Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:29][CH2:28]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH:31]=[CH:32][C:33]([OH:35])=[O:34]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:28][CH2:29]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: O=C(O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 33.5 %

Procedure:
To a suspension of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-acrylic acid (36 mg, 0.07 mmol, 1.0 equiv; Example 172) in ethanol (1.5 mL) was added palladium on carbon (1.5 mg, 0.001 mmol, 0.02 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (3 bar) at rt over night. Removal of the solvent mixture under reduced pressure, filtration over Celite® and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 auto sampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12 mg (33%) of the title compound as a slightly yellow viscous oil. MS (ISP): 513.8 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]([CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:16][CH:17]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: CN(Cc1cc(Br)cs1)C(=O)c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2ccc(C=O)cc2)cs1)C(=O)c1ccccc1
Temperature: 80 °C
Yield: 79.5 %

Procedure:
3 g (20 mmol) of 4-formylbenzeneboronic acid are added to a solution of 4.75 g (15 mmol) of N-(4-bromothiophen-2-ylmethyl) -N-methylbenzamide in 60 ml of toluene, followed by dropwise addition of 5.5 g (40 mmol) of aqueous potassium carbonate solution. The reaction medium is degassed, 530 mg (0.5 mmol) of tetrakis (triphenylphosphine) palladium are then added and the medium is heated at 80° C. for 18 hours. After extraction with ethyl acetate and washing with water, the organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/ethyl acetate mixture. 4 g (78%) of N-[4-(4-formylphenyl)thiophen-2-ylmethyl]-N-methyl-benzamide are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][C:17](O)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl-].[NH4+].C1C[N:33]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([NH2:33])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(CC(=O)O)c2ccncc2)CCN(C)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC(CC(N)=O)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid (175 mg, 0.482 mmol) was dissolved in DCM (5 mL), ammonium chloride (51 mg, 0.964 mmol), PYBOP (300 mg, 0.578 mmol) and triethylamine (0.69 mL, 4.82 mmol) were added and the reaction mixture was stirred at RT for 4 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography to obtain 45 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyramide as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.8 (d, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.9 (d, 1H), 4.63 (t, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 4.3 (dd, 1H), 4.0 (m, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 3.0 (m, 1H), 2.9 (m, 2H), 2.4 (d, 3H). Separation by chiral HPLC provides enantiomers II-229a-b.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([NH:30][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:20]([OH:31])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(NC4CCOCC4)cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.46 mmol) in dry DCE (2 ml) was added dihydro-2H-pyran-4(3H)-one (88 mg, 0.88 mmol), AcOH (0.16 ml, 2.78 mmol), sodium triacetoxyborohydride (275 mg, 1.30 mmol) under nitrogen. The resulting mixture was stirred for 3 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with AcOEt (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was used in the next step without any purification.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([OH:35])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:35]
Reactant: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 12 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 12% yield: mp 58-61° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.48 (m, 3H), 7.69-7.64 (m, 2H), 7.31-7.18 (m, 3H), 6.21 (br s, 1H), 4.58 (s, 2H), 4.56 (d, J=6.0 Hz, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.62 (t, J=9.0 Hz, 2H), 2.59 (s, 3H); MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)C1C=CC=CC=1)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH:4][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(N)c(F)c1OCC
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)c(F)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-Fluoro-3,4-diethoxyaniline (0.17 g) and N,N-diethylaniline (0.13 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.11 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (0.23 g) in a yield of 94.4%. M.P., 79°-81° C.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:13]([C:14]([OH:16])=[O:15])[CH:12]3[CH2:17][CH:9]2[CH2:10][CH2:11]3)=CC=1.[C:20](Cl)(=O)[C:21](Cl)=O.CN(C)C=O.Cl.NO.C(N(CC)CC)C>ClCCl.O1CCCC1.O>[CH:9]12[CH2:17][CH:12]([CH2:11][CH2:10]1)[CH:13]([C:14]([O:16][CH2:20][CH3:21])=[O:15])[NH:8]2
Reactant: COc1ccc(CN2C3CCC(C3)C2C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1NC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (297 mg, 1.14 mmol) in dichloromethane (4.4 ml) were added oxalyl chloride (0.21 ml, 2.34 mmol) and N,N-dimethylformamide (0.09 ml, 1.14 mmol) while being cooled with ice, and the mixture was stirred at room temperature for 30 minutes. Separately, to a suspension of hydroxylamine hydrochloride (316 mg, 4.55 mmol) in tetrahydrofuran (1.5 ml)-water (0.3 ml) was added triethylamine (0.97 ml, 6.94 mmol) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. To this reaction mixture was added the acid chloride solution at 0° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (2% methanol/chloroform), to give the entitled compound (152 mg, 47% through the two steps of (b) and (c)).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (3 g, 11.5 mmol) and 2-fluoro-5-nitropyridine (1.96 g, 13.8 mmol) in DMF (50 mL) was added K2CO3 (4.77 g, 43.5 mmol). After the mixture was stirred at 80° C. under N2 overnight, it was slowly poured into stirred water (200 mL). The resulting precipitate was collected by filtration, washed with methanol (50 mL×3) and dried in vacuo to afford 3-iodo-1-(5-nitropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (61) (3 g, 68%) as a brown solid. LC-MS (ESI): m/z (M+1) 384.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:18].[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH:28](O)[C:29]#[CH:30])[CH2:24][CH2:23]1)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl-].[Na+]>C1COCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH:19]([CH:22]1[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]1)[C:20]#[CH:21]
Reactant: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Reactant: C#CC(O)C1CCC(CCC)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(Oc1cc2c(c(F)c1F)OC(CCCCC)CC2)C1CCC(CCC)CC1
Reaction time: 20 h

Procedure:
8.0 g (31.2 mmol) of 7,8-difluoro-2-pentylchroman-6-ol are initially introduced in 75 ml of THF together with 6.75 g (37.4 mmol) of 1-(4-propylcyclohexyl)prop-2-yn-1-ol and 9.83 g (37.6 mmol) of triphenylphosphine, and 7.89 ml (40.6 mmol) of DIAD are added over the course of 30 min with ice-cooling. After 20 h at RT, semi-saturated sodium chloride solution is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride solution, and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-pentane:MTBE=2:1), giving 7,8-difluoro-2-pentyl-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]chroman as a pale-brown oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 104.5 %

Procedure:
A suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml), a solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) and n-heptyl bromide (4.1 g) were treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-nonanate (6.8 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:28])([F:27])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[F:7][C:8]([F:27])([F:28])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
At room temperature and under argon, 12.3 ml of a 1 M solution of lithium aluminium hydride in THF were slowly added dropwise to a solution of 11.5 g (37.30 mmol) of methyl 4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzoate in 150 ml of dry THF. After the addition had ended, the reaction mixture was stirred at room temperature for another hour. The reaction mixture was then cooled to 0° C., and 150 ml of ice-cooled 1 M hydrochloric acid were added slowly and carefully. About 250 ml of ethyl acetate were then added, the aqueous phase was separated off and the organic phase was washed successively in each case once with 1 M hydrochloric acid and saturated sodium chloride solution. The organic phase was then dried over magnesium sulphate, filtered and concentrated to dryness. This gave 9.69 g (34.57 mmol, 93% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[N:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]1=[O:36])=[O:4].Cl[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][N:42]3[C:48]4[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=4[CH:54]=[C:41]3[C:40]=2[N:39]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:55][C:52]1[C:53]2[CH:54]=[C:41]3[C:40]4[N:39]=[C:38]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([N:29]7[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]7=[O:36])=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:47]=[CH:46][C:45]=4[CH2:44][CH2:43][N:42]3[C:48]=2[CH:49]=[CH:50][CH:51]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-n2ccc(C)cc2=O)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-n2ccc(C)cc2=O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 25.2 %

Procedure:
To a mixture of N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.19 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (63 mg, 0.23 mmol) and K2CO3 (54 mg, 0.39 mmol) in 1,4-dioxane/H2O (3 mL/0.1 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under N2. The reaction mixture was stirred at 80° C. for 5 hours and concentrated in vacuo to remove 1,4-dioxane. The reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (30 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.83˜7.85 (m, 1H), 7.66˜7.68 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.26˜7.18 (m, 2H), 7.14˜7.18 (m, 2H), 6.77˜6.81 (m, 1H), 6.53 (s, 1H), 6.29 (d, J=8.0 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.40 (s, 3H), 3.31 (t, J=6.4 Hz, 2H), 2.90 (d, J=4.8 Hz, 3H), 2.61 (s, 3H), 2.32 (s, 3H). MS (M+H)+: 626.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl.O>CO.[Zn]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCCCC2
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Brc1ccc2c(c1)N=C1CCCCCN1C2
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromo-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (200 mg, 0.21 mmol, 1.0 equiv) and excess zinc powder, HCl (37%, 1 mL) in MeOH (4 mL) was stirred at 75° C. for 30 min. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): 279, 281 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[N:10]O)[CH2:6]2.C(O)(=O)C>[Pt](=O)=O.C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([NH2:10])[CH2:6]2
Reactant: CN1C2CCC1CC(=NO)C2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C2CCC1CC(N)C2
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A 500-mL Parr hydrogenation vessel was purged with nitrogen and charged with platinum (IV) oxide (1.28 g, 5.64 mmol), 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime (4.00 g, 26.0 mmol), acetic acid (11 mL) and ethanol (110 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 24 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The reaction mixture was then mixed with Celite 521 (5.0 g), filtered, and the filtrate evaporated to a solid residue. This residue was dissolved in methanol (100 mL) and this solution treated with sodium carbonate (10 g). The resulting suspension was added diethyl ether (50 mL) and filtered. Evaporation of the filtrate to dryness afforded 3.64 g (100%) of 8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine as a white solid: 1H NMR (300 MHz, CD3OD) δ 5.18 (br s, 2H), 3.35 (br s, 2H), 3.21 (t, J=6.6 Hz, 1H), 2.40 (s, 3H), 2.26-2.00 (m, 6H), 1.68-1.58 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=1
Reactant: CC(=O)CCl
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 4-hydroxybenzyl alcohol (1.0 g, 8.06 mmol) in acetone (80 mL) was added potassium carbonate (1.34 g, 9.68 mmol) and chloroacetone (0.771 mL, 9.68 mmol). After completion of addition the reaction mixture was heated to reflux. After 20 hours the reaction mixture was cooled down to room temperature and the solvent was removed. Water and ethyl acetate were added to the crude material. The aqueous layer was separated and extracted with ethyl acetate (3×, 100 mL). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (gradient from 4:1 to 1:1 pentane:ethyl acetate) to provide the desired product (0.981 g, 5.45 mmol) in 98% yield. 1H (CDCl3, 600 MHz): δ 7.30 (2H, d, J=8.7 Hz), 6.87 (2H, d, J=8.7 Hz), 4.63 (2H, d, J=5.7 Hz), 4.54 (2H, s), 2.27 (3H, s), 1.66 (1H, t, J=5.8 Hz); 13C (CDCl3, 150 MHz): δ 205.7, 157.3, 134.3, 128.8, 114.6, 73.1, 64.8, 26.6.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc(OCCCCOCc3ccccc3)nc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(OCCCCO)nc2N1
Yield: 54.4 %

Procedure:
To the solution of intermediate 10 (900 mg, 2.8 mmol) in EtOH (25 mL) was added 10% Pd/C (400 mg) under an atmosphere of H2 overnight. The reaction was filtered to remove the Pd/C and the filtrate was concentrated and washed with Et2O to give 7-(4-hydroxybutoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (intermediate 11) (360 mg, 55%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:3]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCCC(c2nc3cccnc3[nH]2)C1
Reactant: ClCc1ccccc1
Product: CN1CCCC(c2nc3cccnc3n2Cc2ccccc2)C1

Procedure:
Operation is carried out similarly to the description of Example 5 with the difference that 2-(1-methylpiperidin-3-yl)3H-imidazo [4,5-b] pyridine is reacted with benzylchloride to obtain 3-benzyl-2-(1-methylpiperidin-3-yl)-3H-imidazo [4,5-b] pyridine as an oil, after purification by chromatography on silicagel column (CHCl3 -CH3OH 9:1).