Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[Pb+3]>ClCCl>[CH:1]1([NH:9][C:25]2[C:26]([O:31][CH3:32])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[O:23][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCCC1
Reactant: COc1cc(C)cc(OC)c1[Pb+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1NC1CCCCCCC1
Reaction time: 18 h
Yield: 52 %

Procedure:
10.56 g of cyclooctylamine are dissolved in 500 ml of anhydrous dichloromethane and 1.5 g of cupric acetate are added thereto. A solution of 44.2 g of 2,6-dimethoxy-4-methylphenyllead triacetate, prepared above, in 250 ml of anhydrous dichloromethane is added dropwise to the reaction mixture under an inert atmosphere. The reaction mixture is left at room temperature for 18 hours, the heterogeneous mixture is then filtered over a bed of celite and the filtrate is concentrated to 450 ml. The organic phase is washed with water (3 times). The organic phase is extracted with 3×300 ml of 1N hydrochloric acid. The acidic aqeuous phase is basified with a 2N aqueous sodium hydroxide solution (pH=11). The alkaline aqeuous phase is extracted with dichloromethane and the organic extracts are dried over anhydrous sodium sulphate. Evaporation leaves an oil which is purified by flash chromatography on a column of silica gel, eluent:dichloromethane/methanol:99/1 (v/v) in order to obtain N-cyclooctyl-2,6-dimethoxy-4-methylaniline in the form of an oil. Yield 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH:28]3[CH3:31])=[CH:23][CH:22]=2)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[CH:22][CH:23]=4)[CH:28]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(-c3cccnc3F)cc21
Product: CC1c2cc(-c3cccnc3F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[NH:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[C:28]([N:12]([CH2:13][CH3:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:18]([O-:20])=[O:19])(=[O:30])[CH3:29]
Reactant: CCNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(C)=O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 3-benzyloxy-N-ethyl-2-nitroaniline (2.20 g) and triethylamine (1.23 g) in dichloromethane (21 ml) was added acetyl chloride (698 mg) under ice-cooling, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was washed with water, saturated sodium bicarbonate solution, water and brine successively, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (dichloromethane-ethyl acetate) to give N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.71 g).
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.C(O)(C)C>ClCCl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH:1]([CH3:8])[CH3:3])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
Carbonyl diimidazole (18.6 g, 0.115 mol) was added to a suspension of 6-chloronicotinic acid (16.6 g, 0.105 mol) in dichloromethane (250 mL). After all of the solid had dissolved the reaction solution was stirred at ambient temperature for 1 hour and then isopropyl alcohol (100 mL) was added. The dichloromethane was removed under vacuum. A catalytic amount of sodium isopropoxide was added to the solution and the solution was heated at reflux for 1 hour. The solution was then concentrated under vacuum. The resulting residue was slurried with water and then extracted with diethyl ether. The extract was dried over magnesium sulfate and then concentrated under vacuum to provide 23.9 g of isopropyl 6-chloronicotinate.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cccc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-(trifluoromethyl)phenyl isocyanate (0.37 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.38 g, 51% yield), mp=66–68° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+22.0° (c=1, EtOH).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of methyl 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoate (Part B) (2.232 g, 7.03 mmol) and 10.6 mL (10.6 mmol) of 1.0 N NaOH in 60 mL of 1:1 mixture of MeOH/THF was stirred at 80° C. for 20 h. The mixture was then cooled to room temperature, stirred for additional 7 h, and concentrated under reduced pressure. The residue was dissolved in 50 mL of 1.0 N HCl. This solution was extracted with 200 mL of EtOAc. The organic layer was washed with 200 mL of water. The combined aqueous layers were cooled to 0° C. and neutralized with 15 mL of 2.0 N NaOH. They were then concentrated under reduced pressure and the residue was taken up in 10% MeOH in CH2Cl2 and then filtered. The filtrate was concentrated and the residue was dried over P2O5 in a vacuum oven at 55° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-amino-2-methylpropan-1-ol (CAS 124-68-5) (53 mg, 0.6 mmol), HATU (129 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide 18. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.69-8.55 (m, 2H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.05 (d, J=39.6 Hz, 2H), 7.91 (d, J=7.7 Hz, 1H), 7.76 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 3.57 (d, J=6.0 Hz, 2H), 1.36 (s, 6H).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([I:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.ClC[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(O)(=O)C.Br>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([I:21])=[C:16]([O:19][CH2:20][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(NCc3ccccc3)nccc2cc1I
Reactant: CC(C)(C)OC(=O)NCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1cc2c(N)nccc2cc1I
Temperature: 140 °C
Reaction time: 8 h

Procedure:
10.4 g (26.7 mmol) of benzyl-(6-iodo-7-methoxyisoquinoline-1-yl)amine was dissolved in a mixture of 8 ml of acetic acid and 40 ml of hydrobromic acid, and the obtained solution was stirred at 140° C. overnight. The solvent was evaporated, and the residue was dissolved in 50 ml of DMF. 14.6 g (65.2 mmol) of t-butyl (2-chloroethyl)carbamate and 4.95 g (163 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 70° C. overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:34])(=[O:33])[NH:28]C(C)(C)C)=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH2:28])=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Anisole (2 drops) was added to a solution of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-isopropyl-3H-1,2,4-triazol-3-one (from Step H) (97.5 mg; 0.201 mmole) in 2 ml of trifluoroacetic acid stirred under N2 at room temperature. After 24 hours, the solution was concentrated in vacuo. Chromatography of the residue on silica gel (gradient elution with 1.5 to 2% MeOH in CH2Cl2, containing 0.2% concentrated ammonium hydroxide) afforded 67.4 mg (78%) of the title compound as a white solid; satisfactory purity by TLC in 98:2:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 429 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:12][CH3:13]
Reactant: CC[Mg]Br
Reactant: O=C(CCCl)c1ccccc1
Product: CCC(O)(CCCl)c1ccccc1

Procedure:
1-chloro-3-phenylpentan-3-ol was prepared from 3-chloro-1-phenylpropan-1-one and ethylmagnesium bromide following a procedure analogous to that described in Preparation 1 Method 1 Step 2.
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([NH:6][C:7](=[O:39])[NH:8][C:9]1[CH:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1)[CH3:5]>C1COCC1>[CH2:4]([NH:6][C:7](=[O:39])[NH:8][C:9]1[CH:31]=[C:30]([NH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:25])[CH3:1])=[CH:20][CH:21]=2)=[O:14])=[CH:11][N:10]=1)[CH3:5]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)N(C)OC)cc2)cn1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(C)=O)cc2)cn1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
Methylmagnesium chloride (100 μmol, 0.3 mmol) was added to THF (1 mL) and cooled to 0° C. Compound 123 (8 mg, 0.016 mmol) was dissolved in THF (1 mL) and this solution added dropwise to the Grignard at 0° C. The mixture was allowed to warm slowly to RT over 1 h then quenched with NH4Cl and diluted with water and EtOAc. The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4 then evaporated to dryness. The residue was applied to a silica column in DCM (1 mL) and MeOH (2 drops) and eluted with MeOH in DCM to afford Compound 122 (4 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:27]=[C:26]([C:28]4[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (diethyl ether/MeOH) as a pink solid (147 mg, 58%). MS (EI) 505.1 [(M)+]; mp 285° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:37])[C:4](=O)[O:5]C1C=C2C(=CC=1)C(CN(CCC(N1CCC3C=C(OC)C(OC)=CC=3CC1)=O)C)C2.[CH3:38][O:39][C:40]1[C:66]([O:67][CH3:68])=[CH:65][C:43]2[CH2:44][CH2:45][N:46]([C:49](=[O:64])[CH2:50][CH2:51][N:52]([CH2:54][CH:55]3[C:62]4[C:57](=[CH:58][CH:59]=[C:60]([OH:63])[CH:61]=4)[CH2:56]3)[CH3:53])[CH2:47][CH2:48][C:42]=2[CH:41]=1>>[ClH:1].[CH3:2][N:3]([CH3:37])[C:4](=[O:5])[O:63][C:60]1[CH:61]=[C:62]2[C:57](=[CH:58][CH:59]=1)[CH2:56][CH:55]2[CH2:54][N:52]([CH2:51][CH2:50][C:49]([N:46]1[CH2:47][CH2:48][C:42]2[CH:41]=[C:40]([O:39][CH3:38])[C:66]([O:67][CH3:68])=[CH:65][C:43]=2[CH2:44][CH2:45]1)=[O:64])[CH3:53]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(O)cc31)CC2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC(=O)N(C)C)ccc31)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(OC(=O)N(C)C)cc31)CC2

Procedure:
Obtained in the same manner as the compound of Example 47 but using the compound of Example 45 instead of the compound of Example 43.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([O:9]N)[CH:6]=[CH:7][CH:8]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:12]=3[O:9][C:5]=2[CH:4]=1
Reactant: NOc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2oc3cc(Br)ccc3c2C1
Yield: 11 %

Procedure:
The product of step B was reacted with tert-butyl 4-oxopiperidine-1-carboxylate then Boc protected following the procedure of Example 29, step B to give tert-butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (181 mg, 11%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.3 Hz, 1.8 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 4.53 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.52 (s, 9H); ESI MS m/z 352 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1
Reactant: COc1cccc(CC(=O)c2cc(OC)ccc2OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cc1cccc(O)c1)c1cc(O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Boron tribromide (1M in DCM, 48.0 mL, 48.0 mmol) was added dropwise to a solution of 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone (3.35 g, 11.7 mmol) in DCM (50 mL) at −78° C. The reaction mixture was warmed to 0° C., stirred for 30 min, re-cooled to −78° C., and then quenched with methanol (15 mL). The reaction mixture was warmed to room temperature, concentrated under reduced pressure and purified by silica gel chromatography to give 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (1.78 g, 62%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.24 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 7.26 (m, 1H), 7.10 (t, 1H), 6.98 (dd, 1H), 6.83 (d, 1H), 6.70 (m, 3H), 4.24 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)=[O:9].B.[Na].O>CO>[OH:9][CH:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)C4CCCCN4C)cc2)CCO3)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
In methanol (40 ml) was dissolved N-(4—(1-methylpiperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) under ice-cooling, and to the mixture was added sodium boron hydride (10 mg). The mixture was stirred for 15 minutes, and to the mixture was added water. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4—(hydroxy(l-methylpiperidin-2-yl)methyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 158) (0.07 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:24]=[CH:25][N:26]=1>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:20][CH2:21][C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:24]=[CH:25][N:26]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: C[Si](C)(C)CCOCn1ncnc1CO
Product: C[Si](C)(C)CCOCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34, part b) and 3-(hydroxymethyl)-2-{[2-(trimethylsilyl)ethoxyjmethyl}-1,2,4-triazole (described in Example 45, part c) following the procedure described in Example 45, part d, 1H NMR (360 MHz, CDCl3) δ 0.00 (9H, s, 3 of CH3), 0.88 (2H, q, J=8.4 Hz, CH2), 3.67 (2H, t, J=8.3 Hz, CH2), 5.84 (2H, s, CH2), 5.92 (2H, s, CH2), 7.30 (1H, d, J=1.7 Hz, Ar—H), 7.89 (1H, t, J=7.1 Hz, Ar—H), 7.96 (1H, s, Ar—H), 8.02 (1H, t, J=7.6 Hz, Ar—H), 8.32 (1H, d, J=8.2 Hz, Ar—H), 8.70 (1H, s, Ar—H), 8.75 (1H, d, J=8.2 Hz, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(Nc2ccc3[nH]ncc3c2)n1
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-aminoindazole (1 mmol) dissolved in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulted oil was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine in a yield of 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](/[N:1]=[CH:23]/[C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)=[C:3]([NH:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: Cc1ccc(N)c(NC(=O)c2ccccc2)c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Product: COc1cc(/C=N/c2ccc(C)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-(2-amino-5-methylphenyl)benzamide (2 mmol) and 3,4,5-trimethoxybenzaldehyde (3 mmol) in methanol was stirred at room temperature for 12 h. The suspension was filtered and the solid was washed with methanol to afford (E)-N-(5-methyl-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#N>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH2:17][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccncc1
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]CCCC
Product: c1ccc2cc(Cc3ccncc3)ccc2c1

Procedure:
4-((2-Naphthyl)methyl)pyridine was prepared from 2-bromonaphthalene, n-BuLi and 4-cyanopyridine in two steps as a yellow solid: mp 66-67° C., 1H NMR (CDCl3) 4.13 (s, 2H), 7.14 (d, J=6.0 Hz, 2H), 7.27 (dd, J=5.7 and 1.8 Hz, 1H), 7.42-7.52 (m, 2H), 7.64 (s, 1H), 7.74-7.86 (m, 3H), 8.51 (dd, 4.8 and 1.5 Hz, 2H).