 h
Yield: 27.5 %

Procedure:
To 2-[4-(2-Amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.1 g, 0.22 mmol) in ethanol (5 ml) was added tert-butyl N-(3 formylbenzyl)carbamate (69 mg, 0.29 mmol) and 1M aq. Na2S2O4 (900 μL, 0.9 mmol). The reaction mixture was stirred at 80° C. for 16 h. tert-Butyl N-(3 formylbenzyl)carbamate (20 mg, 0.08 mmol) and 1M aq. Na2S2O4 (200 μL, 0.2 mmol) were added and the reaction mixture was stirred for another 5 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (100% dichloromethane to dichloromethane/ethyl acetate 1:1+1% methanol to 2% methanol in ethyl acetate). The isolated product was further triturated in ether, filtered, and dried in vacuo to give the title compound as a pale yellow solid (0.038 g, 27%); 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, CH3 Boc), 2.78 (broad s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, CH2CO), 3.70 (broad s, 4H, piperazine N(CH2)2), 4.22 (d, J=6.23 Hz, 2H, CH2NHBOC), 7.24 (d, 1H, J=3.60 Hz, thiazole 4-H or 5-H), 7.37 (d, J=7.21 Hz, 1H) and 8.02 (d, J=7.21 Hz, 1H) (4-ArH, and 6-ArH), 7.47 (m, 1H, 5-ArH), 7.49 (d, J=4.12 Hz, 1H, thiazole 4-H or 5-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.54 (s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:11]2[O:12]CC(C)(C)N=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O:27]C1C=C(CC#N)C=C(CCC)C=1OC>>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([OH:12])=[O:27]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reactant: CCCc1cc(CC#N)cc(OC)c1OC
Product: COc1ccc(C(=O)O)c(CCc2ccccc2)c1OC

Procedure:
Similarly prepared from the corresponding product of step (a) or (b) were:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[O:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[CH:23]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[O:26][CH:25]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)furan-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 14%). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.40-8.35 (m, 2H), 8.16 (m, 1H), 8.02-7.94 (m, 4H), 7.82-7.80 (m, 1H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.36-7.31 (t, J=9.0 Hz, 2H), 3.53-3.51 (d, J=6.1 Hz, 2H), 1.30 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O4: 500.14. found: 499.5 (M−H)−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(C)c1ccccc1
Reactant: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate is made by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of alpha-methylstyrene in the presence of 25.7 grams (0.135 moles) of P-toluenesulfonic acid monohydrate catalyst. This mixture is heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture is cooled at 110° C. and 1125 ml of toluene is added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride, the organic phase is washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product is obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melts at 63°-65° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a suspension of methanesulfonamide (4.75 g, 50 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (1.98 g, 49.5 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3.66 g, 10 mmol) and 1,1′-carbonyldiimidazole (3.24 g, 20 mmol) in N,N-dimethylformamide (7 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (0.99 g, 22%) as a white solid: LC/MS m/e calcd for C23H29N3O4S (M+H)+: 444.57, observed: 444.1.