Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:32]1[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[C:34]([CH:42]=O)[N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH:32]1[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[C:34]([CH2:42][NH:3][CH:4]2[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]3[N:21]4[C:22]5[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=5[CH:18]=[CH:19][C:20]4=[O:23])[CH2:12]3)[CH2:8][CH2:9]2)[N:33]=1
Reactant: O=Cc1cc2c(cn1)CCCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)CCCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (87 mg, 0.233 mmol) (for a preparation see Example 5(j)) in chloroform (5 ml) and methanol (0.2 ml) at rt under argon was treated with triethylamine (970.699 mmol) and stirred at rt for 0.25 h. The solution was then treated with 5,6,7,8-tetrahydro-3-isoquinolinecarbaldehyde (37.6 mg, 0.233 mmol) and stirred for a further 0.5 h. The solution was then treated with NaBH(OAc)3 (148 mg, 0.699 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (100 ml) and extracted with 20% methanol/DCM (3×200 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (66 mg, 64%).
Reaction SMILES: Br[CH:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].Cl.CCOC(C)=O.CC(O)=O>[OH-].[Na+]>[C:21]([S:23][CH:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1)(=[O:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1ccc(CCC(Br)C(=O)O)cc1
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)SC(CCc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 0.125 g (0.36 mM) of the ester obtained in step 1 in 0.364 ml of 1 N sodium hydroxide is cooled to 0° C. 0.05 g (1.2 eq) of potassium thioacetate is added and the mixture is stirred at room temperature for 48 hours. The resulting mixture is acidified to 0° C. with 1N hydrochloric acid solution. It is extracted with ethyl acetate and the organic phase is washed with water and with saturated sodium chloride solution. After drying and evaporation, a colorless oil is obtained. (Mass: 0.12 g, 98%). Rf (c.Hex/EtOAc/AcOH: 7/3/0.5)=0.11.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([CH:27]1[C:10]2[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[N:13][N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[S:26]1(=[O:28])=[O:29])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1nn(-c2ccccc2)c2c1C(Cc1ccccc1)S(=O)(=O)c1ccccc1-2)N1CCOCC1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg; 0.24 mmol; 1.0 eq.) in THF (4.0 mL) is added NaH (55% w/w in mineral oil) (12.79 mg; 0.29 mmol; 1.2 Eq.). After 15 min stirring, benzyl bromide (34.81 μL; 0.29 mmol; 1.2 eq.) is added and the reaction mixture is stirred at room temperature for 3h. The reaction is quenched with water and the product extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude residue is recrystallized from EtOH and dried under vacuum to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 300MHz) δ 8.01-7.98 (m, 1H), 7.63-7.58 (m, 4H), 7.53-7.46 (m, 3H), 7.12-7.07 (m, 3H), 6.89-6.86 (m, 2H), 6.66-6.64 (m, 1H), 5.29-5.25 (m, 1H), 3.93-3.88 (m, 1H), 3.63-3.53 (m, 5H), 3.45-3.36 (m, 2H), 3.26-3.20 (m, 1H), 2.76-2.69 (m, 1H). UPLC/MS: (ES+): 500.2, (ES−): 498.3. HPLC (max plot) 97.6%; Rt 4.32 min.
Reaction SMILES: [CH3:1][C:2]([OH:26])([CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.C(O[K])=O>O.C1COCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][C:2]([CH3:25])([OH:26])[CH3:1])=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 45 °C
Reaction time: 21 h
Yield: 97.6 %

Procedure:
To a solution of 2-methyl-1-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)propan-2-ol (2.8 g, 7.9 mmol) and HCOOK (4.6 g, 55.3 mmol) in water (4 mL) and THF (12 mL) was added 10% Pd/C (0.24 g). The reaction mixture was stirred at 45° C. for 21 hours and then cooled to room temperature. The mixture was filtered through a Celite pad. The organic phase was separated and washed with brine (20 mL). The aqueous phase was extracted with EtOAc (15 mL). The combined organic phases were concentrated in vacuo and the residue was dried in vacuo at 50° C. overnight to give the title compound as a yellow solid (2.5 g, 97.7%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:11]([NH:18][CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([N:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCCCCCCBr
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCCCCCCO)Cc1ccccc1
Temperature: 35 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
8-Bromo-1-octanol (25 g, 119.6 mmol) in acetonitrile (50 mL) was added to a stirred solution of N-benzyl-N-methylamine (43.49 g, 358.9 mmol) and potassium carbonate (49.52 g, 358.9 mmol) in acetonitrile (250 mL) at 35° C. The reaction mixture was then stirred at 35° C. for 7 h and then cooled to ambient temperature. The potassium carbonate was filtered and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in MTBE (400 mL) and the organic phase was washed with water, brine and dried over magnesium sulfate. N-methyl-2-pyrrolidone was added and the mixture was concentrated under reduced pressure to remove excess N-benzyl-N-methylamine. MTBE (400 mL) was added and the organic phase was washed with water, brine, and dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title intermediate as an oil (˜100% conversion).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:17]>O>[Na+:17].[NH:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12]([O-:15])(=[O:13])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)CCCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])CCCCNc1ccccc1
Yield: 92 %

Procedure:
A solution of butanesultone (27.2 g, 0.2 mol) and aniline (46.5 g, 0.5 mol) in ethanol is heated under reflux for 4 hr. and cooled to room temperature to precipitate a white solid. The precipitates are filtered and recrystallized in ethanol to obtain 4-anilino-1-butanesulfonic acid (42.2 g, 90%) as white crystals. 4-Anilino-1-butanesulfonic acid (10 g) is dissolved in water and neutralized by sodium hydroxide. The neutral solution is concentrated under reduced pressure to give white solids. The solids are crystallized in methanol-chloroform to obtain 4-anilino-1-butanesulfonic acid sodium salt (10.0 g, 92%) as white crystals.
Reaction SMILES: [CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C>C(Cl)Cl>[CH2:20]([N:14]1[CH2:13][CH2:2][CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:15]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=CP(=O)(OCC)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCN(Cc2ccccc2)C1
Yield: 86.7 %

Procedure:
A solution of 6.0 g (36.6 mmol) of diethyl vinylphosphonate and 11 mL (44 mmol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 150 mL of CH2Cl2 at 0° C. was stirred for 30 min. The reaction mixture was washed with 150 mL of 1N NaHCO3 and 150 mL of sat'd NaCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a 40L Biotage column using 3:2 and 1:1 v/v hexane/acetone as the gradient to afford 9.44 g (87%) of the title compound as a pale yellow oil: RF: 0.24 (3:2 v/v hexane/acetone); 1H-NMR (500 MHz) δ 1.32 (t, J=7.0, 6H), 2.04-2.12 (m, 2H), 2.39-2.58 (m, 3H), 2.83 (m, 1H), 2.97 (m, 1H), 3.64 (s, 2H), 4.06-4.16 (m, 4H), 7.24-7.34 (m, 5H); ESI-MS 298 (M+H); LC-1: 1.2 min.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH2:13][OH:14])=[CH:4]2>CN(C)C=O.[O-2].[O-2].[Mn+4]>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[O:14])=[CH:4]2
Reactant: OCC1=Cc2cnc3cccc(n23)S1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=CC1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.541 g (12.441 mM) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in 30 ml of N,N-dimethylformamide was added 6 g of activated manganese dioxide (Aldrich), and the mixture was stirred at room temperature overnight. This reaction mixture was filtered and the filter cake was washed with N,N-dimethylformamide. The filtrate and washes were combined and the solvent was distilled off under reduced pressure. The crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde thus obtained was not purified but used as it was in the next reaction.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Li+].C[Si]([N-:67][Si](C)(C)C)(C)C.Cl>C1COCC1.O.ClCCl.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]>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:67])[CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Clc1cc(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)ccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Nc1cc(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyridin-4-yloxy)quinoline (0.105 g, 0.281 mmol) in 71 mL THF (degassed with nitrogen 30 minutes prior to use) was added sequentially XPHOS (0.0107 g, 0.0225 mmol), Pd2 dba3 (0.0103 g, 0.0112 mmol), and 1M LHMDS in THF (0.590 mL, 0.590 mmol) by syringe. The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was cooled to 0° C. and 1M aqueous HCl (1.40 mL, 1.40 mmol) was added, causing milky solids to form. The reaction mixture was stirred 30 minutes, then diluted with water and dichloromethane, and the aqueous layer was washed with dichloromethane. The aqueous layer was basified with 1M NaOH (pH>10), and the milky mixture was extracted with chloroform. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (9:1 chloroform:6% NH4OH in methanol) to give the title compound (0.027 g, 0.0762 mmol, 27.1% yield) as a yellow/orange powder. MS APCI (+) m/z 355 (M+1) detected.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:21]=4)[CH:8]=2)[CH2:5][CH2:6]1)(=[O:36])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccn5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccn5)nc4c3)c3c(N)ncnn23)CC1
Yield: 83 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 7 7-piperidin-4-yl-5-[2-(pyridin-2-ylmethyl)-2H-indazol-6-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 43 mg (83%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (d, 1 H) 8.41 (s, 1 H) 7.65-7.81 (m, 3 H) 7.39 (s, 1 H) 7.19-7.26 (m, 3 H) 6.57 (s, 1 H) 5.78 (s, 2 H) 4.68 (d, 1 H) 4.02 (d, 1 H) 3.21-3.41 (m, 2 H) 2.76 (dd, 1 H) 2.01-2.19 (m, 5 H) 1.87 (dt, 2 H) LC-MS [M+H]+=467.4, RT=2.07 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])=[O:5])[CH3:2].BrN1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:14])[F:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(=O)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)F
Temperature: 70 °C
Yield: 114.4 %

Procedure:
To a suspension of 1,4,5,6-tetrahydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (136.15 g, 0.57 mol) in tetrachloromethane (450 mL) was added N-bromosuccinimide (113 g, 0.60 mol). The temperature was slowly raised with stirring to 70° C. and reflux temperature was maintained for 20 h. The mixture was cooled and extracted with water (1000 mL) and dichlormethane (1000 mL). The water phase was extracted twice more with dichloromethane (2×500 mL) and the dichloromethane phases washed with water (2×1000 mL) and dried with MgSO4. Removal of the solvents yielded the title compound (153.4 g), which was used without further purification in the next reaction.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[O:18]=[C:12]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Brc1cccc2ncccc12
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)c1cccc2ncccc12

Procedure:
Prepared from 5-bromoquinoline and diethyl oxalate using Method KE-A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH:24]=O)=[O:4].Cl.[NH2:27]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:24]([C:6]1[NH:7][C:8]([CH3:23])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])#[N:27]
Reactant: NO
Reactant: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C=O)=C2C(=O)OC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C#N)=C2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
In 16 ml of acetic acid was dissolved 1.87 g (5.5 mmol) of 3,5-dimethoxycarbonyl-2-formyl-1,4-dihydro-6-methyl-4-(3 -ethynylphenyl)pyridine obtained in Example 15. Thereto were added 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.67 g (8.2 mmol) of sodium acetate. The admixture was stirred for 2.5 hours at room temperature. Then 1.96 g (19.2 mmol) of acetic anhydride was added thereto, and the admixture was reacted for 1.5 hours at room temperature, further for 4 hours at 95°-100° C. After completing the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue. After neutralization of the reaction mixture with saturated solution of sodium hydrogencarbonate, the reaction mixture was extracted with ethyl acetate several times. The organic layer thereof was washed with water, dehydrated and concentrated. The residue was purified by subjecting to silica gel column chromatography [eluent: benzene-ethyl acetate (10 : 1)] and recrystallized from the mixture of ethyl acetate and n-hexane to give 1.2 g of the desired compound as yellow prism crystals (yield: 66.7%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][O:12][C:13]1[CH:59]=[CH:58][C:16]([CH2:17][N:18]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:26]4[CH2:39][CH2:38][N:37]([C:40]5[CH:48]=[CH:47][C:43]([C:44]([OH:46])=O)=[CH:42][CH:41]=5)[C:27]=4[N:28]=[C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:30]=3)=[CH:21][N:20]=2)=[CH:15][CH:14]=1>>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][N:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:59][CH:58]=2)[C:19]2[N:20]=[CH:21][C:22]([C:25]3[C:26]4[CH2:39][CH2:38][N:37]([C:40]5[CH:48]=[CH:47][C:43]([C:44]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)=[O:46])=[CH:42][CH:41]=5)[C:27]=4[N:28]=[C:29]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[N:30]=3)=[CH:23][N:24]=2)=[CH:51][CH:52]=1
Reactant: CNCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN4CCOCC4)cc3)cn2)cc1
Yield: 86.7 %

Procedure:
Using methyl-(2-morpholin-4-yl-ethyl)-amine (29.8 mg, 0.206 mmol) obtained in Step A instead of 3-(aminomethyl)pyridine, and 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (68.1 mg, 0.103 mmol) obtained in Step A in Example 1-D-19, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-methyl-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (70.2 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-139) as a yellow powder (42.0 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:31]2[N:30]=[C:29]([C:22]3[C:23]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][CH:21]=3)[CH:34]=[CH:33][N:32]=2)=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: COc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c(C)c1
Yield: 20.1 %

Procedure:
Using the procedure of example 1, 4-methoxy-2-methylaniline, (111 mg) was reacted with compound 1f (100 mg) to provide compound 27 (18 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7.2 Hz, 1H), 8.20 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 7.03 (m, 1H), 6.90 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 332 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:6].[CH3:20]I>O1CCCC1>[F:3][C:4]([F:18])([F:19])[C:5]([N:7]([CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:6]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a suspension of a 60% dispersion of sodium hydride in mineral oil (96 mg, 2.4 mmol) in dry tetrahydrofuran (5 mL), cooled to 0° C., was added a solution of 2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (500 mg, 2.0 mmol) in 5 mL dry teterahydrofuran. After stirring for 1 hour at 0° C., methyl iodide (132 μL, 2.2 mmol) was added in one portion. The reaction was stirred for 1 hour at 0° C., and warmed to rt overnight. After 16 h, the reaction mixture was concentrated, and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over Na2SO4, filtered, adsorbed onto silica, and purified by column chromatography to yield the desired compound (0.36 g, 1.4 mmol, 69% yield). 1H NMR (400 MHz, CDCl3): δ 8.13-8.22 (m, 2H), 7.56-7.64 (m, 2H), 4.74 (s, 2H), 3.14 (s, 3H). MS (ESI) m/z=263 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1.[H-].[Na+].Br[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:20])=[O:21])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:4][C:3]=1[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)[nH]c3cc2Br)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)n(CCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1
Yield: 36 %

Procedure:
The title compound was prepared in analogy to example 12, from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4-cyclopropanesulfonyl-piperazin-1-yl)-methanone (example 17), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane in N,N-dimethylformamide, to afford the title compound as a colourless foam (36%).