Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.FC1[N:44]=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:1][C:2]1[N:44]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (6-fluoropyridin-3-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=516, obsd.=516).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Reaction time: 2 h
Yield: 87.8 %

Procedure:
1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (45 g, 191 mmol), pyridine (15.09 g, 191 mmol), and toluene (450 ml) were added to a 1000 ml flask, and N-bromosuccinimide (37.31 g, 210 mmol) was slowly added thereto at 20° C., followed by allowing the reaction to proceed for two hours. After the reaction, the solution was washed with water (180 mL,×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The resulting solid was recrystallized with toluene (67.5 ml) and hexane (337.5 ml), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (39.26 g, yield: 88.0%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCO
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6 g (0.2 mol) of a sodium hydride dispersion (80% in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room temperature. 23.1 ml (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a water-jet vacuum over a 10 cm Vigreux column. 4-benzyloxybutanol is obtained, b.p.22 =161°-162°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH:33]([OH:36])[CH2:34][CH3:35]>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[C:33](=[O:36])[CH2:34][CH3:35]
Reactant: CCC(O)c1ccc(C)cc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1ccc(C)cc1OC
Reaction time: 0.17 h

Procedure:
Dess-Martin periodinane (2.89 g, 6.82 mmol) and H2O (0.123 ml, 6.82 mmol) are added to DCM (20 ml) and left to stir for 10 minutes. This mixture is treated with 1-(2-methoxy-4-methyl-phenyl)-propan-1-ol (step 1) (1.17 g, 6.49 mmol) in DCM (15 ml) and stirred for 1 hour. The reaction mixture is diluted with DCM and washed with Na2S2O3, NaHCO3, water, brine, dried (MgSO4) and concentrated under vacuum to yield the title product as a clear oil; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 6.82 (d, 1H), 6.77 (s, 1H), 3.90 (s, 3H), 3.00 (q, 2H), 2.39 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65])=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)=[O:65])=[O:61])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h Gly-Gly-OCH2Ph.TsOH (0.62 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture washed with water (20 mL), 0.5 M aqueous HCI (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH to yield (C18H37)2NCOCH2OCH2CO-Gly-Gly-OCH2Ph as a deliquescent white solid (1.32 g, 94%). 1H-NMR (300 MHz, 6, CDCl3) 0.87 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.48 (4H, bs), 3.05 (2H, t, J=7.5 Hz), 3.22 (2H, t, J=7.5 Hz), 4.06–4.10 (6H, m), 4.28 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 7.51 (1H, t, J=5.7 Hz), 8.23 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 2.8, 27.0, 27.1, 27.6, 29.5, 29.7, 29.8, 32.0, 41.3, 42.8, 46.9, 67.1, 69.9, 72.2, 128.5, 128.7, 128.9, 135.6, 168.7, 169.9, 170.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[C:20]([O:32][CH3:33])[CH:19]=3)[CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:9]=[C:10]([CH2:11][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:19][C:20]=1[O:32][CH3:33]
Reactant: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of t-butyl {4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2methoxyphenyl}carbamate (100 mg, 0.22 mmol) in CH2Cl2 (4 ml) was added trifluoroacetic acid (1.5 ml) and was stirred at rt for 3 h. The reaction mixture was partially evaporated and was added 10 ml ethyl acetate and washed with saturated aq. NaHCO3. The organic was dried over Na2SO4 and concentrated to afford 80 mg of the title compound. 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 6.84 (d, J=2 Hz, 1H), 6.84 to 6.68 (m, 2H), 6.55 (s, 1H), 4.87 (s, 2H), 4.01 to 3.99(m, 5H), 3.53 (t, J=4 Hz, 4H), 2.42(t, J=4 Hz, 4H).
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])=[N:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[NH:9]1[C:10]2[C:15](=[C:14]([O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:32])[CH:13]=[CH:12][CH:11]=2)[CH:16]=[N:8]1
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc2nn(Cc3ccccc3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]ncc12

Procedure:
6.8 g. 1-(2-Benzylindazol-4-yloxy)-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propan-2-ol in 100 ml. methanol and 10 ml. concentrated hydrochloric acid are hydrogenated over 0.9 g. of 10% palladium-charcoal. After suction filtration, the filtrate is evaporated, the residue is dissolved in water, rendered alkaline with aqueous sodium hydroxide solution and extracted with methylene chloride. The organic phase is evaporated and the residue is triturated with diethyl ether and filtered off with suction. After recrystallization from ethyl acetate, the desired compound is obtained in a yield of 3.9 g. (72% of theory); m.p. 127°-128° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:3]1.Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.N1C(C)=CC=CC=1C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]([F:13])([F:14])[C:9]([F:11])([F:10])[F:12])[CH:5]=2)[N:17]=[N:18][CH:19]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)cc1O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cnnc(Oc2cc(C(F)(F)C(F)(F)F)nn2C)c1

Procedure:
1-Methyl-3-(pentafluoroethyl)-1H-pyrazol-5-ol (0.44 g, 0.002 mole), 3-chloro-5-methoxypyridazine (0.29 g, 0.002 mole), and 2,6-lutidine (0.27 g, 0.0024 mole) were refluxed under N2 in toluene (8 mL) for 15 h. This mixture was poured into ethyl acetate and washed with 7% HCl, water and then with saturated sodium bicarbonate. The organic layer was dried (MgSO4), filtered through silica gel with ethyl acetate, and evaporated in vacuo to give 5-methoxy-3-[[1-methyl-3-(pentafluoroethyl)-1H-pyrazol-5-yl]oxy]pyridazine as a light yellow solid. The compound was recrystallized to give (0.45 g, 69% yield) Compound 18, a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(Br)cc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(Br)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 45.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (200 mg, 1.06 mmol) and methyl 2-(5-bromo-1H-indol-3-yl)oxoacetate (300 mg, 1.06 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.06 mL, 1.06 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.12 mL, 2.12 mmol) was added. The resulting dark red solution was heated up to 50° C. overnight. The mixture was cooled to room temperature, quenched with 1N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to an orange solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (201 mg, 45%) as an orange solid, mp 270–290° C. dec.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:25])=O.[OH-].[Na+]>>[Cl:25][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2c(-c3ccccc3)nn3ccccc23)cc[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(-c2c(-c3ccccc3)nn3ccccc23)ccn1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.6 g) and phosphorus oxychloride (1.8 ml) was stirred for 6 hours at 70° C. After cooling, the reaction mixture was poured onto ice (30 g) and made alkaline with 24% aqueous solution of sodium hydroxide (pH=10) and extracted with chloroform (18 ml). The combined extract was washed with water and sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (12 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-(2-chloropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.21 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH3:26])[CH2:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>COCCOC.C(O)C.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C@:9]2([CH3:26])[CH2:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10]2)=[CH:3][C:2]=1[C:31]1[CH:32]=[N:27][CH:28]=[N:29][CH:30]=1
Reactant: CC1(C)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)C[C@@](C)(c2ccc(F)c(-c3cncnc3)c2)N=C(NC(=O)c2ccccc2)S1
Temperature: 97 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a 97° C. solution of (S)-N-(4-(3-bromo-4-fluorophenyl)-4,6,6-trimethyl-5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (0.067 g, 0.15 mmoles, 1.0 equiv) in 1,2-dimethoxyethane (1.5 mL), ethanol (0.7 mL) and water (1.0 mL) is added pyrimidine-5-boronic acid (0.095 g, 0.77 mmoles, 5.0 equiv), cesium carbonate (0.301 g, 0.92 mmoles, 6.1 equiv) and bis(triphenylphoshine)palladium (II) chloride (0.022 g, 0.03 mmoles, 0.2 equiv). The reaction mixture is stirred at 97° C. for 20 minutes. After cooling to room temperature, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solvent is removed under reduced pressure and the residue is purified by silica gel flash column chromatography eluting with a linear gradient of dichloromethane to 15% ethyl acetate: dichloromethane to give the title compound (46% yield): MS (m/z): 435 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[NH:26][CH:27]=[CH:28][N:29]=4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Na+].I[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[N:29]([CH3:36])[CH:28]=[CH:27][N:26]=4)=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4nccn4C)c4cccnc43)CC2)ccc1Cl
Reaction time: 1 h

Procedure:
To the solution of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone (50 Mg, 0.11 Mmol, 1 eq) in THF was added 60% sodium hydride (5.7 Mg, 0.14 Mmol, 1.3 eq) and stirred for 1 hr, followed by the addition of iodomethane (25.8 Mg, 0.16 Mmol, 1.5 eq). 2 hrs later, LCMS indicated that the major peak is the desired product. preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1-methyl-1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 465.2.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(O)(O)([O-])=[O:55].[K+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:52][OH:53])[C:50]([OH:55])=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](CO)(C(=O)O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 8a (1.40 g, 1.98 mmol, obtained from the synthetic method described in step 1 of example 8) in tert-butanol (10 mL) were added monopotassium phosphate (2.43 g, 17.82 mmol) and 2-methylbut-2-ene (68.88 mg, 97.02 mmol) at room temperature in turn, and then sodium chlorite (1.26 g, 13.90 mmol) and water (5 mL) were added. The mixture was stirred at 35° C. for 24 hours and quenched with 10 mL of saturated aqueous sodium bicarbonate. Tert-butanol was removed in vavuo. The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 9a as pale yellow oil (1.50 g, 100%). The crude product was used in next step without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1[NH:14][N:15]=[C:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=1.N[CH2:23][CH2:24][C:25]([N:27]1[CH2:46][CH2:45][C:30]2[N:31]=[C:32]([NH:35][CH:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)[N:33]=[CH:34][C:29]=2[CH2:28]1)=[O:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:44][CH:36]1[NH:35][C:32]1[N:33]=[CH:34][C:29]2[CH2:28][N:27]([C:25](=[O:26])[CH2:24][CH2:23][NH:21][C:19](=[O:20])[CH2:18][C:16]3[NH:15][N:14]=[N:13][CH:17]=3)[CH2:46][CH2:45][C:30]=2[N:31]=1
Reactant: NC(=O)Cc1cn[nH]n1
Reactant: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1cnn[nH]1)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.111 g; 1.5 equiv; 0.58 mmoles) to a solution of 2-(2H-triazol-4-yl)acetamide (0.056 g; 1.1 equiv; 0.42 mmoles), 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.13 g; 1.0 equiv; 0.39 mmoles), and N,N-dimethyl-4-pyridinamine, (0.0094 g; 0.2 equiv; 0.077 mmoles) in dichloromethane (1.28 mL). Stir the reaction mixture for 16 hours at ambient temperature. Load the solution directly onto a silica gel column and purify by column chromatography (0 to 10% methanol in dichloromethane) to give N-{3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}-2-(1H-1,2,3-triazol-5-yl)acetamide (0.098 g; 57%) as a white solid: MS (m/z): 447(M+1).
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH:36]2[CH2:38][CH2:37]2)=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: NCC1CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCC4CC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-cyclopropylmethyl-benzamide was prepared from 2-{5-chloro-2[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and cyclopropylmethylamine in an analogous manner to Example 1396. Product isolated as a tan solid (30 mg, 47%). m.p.=173-175° C.; LCMS (m/e) 521 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.49-7.40 (m, 1H), 7.35 (s, 1H), 7.24 (d, 1H, J=8.0 Hz), 7.16-7.04 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 6.40-6.30 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.37-3.30 (m, 2H), 2.98-2.83 (m, 4H), 2.82-2.67 (m, 6H), 1.14-1.01 (m, 1H), 0.64-0.55 (m, 2H), 0.35-0.27 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:2]([O:1][C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:34][CH:35]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-trifluoromethyphenol: ESMS m/e: 555.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14]O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].P(Br)(Br)[Br:18]>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][Br:18])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCC(C)(C)c1ccc(CC(C)CO)cc1
Product: CCC(C)(C)c1ccc(CC(C)CBr)cc1
Reaction time: 16 h

Procedure:
32.2 g of 3-(p-tert.amyl-phenyl)-2-methyl-propanol are added dropwise at 20°-30° C. over a period of 2 hours to 21.8 g of phosphorus tribromide and the mixture is left to stand for 16 hours. The mixture is subsequently heated to 55°-60° C. for a period of 1.5 hours, cooled down to ca 10° C. and cautiously poured on to ice. The aqueous solution is exhaustively extracted with ether, the combined ether phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By fractional distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide of boiling point 117°-119° C./0.035 Torr.