Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.Cl.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1([NH:29][C:16]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=2)=[O:18])[CH2:28][O:27][CH2:26]1
Reactant: NC1(c2nccs2)COC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1ccc(C2CC2)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=400.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].I[CH2:16][CH3:17].C[O-].[Na+].C(OC1C=CC(OC)=CC=1C(N)=O)C>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:16][CH3:17])=[C:9]([CH:13]=1)[C:10]([NH2:12])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C(N)=O)c1
Reactant: CCI
Agent: CCOc1ccc(OC)cc1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(=O)OC)cc1C(N)=O

Procedure:
5-Carbomethoxy-2-ethoxybenzamide (m.p. 159°-161°) was prepared from 5-carbomethoxysalicylamide, iodoethane, and sodium methoxide in methanol in a manner analogous to that described for the preparation of 2-ethoxy-5-methoxybenzamide in Preparation 14A.
Reaction SMILES: [F:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:26]=[N:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[F:1][C:2]1[C:12]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:26]=[N:27][CH:28]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: CCS(=O)(=O)Nc1cncc(Br)c1
Reactant: Cn1c(=O)oc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1cncc(-c2cc3c(cc2F)oc(=O)n3C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A flask was charged with 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (220 mg, 0.751 mmol), N-(5-bromopyridin-3-yl)ethanesulfonamide (133 mg, 0.5 mmol), K3PO4 (212 mg, 1.0 mmol) and Pd(PPh3)4 (28.9 mg, 0.025 mmol). The flask was flushed with N2 and DMF (5 mL) was added. The mixture was stirred under N2 at 100° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and filtered through a pad of celite. The celite pad was washed with EtOAc (100 mL) and the combined organic phase was washed with water (50 mL*2) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0 to 80% EtOAc-heptane gradient to give N-(5-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) d ppm 1.23 (t, J=7.33 Hz, 3H) 3.21 (q, J=7.33 Hz, 2H) 3.38 (s, 3H) 7.53 (d, J=6.57 Hz, 1H) 7.58 (d, J=10.11 Hz, 1H) 7.79 (q, J=1.85 Hz, 1H) 8.47 (d, J=2.27 Hz, 1H) 8.49 (t, J=1.52 Hz, 1H) 10.20 (s, 1H). HRMS: (ESI) m/z 352.0769 [(M+H)+Calcd for C15H15FN3O4S 352.07618].
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1.[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:3]=12
Reactant: BrCCOC1CCCCO1
Reactant: Ic1ccnc2c[nH]nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1ccnc2cn(CCOC3CCCCO3)nc12
Product: Ic1ccnc2cnn(CCOC3CCCCO3)c12
Temperature: 120 °C
Yield: 6.57 %
Yield: 24.29 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (200 mg, 0.816 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.123 mL, 0.816 mmol) and Cs2CO3 (266 mg, 0.816 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 30 minutes using a microwave. The crude reaction mixture was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-50% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to afford 7-iodo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2H-pyrazolo[4,3-b]pyridine (74 mg, 0.198 mmol, 24.29% yield) and 7-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazolo[4,3-b]pyridine (20 mg, 0.054 mmol, 6.57% yield). MS [M+H] found 374.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:10][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (5 g, 22.8 mmol) in DMF (100 ml) is added benzyl bromide (5.7 ml, 48 mmol) and cesium carbonate (11.9 g, 37 mmol). The reaction mixture is stirred at room temperature for 20 hours then diluted with water (150 ml) and extracted with EtOAc (2×150 ml), the organic portions are combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give a waxy off-white solid. The solid is stirred in iso-hexanes (30 ml) for 30 minutes, filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:38](=[O:39])[CH2:37][N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH2:36][CH2:35]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-carboxymethyl-piperazine-1-carboxylic acid tert-butyl ester to yield (3aR,4S,7aR)-4-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-methyl 4-(2-(piperazin-1-yl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 440; RT=4.882 min; LCMS Method III
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH2:16])[CH:10]=2)=[C:4]([CH2:17][CH3:18])[N:3]=1.[C:19](Cl)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1.O1CCCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:30])[CH:10]=2)=[C:4]([CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)c(N)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(=O)Nc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Reaction time: 96 h
Yield: 648.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 2.5 grams (0.001 mole) of 2,4-diamino-6-ethyl-5-(3-amino-4-chlorophenyl)pyrimidine (prepared in Step B of this Example) in 75 mL of pyridine and 25 mL of tetrahydrofuran was stirred and cooled in an ice bath. To this was added dropwise during a 10 minute period, a solution of 2.2 grams (0.001 mole) of undecanoyl chloride in 50 mL of tetrahydrofuran. The reaction mixture was maintained below about 10° C. throughout the addition. Upon completion of addition, the reaction mixture was stirred under a nitrogen atmosphere for about 4 days. After this time, the reaction mixture was taken up in 100 mL of water and poured into 500 mL of water. The mixture was then extracted with two 200 mL portions of ethyl acetate. The combined extracts were washed with 150 mL of aqueous 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. In an effort to remove any excess pyridine, the residue was taken up in 50 mL of toluene, and the solution was concentrated under reduced pressure to a residue. This procedure was repeated two more times. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 10:1 methylene chloride and methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.8 grams of 2,4-diamino-6-ethyl-5-(4-chloro-3-decylcarbonylaminophenyl)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=3)[C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(=O)Nc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Yield: 27.3 %

Procedure:
To a solution of Example 107 (0.080 g, 0.149 mmoles) in ethanol (5 ml), Con.HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixture was basified with sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.020 g, 27% yield). MP: 91-94° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.04 (dd, J=8.3, 1.5 Hz, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.29 (m, 3H), 7.06 (dt, J=8.7, 2.3 Hz, 1H), 6.91 (br s, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.00 (q, J=7.0 Hz, 1H), 5.42 (s, 2H), 1.87 (d, J=7.0 Hz, 3H). Mass: 492.83 (M+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:9]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]1>CN(C=O)C>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[CH2:7][CH2:6][N:31]3[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]3)=[N:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OCCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 95 °C

Procedure:
3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl methanesulfonate 42b (0.7 mmol) and ethyl piperidine-4-carboxylate (1.7 mmol) are dissolved in DMF (6 mL) and heated to 95° C. for 6 h then cooled to rt. The reaction mixture is partitioned with EtOAc and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude material is purified by column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAc as eluant to yield ethyl 1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 43 as clear crystalline solid. MS (m/z) (M+1)+: 497.2.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([O-:19])=[O:18])[S:13][C:11]=2[N:12]=1.[OH-].[Na+].Cl>O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[S:13][C:11]=2[N:12]=1
Reactant: Cc1c(C(=O)[O-])sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.503 g), 1 mol/L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was dissolved by stirring with heating. The reaction mixture was allowed to cool under room temperature, neutralized with 1 mol/L hydrochloric acid (12.8 mL), and water (8.3 mL) was added. The mixture was stirred with heating under reflux for 8 hr, and further at about 70° C. for 8 hr. Water (50 mL) was added (solvent amount was set to 100 ml), and the mixture was cooled to about 21° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 4 minutes 5 seconds. The height of the solid at that time was 2.1 cm (bulk 14.8 cm3). Then, an operation of washing the obtained solid with water (25 mL), followed by reduced pressure filtration at 50 hpa was repeated 3 times to confirm that the filtrate had pH 7. At this point, the total filtration time necessary for increasing the pressure was 6 minutes 33 seconds and the height of the final solid was 1.6 cm (bulk 11.3 cm3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[N+](C)C)=[C:4]2[CH:3]=1.C(=O)(O)[O-:26].[K+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[O:26])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=[N+](C)C)cc1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (E)-N-(3-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminium (470 mg, 1.22 mmol) in methanol (5 mL) was added a 15% solution of potassium bicarbonate (5 mL) and the mixture was stirred at room temperature for 1 h. Water was added and methanol was evaporated under reduced pressure. Filtration of the precipitate afforded 322 mg of the title compound. LCMS m/z 357.0, 359.0 (M+H)+, ret. time=2.70 min.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:23][C:24]2[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2S(=O)(=O)c2ccccc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in Example 30 (4) (0.1722 g) in ethanol (14 ml), potassium hydroxide (0.047 g) was added and the mixture was stirred at 15 to 30° C. for 30 minutes. To the mixture was added 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.0748 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH:40]=O)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH2:40][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[N:14][C:15]=4[NH2:17])[N:10]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:20][CH2:19]4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NCc5cc6ccccc6o5)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.8 %

Procedure:
A mixture of cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.107 g, 0.263 mmol, 1 equiv), glacial acetic acid (0.06 mL, 1.0 mmol, 3.8 equiv), benzo[B]furan-2-carboxaldehyde (0.1 g, 0.3 mmol, 1 equiv), sodium triacetoxyborohydride (0.212 g, 1.0 mmol, 3.8 equiv), and dichloroethane (2 mL) was stirred at ambient temperature for 4.5 h. Aqueous sodium bicarbonate was added, the organic layer was separated, and the aqueous layer was extracted with two portions of CH2Cl2 (10 mL each). The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford a yellow oil which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give cis-3-{3-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine monoacetate salt as a white solid (0.017 g, 0.031 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.22 (1H, s), 7.51-7.58 (2H, m), 7.22-7.28 (3H, m), 6.98 (1H, s), 6.79-6.84 (2H, m), 6.59-6.62 (1H, m), 4.76-4.81 (1H, m), 4.50 (2H, d, J=5.6 Hz), 2.19-2.24 (14H, m), 2.05-2.07 (2H, m), 1.91 (3H, s), 1.60-1.75 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.99 min. MS: MH+ 537.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][NH:3]1.[CH2:19](O)C=C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH:16]=[CH2:19])=[O:13])=[CH:10][CH:9]=2)=[CH:4][NH:3]1
Reactant: C=CCO
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1

Procedure:
To a solution of ethyl 4-(2-oxo-2H-pyridin-5-yl)benzoate (1.24 g, 5.10 mmoles, reference example 36f) in allyl alcohol (50 mL) was added titanium (IV) isopropoxide. The resulting mixture was heated to 70° C. for seven hours at which point more titanium (IV) isopropoxide (3 mL) was added. After 18 hours the heat was removed and 1N HCl solution (50 mL) was added followed by extraction with CH2Cl2 (200 mL). The organic layer was isolated and concentrated to give the title compound in quantitative yield. MS (ion spray) m/z 256 (M+H)+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([NH2:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([N:34]=[C:2]=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:15]
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (30 mL) at 0° C. is added triphosgene. After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 mL) is added (R)-2-amino-propionic acid benzyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1M HCl and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.62 ml (22.73 mmol) of dimethylsulfoxide in 60 ml dry methylene chloride is cooled to -78° and 1.44 ml (16.53 mmol) oxalyl chloride is added dropwise. The mixture is stirred for 0.5 h at -78° and a solution of 1.0 g (3.31 mmol) of 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-octane [=5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane, see example 37] in 15 ml dry methylene chloride is added and the mixture is stirred for 10 min at -78°. The mixture is warmed to -60° and maintained for 15 min at that temperature. The reaction is quenched by the addition of 6.9 ml triethylamine. The cold bath is removed and the mixture allowed to warm to room temperature. The reaction mixture is extracted with 150 ml methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried, filtered, concentrated and chromatographed using 3:2 ethyl acetate/hexane to yield 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3): delta 2.6 (t,2H), 2.4 (t,4H).