Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:19]Br)=[O:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:19][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH:8]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (501 mg) and 2-bromo-4-methylacetophenone (638 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one and three quarter hours, then cooled and the solid filtered off. The filtrate was evaporated, the residue was diluted with water (100 ml) and the product was extracted with ethyl acetate (3×50 ml). This was combined with the solid and crystallised from acetone: yield 306 mg, m.p. 214°-217° dec: λmaxEtOH 253 nm (ε 19760), 332 nm (ε 2620), λinf 232 nm (ε 11040).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCC1CCN(Cc2ccccc2)CC1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCCC(=O)c1ccc(F)cc1)CC1CCN(Cc2ccccc2)CC1
Yield: 77 %

Procedure:
Following the procedure of step F of Example 3, starting from 1-benzyl-4-(methylaminomethyl)piperidine and 1-iodo-3-[(p-fluorophenyl)carbonyl]propane, in the presence of potassium carbonate and in acetone as solvent, the desired compound is obtained in the form of an oil, in a yield of 77%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
4-Hydroxybenzaldehyde of the formula (7) (100 g), potassium carbonate (226 g) and dimethylformamide (500 ml) were taken in a reaction flask and stirred for 15 minutes. Benzylchloride (114 g) was then added at room temperature and the reaction mass was stirred at the same temperature for a period of 8-10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with 10% aq. sodium hydroxide solution followed by water. The solvent was removed under reduced pressure and the resulting residue was triturated with pet. ether to afford the title compound of the formula (8) (160-165 g, 93-95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Yield: 99.7 %

Procedure:
A solution of 2-amino-5-bromobenzotrifluoride (1.623 g, 6.76 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.840 g (99.7%) of title compound. Mp: 140°-2° C., 1HNMR (CDCl3): δ 2.212 (s, 3H); 7.358 (s, 1H); 7.659 (d, 1H, J =8.7 Hz); 7.726 (d, 1H, J=1.8 Hz); 8.118 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([N:18]([CH2:19][CH2:20][CH3:21])[CH:15]2[CH2:14][CH2:13][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH2:17][CH2:16]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCNC1CCN(c2nc(C)c(C(=O)OCC)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CCN(c2nc(C)c(C(=O)OCC)s2)CC1
Yield: 22.3 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 4-methyl-2-[4-(n-propylamino)piperidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (241d) (206 mg, 0.66 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (115 mg, 0.66 mmol), WSC hydrochloride (380 mg, 1.98 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol) and N-methylmorpholine (0.15 mL, 1.32 mmol), to obtain 69 mg of the title compound as a white solid (22%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15](F)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2]
Reactant: Cn1cc(C#N)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C#N)cn4C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 100 cm3 of dimethyl sulphoxide is heated to 80° C. in the presence of 2 cm3 of N-methylpiperazine. The reaction mixture is maintained at this temperature for 8 hours. The solution obtained is cooled to room temperature and stirred at this temperature for 15 hours. The precipitate formed is filtered off, washed with 3 times 20 cm3 of water and dried under vacuum (20 kPa) at 50° C. 2.6 g of 3-cyano-7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4oxobenzo[b][1,8]naphthyridine are obtained in the form of a yellow precipitate, melting point 335° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][N:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:30][C:27]([C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)([OH:28])[CH3:29])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C2(C)CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) was dissolved in DMF (3 mL), sodium hydride (106 mg, 2.65 mmol) was added and stirred for 15 min. at RT. 2-Methyl-5-(2-methyl-oxiranyl)-pyridine (263 mg, 1.76 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 3 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (2×60 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 200 mg of 1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-(6-methyl-pyridin-3-yl)-propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.5 (d, 1H), 8.3 (s, 1H), 7.79 (d, 1H), 7.22 (s, 1H), 6.82 (s, 2H), 5.03 (t, 1H), 4.38 (dd, 2H), 3.8 (m, 1H), 3.66 (m, 2H), 3.46 (m, 2H), 3.2 (m, 2H), 2.7 (m, 1H), 2.67 (s, 3H), 2.36 (s, 3H), 2.22 (m, 2H), 1.77 (s, 3H). Separation by chiral HPLC provided enantiomers II-128a-b.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[Cl:22])[C:8]2[CH:24]=[CH:25][S:26][C:7]=2[CH2:6]1)C.[NH2:27]N>C(O)C>[Cl:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[C:12]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[N:2][NH:27][C:6]=2[C:7]2[S:26][CH:25]=[CH:24][C:8]1=2)=[O:23]
Reactant: NN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc2C1
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cn[nH]c2-c2sccc21
Temperature: 60 °C

Procedure:
To a mixture of 2.2 g of 7-[(dimethyl-amino)methylene]-4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)-8H-thieno[3,2-b]azepine in 40 ml of ethanol is added 341 μl of hydrazine followed by heating at 60° C. for 1.5 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in 100 ml of ethyl acetate and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 1.85 g of the desired product as a yellow-orange solid.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[S:23])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]1=[S:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)n1c(=S)nc(-c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of 2 grams of 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione, 100 ml. of methylene chloride and 4 grams of manganese dioxide is stirred for 48 hours at room temperature. Precipitated solids are removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ethyl acetate and then methanol and then eluted with benzene in a silica gel column to give 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinthione, m.p. 202°-205°C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20](=O)([O:23]C)[O:21][CH3:22].[NH4+].[Cl-]>C1COCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C:20]([O:21][CH3:22])=[O:23])[N:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of diisopropylamine (19 ml, 130 mmol, 1.3 equiv) in dry THF (100 mL) at 0° C. under a N2, was added n-butyllithium (81 ml, 130 mmol, 1.3 equiv) slowly. The mixture was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of 3-methylpyridazine (9 ml, 100 mmol, 1.0 equiv) in THF (50 mL) was added dropwise over a period of 1:5 min. The resulting mixture was stirred at −78° C. for 1 h, and a solution of dimethyl carbonate (17 ml, 200 mmol, 2 equiv) in THF (50 mL) was added dropwise. The mixture was allowed to warm slowly to 25° C. and stirred for 2 days. Sat.NH4Cl was added and the resulting solution was extracted with 10% MeOH/DCM. The combined organics were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (2.5% MeOH/DCM) to give 1.6 g of methyl 2-(pyridazin-3-yl)acetate as a brown liquid (11 mmol, 11%).
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](F)[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6].O>CN(C=O)C>[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([S:2][CH3:1])[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6]
Reactant: CS
Reactant: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(F)cc(C2(C#N)CCOCC2)c1
Temperature: 100 °C

Procedure:
Methanethiol was bubbled into a stirred suspension of sodium hydride (65% w/w dispersion in mineral oil, 273 mg, 7.4 mmol) in DMF (10 ml) until a clear solution was obtained. 4-Cyano-4-(3,5-difluorophenyl)-3,4,5,6-tetrahydro-2H-pyran (1.65 g, 7.4 mmol) was added and the resulting mixture was heated at 100° C. for 22 h, cooled and poured into water (100 ml). The mixture was extracted with Et2O (100 ml) and extract washed with water (100 ml), brine (100 ml) and dried (MgSO4). Removal of solvent gave 1.87 g (quant.) of the titled compound as a tan oil.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[C:17]2[O:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH:12]=[C:11]([O:19]C)[CH:10]=1)=[O:8].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:17]2[O:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH:12]=[C:11]([OH:19])[CH:10]=1)=[O:8]
Reactant: COC(=O)c1cc(OC)cc2cc(C)oc12
Agent: BrB(Br)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc2cc(C)oc12
Temperature: 25 °C
Yield: 83.9 %

Procedure:
BBr3 (10 mL, 10.08 mmol, 1.0 M in CH2Cl2) was added drop-wise to a solution of 5-methoxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4c) (951 mg, 4.31 mmol) and 2,6-lutidine (1.17 mL, 10.08 mmol) in CH2Cl2 (20 mL) at 0° C. The mixture was stirred and warmed to RT overnight. The mixture was quenched with H2O (60 mL) and extracted with CH2Cl2 (2×60 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5% CH3OH/CH2Cl2 to afford a white solid (746 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.53 Hz, 1 H) 7.13 (d, J=2.53 Hz, 1 H) 6.33 (d, J=1.01 Hz, 1 H) 5.50 (s, 1 H) 4.00 (s, 3 H) 2.49 (d, J=1.01 Hz, 3 H).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:24]1>C(#N)C>[C:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1)(=[O:30])[NH2:31]
Reactant: NC(=O)C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml). DIPEA (0.28 ml, 1.60 mmol) and piperidine-4-carboxamide (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by flash chromatography (DCM/Acetone=8/2). The solid was triturated with i-Pr2O to obtain ethyl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (239 mg, 66.7% yield) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(CO)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCC(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carboxylat (450 mg, 1.08 mmol) in dioxane (5 mL) was added HCl/dioxane (5 mL). The mixture was stirred at RT overnight. LCMS showed the reaction was completed. The solution was concentrated and purified by silica gel chromatography (DCM:CH3OH=10:1) to get the title compound as a yellow solid (0.2 g, 53%). MS (ES+) C16H19FN4O requires: 302. found: 303 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B.[Na].C(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Agent: B
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(C(O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
[4-(Tert-butyl)phenyl]{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-methanone (111 mg) and sodium boron hydride (76 mg) were added to ethanol (15 ml), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. Chloroform was removed by evaporation under the reduced pressure to give a crude which was then purified by thin-layer chromatography on silica gel using chloroform/ethyl acetate for development to give (4-tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]methanol (108 mg, yield 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[O:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])=[O:16])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1c(F)cccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4c(F)cccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2,6-difluoro-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:16])[CH3:15].O.O.[Sn](Cl)Cl>CN1C(=O)CCC1>[Cl:24][C:17]1[CH:18]=[C:19]([CH:20]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:15])[CH3:16])[NH2:21]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(N)cc3Cl)cc12

Procedure:
500 mg of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (Example I) are stirred with 6.18 g of tin(II) chloride dihydrate in 5 ml of NMP for 17 hours at 50° C. The solvent is removed in vacuo and the residue is taken up in ethyl acetate. The mixture is washed with saturated ammonium chloride solution and saturated sodium chloride solution, the organic phase is dried and the solvent is removed in vacuo. The product is precipitated with diethyl ether. By chromatographic purification (cyclohexane/ethyl acetate) of the solid, 174 mg of 3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]aniline are obtained.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.11 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 2 mL of tetrahydrofuran containing 70 mg of methyl 2-(benzamido)-4-(benzyloxy)benzoate at room temperature, and stirred at the same temperature for 6 hours and 30 minutes, at 40° C. for 1 hour and 30 minutes and at 50° C. for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and water and diethyl ether were added. The aqueous layer was separated and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 35 mg of 2-(benzamido)-4-(benzyloxy)benzoic acid as white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].O>CN1CCCC1=O>[Br:1][C:2]1[N:3]=[C:4]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1nc(Br)cn2c(I)cnc12
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CNc1nc(Br)cn2c(I)cnc12
Temperature: 23 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 5.08 g (12.64 mmol) 6-bromo-3-iodo-8-methanesulfonyl-imidazo[1,2-a]pyrazine which was prepared according to intermediate example 1c in 100 mL 1-methylpyrrolidin-2-one were added 3.77 mL isobutylamine. After stirring at 23° C. for 2 hours, 500 mL water were added and the mixture was extracted with ethyl acetate. The organic phase was filtered, evaporated and the residue was recrystallized from methanol/water to yield 3.87 g (78%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11].O>CO>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(F)cncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(F)cncc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of sodium borohydride (198 mg, 5.2 mmol) in anhydrous methanol (8 mL) was added a solution of 3,5-difluoropyridine-4-carbaldehyde (0.5 g, 3.5 mmol) in anhydrous methanol (2 mL) at 0° C. The mixture was stirred for 6 hours at room temperature. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3,5-difluoropyridin-4-yl)methanol was obtained and used in the next step without purification; 1H NMR (400 MHz, CDCl3): δ 2.25 (bs, 1H), 4.85 (s, 2H), 8.36 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[C:5]3[C:6](=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2n1
Solvent: c1ccncc1
Product: Nc1ccc2c(n1)c(C1=CCN3CCCC3C1)cn2C(=O)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 0.10 gm (0.39 mMol) 5-amino-3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)pyrrolo[3,2-b]pyridine and 0.56 μL (0.47 mMol) 4-fluorobenzoyl chloride in 10 mL pyridine was stirred at 55° C. for 18 hours. The reaction mixture was then partitioned between 1N sodium hydroxide and 3:1 chloroform:isopropanol. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica plate) eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.077 gm (57%) of the title compound. The title compound was recrystallized twice from ethanol:water and dried under reduced pressure to provide a sample for analysis.