Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])([CH3:8])[CH2:3]1>CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:14][NH2:15])[CH:16]=[CH:17][CH:18]=2)([CH3:8])[CH2:3]1
Reactant: CN1CCCC(C)(COc2cccc(C#N)c2)C1
Agent: [Ni]
Solvent: CO
Product: CN1CCCC(C)(COc2cccc(CN)c2)C1

Procedure:
3-[(1,3-Dimethylpiperidin-3-yl)methoxy]benzonitrile (0.53 g, 2.2 mmol) was dissolved in MeOH (30 mL)/NH3(sat) (0.05M) and hydrogenated over a Raney Nickel CatCart (30×4 mm) using the H-Cube system at 50 bar and 50° C. at a flow rate of 1 mL/min. LC-MS showed <100% conversion so the process was repeated. The reaction mixture was concentrated and dried in vacuo, which gave the product as a clear oil. Yield: 0.48 g (90%). 1H NMR (400 MHz, CD3OD) δ 7.13 (t, 1H, J=8.12 Hz), 6.85 (s, 1H), 6.80 (d, 1H, J=7.61 Hz), 6.72 (d, 1H, J=7.61 Hz), 3.74 (m, 2H), 3.67 (s, 2H), 3.23 (s, 2H), 2.04-2.43 (m, 7H), 1.48-1.63 (m, 3H), 1.20 (m, 1H), 1.02 (s, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[CH:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:42][CH3:43]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH2:42][CH3:43])[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
LiHMDS (20 mL, 0.020 mol) was added dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (4.32 g, 0.010 mol) in THF (80 mL) and HMPA (20 mL) at −78° C. The resulting mixture was stirred for another 1 h at −78° C. Iodoethane (2.3 g, 0.015 mol) was added to the above solution. The reaction mixture was warmed to −20° C. and stirred for 20 min. The mixture was quenched with sat. ammonium chloride and extracted with EA, washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=8:1) to afford the title compound. LC/MS m/z=405.1 [M-tBu+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([C:32](OC)=[O:33])[C:19]=2[C:36](OC)=[O:37])[CH:15]=[CH:14][N:13]=1.[BH4-].[Na+].CO.Cl>O1CCCC1.C(Cl)Cl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([CH2:32][OH:33])[C:19]=2[CH2:36][OH:37])[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(-n3c(=O)ccc4ccccc43)c2)c1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)ccc5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Yield: 50.4 %

Procedure:
To a suspension of 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (200 mg) in tetrahydrofuran is added sodium borohydride (36 mg), and the mixture is refluxed. To the mixture is added methanol (0.3 ml) under reflux over a period of one hour. The mixture is cooled to room temperature, and thereto is added sodium borohydride (36 mg). To the mixture is added methanol (0.3 ml) under reflux over a period of one hour. After the reaction is complete, methylene chloride and diluted hydrochloric acid are added to the mixture. The methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (90 mg), which is listed in Table 6.
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:15]([OH:22])[C:16]([O:18]C(C)C)=[O:17])[C:9]([O:11]C(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([OH:18])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)[C@@H](Cc1ccccc1)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 29.3 %

Procedure:
Diisopropyl (2S,3R)-2-benzyl-3-hydroxysuccinate (9.76 g; 31.65 mmol; 1.00 eq.) was taken in THF (150 mL), cooled to 0° C. and was treated with KOH (10.65 g; 189.90 mmol; 6.00 eq.) in water (50 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was chilled to 0° C. and cautiously acidified with an aqueous solution of HCl (1 N) until pH 3.8. The solid that separated was collected by filtration to give the title product (single diastereoisomer) as white solid (2.08 g, 29%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](O)=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl.CN(C)C=O>[C:1]1([N:7]2[C:11]([C:12]([Cl:22])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1
Reaction time: 0.33 h

Procedure:
A sample of crude 1-phenyl-3-(trifluoromethyl)pyrazole-5-carboxylic acid (i.e. the product of Step B) (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45 mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol), followed by N,N-dimethylformamide (0.010 mL, 0.13 mmol). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for ˜20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by stripping the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The product consisted of 4.43 g of a light-yellow oil. The only impurity observed by 1H NMR was N,N-dimethylformamide.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C\CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC/C=C\CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of cis-dec-4-en-1-ol (1.00 g, 6.41 mmol) in DMF (15 mL) was added triphenylphosphine (1.87 g, 7.13 mmol). The solution was cooled to 0° C. and NBS (1.23 g, 6.91 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.6 mL). The solution was diluted with ether (60 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford cis-1-bromo-dec-4-ene (1.23 g, 96%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.38 (1H, m), 5.29 (1H, m), 3.39 (2H, t, J=6.9 Hz), 2.17 (2H, m), 2.03 (2H, m), 1.88 (2H, m), 1.28 (6H, m), 0.87 (3H, t, J=6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 131.87, 127.39, 33.65, 32.90, 31.76, 29.63, 27.51, 25.87, 22.83, 14.35.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[C:22]([CH2:23][OH:24])=[CH:21][CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[O-2].[O-2].[O-2].[O-2].[Mn+2].[Mn+2].[Mn+2].[Mn+2].C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[C:22]([CH:23]=[O:24])=[CH:21][CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CO)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Agent: [Mn+2]
Agent: [O-2]
Solvent: c1ccccc1
Product: COc1ccc(C=O)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of the compound (24 mg) obtained in Example 454, manganese tetraoxide (40 mg) and benzene (8 ml) was stirred at room temperature for 2 days.
Reaction SMILES: Cl[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C(O)C.O.[NH2:17][NH2:18].ClCCl>O>[NH:17]([C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:18]
Reactant: CSc1nc(Cl)c2sccc2n1
Reactant: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CSc1nc(NN)c2sccc2n1
Temperature: 25 °C
Yield: 93 %

Procedure:
4-Chloro-2-methylthiothiopheno[3,2-d]pyrimidine (15.26 g, 70.4 mmol) was mixed with 400 mL of ethanol and then 7.2 mL (148 mmol) of hydrazine hydrate was added with stirring at ambient temperature and the mixture was allowed to stir overnight. The solid materials present were recovered by filtration and the filtrate was evaporated to dryness under reduced pressure to obtain additional solid material. All of the solids were combined and mixed vigorously with a mixture of 500 mL of dichloromethane and 500 mL of water for 6 hours. The solids present were recovered by filtration and dried to obtain 13.9 g of the title compound as a slightly yellow solid melting at 242°-244° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.Cl.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][NH2:17])=[CH:11][CH:10]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccn2)cc1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: NNc1ccc(OCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(Pyrid-2-ylmethoxy)aniline (86.7 g; 433 mmol), prepared as in step 2, was suspended in 200 mL water and 108 mL concentrated HCl was added. The solution was cooled to 0° C. and sodium nitrite (30.8 g; 446 mmol) in 75 mL water was added dropwise. The reaction was stirred for 1 hour at 0° C. The diazonium salt was then transferred dropwise to a solution of sodium hydrosulfite (85% purity; 487 g; 2.80 mol) in 2000 mL water, 2000 mL diethyl ether, and 20 mL 2N aqueous NaOH at 0°-5° C. with vigorous stirring. When addition was complete 775 mL 2N aqueous NaOH was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. The precipitate was collected by vacuum filtration and washed with water then diethyl ether. The reaction yielded 4-(pyrid-2-ylmethoxy)phenylhydrazine as a pale green solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH:35]=[C:34]([OH:47])[CH:33]=1)(C(C)(C)C)(C)C.O>CC(C)=O.Cl>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH:35]=[C:34]([OH:47])[CH:33]=1
Reactant: CN(C)C(=O)CCCOc1cc(O)cc(CCC[C@@H]2C[C@H]3CC(=O)CC[C@]3(C)[C@H]3CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@H]23)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)CCCOc1cc(O)cc(CCC[C@@H]2C[C@H]3CC(=O)CC[C@]3(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@H]23)c1
Reaction time: 0.58 h
Yield: 65.3 %

Procedure:
To a solution of 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-hydroxy-5-(3-(N,N-dimethylaminocarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one (12.0 mg) in acetone (1 ml), 2N hydrochloric acid (1 ml) was added at 25° C. and stirred for 35 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 17β-hydroxy-7α-(3-(3-hydroxy-5-(3-(N,N-dimethylaminocarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one (6.5 mg, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23]>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1ccncn1)c1ccc(F)c(Cl)c1
Reaction time: 16 h
Yield: 27 %

Procedure:
4-Aminopyrimidine (1.0 g, 10.5 mmol) and DABCO™ (1.18 g, 10.5 mmol) were added concurrently to a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (1.25 mL, 10.0 mmol) in anhydrous acetonitrile (49 mL). The reaction mixture immediately turned yellow and a precipitate was formed. After stirring for 16 hours, the mixture was concentrated in vacuo. The crude material was suspended in ethyl acetate (75 mL) and water (75 mL) and stirred for 15 minutes. The resulting solid was filtered and dried in vacuo to afford the title compound, 0.83 g, 27% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[CH:16][C:17](C)=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[C:21]1C=C(C=CC=1C)N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[CH:16][CH:17]=[C:18]([CH3:21])[N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1O
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Product: Cc1ccc(Nc2ncnn3c(C)ccc23)cc1O

Procedure:
Example 11 was prepared as a white solid in 30% overall yield from Compound E using the 2 step sequence of Compound A of Example 1 and Compound B of Example 1, using 3-hydroxy-4-methylaniline. The product was purified by flash chromatography on silica with 25% ethyl acetate/hexanes. (M+H)+ 255.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31]([NH:1][CH:2]1[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]1=[O:20])=[O:32])=[CH:25]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2cc(O)ccc2[nH]1
Reaction time: 48 h
Yield: 126.2 %

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmole) and 5-hydroxyindole-2-carboxylic acid (75 mg, 0.44 mmole) were combined at room temperature in a mixture of 1 ml of dimethylformamide and 5 ml of methylene chloride. To this reaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.40 mmol). The pH of the reaction mixture was then adjusted to 8.5 with triethylamine and stirring was continued at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 10% citric acid solution. The phases were separated and the organic layer was washed in succession with 20% citric acid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml) and brine. The dried (MgSO4) extracts were concentrated to yield 200 mg of the product. Preparative thick layer chromatography (chloroform - ethanol - ammonia, 90:10:1, v/v) afforded the analytical sample (80 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Yield: 38.6 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 21.6 mmol), 4-benzyloxyphenol (4.3 g, 21.6 mmol), pyridinium p-toluenesulfonate (100 mg) and chloroform (150 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with water and brine. After drying over sodium sulfate, volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a light brown solid which was recrystallised to afford the title compound (3.6 g) as a white solid. (from diethyl etherhexanes).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[NH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCN
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Reaction time: 24 h
Yield: 90.8 %

Procedure:
A solution of 1-(2-aminoethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine dihydrochloride (7.20 g, 22.9 mmol) in trifluoroacetic acid (75 mL) was treated with platinum (IV) oxide (7.0 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours on a Parr apparatus. The reaction mixture was diluted with chloroform (50 mL) and methanol (25 mL) and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (5 mL), stirred for 2 hours, treated with 50% aqueous sodium hydroxide to adjust the pH to 13, and stirred at ambient temperature overnight. The mixture was diluted with water (100 mL) and was extracted with chloroform (5×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 5.10 g of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-white foam.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:31])[N:10]([C:20]1[CH:25]=[C:24](Br)[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:7]>[Cl-].[Cl-].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.[Pd+2]>[CH2:6]([O:8][C:9](=[O:31])[N:10]([C:20]1[CH:25]=[C:24]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:7]
Reactant: c1cocn1
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(-c2ncco2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using oxazole (33 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano-benzyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (33 mg), giving the product (67 mg) as a yellow solid.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][CH2:5][CH:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:14]=[C:13]([C:32](=[O:34])[CH3:33])[CH:12]=1)[CH2:7][F:8].[Cl-].[NH4+]>C1COCC1>[F:8][CH2:7][CH:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:14]=[C:13]([C:32]([OH:34])([CH3:1])[CH3:33])[CH:12]=1)[CH2:5][F:4]
Reactant: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methylmagnesium bromide (0.71 mL, 1.0 mmol) in THF (6 mL) was added over 5 min a solution of 1-(6-((1,3-difluoropropan-2-yloxy)methyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)pyrimidin-4-yl)ethanone (43 mg, 0.1 mmol) of in THF (3 mL). The reaction was stirred at 0° C. for 30 minutes. Ammonium chloride (sat, aq) was added. The solvent volume was reduced by evaporation. DCM was added and the phases were separated. The organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound as a dry film (34 mg, 76%).
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[O:4]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(=O)C(Cl)c1ccccc1
Yield: 85.8 %

Procedure:
21.0 g (0.11 m) α-chlorophenylacetyl chloride and 14.0 g (0.10 m) glycine ethyl ester hydrochloride are suspended in 500 ml toluene and the mixture is heated to reflux overnight. The reaction mixture is filtered, and after the solvent is removed, the residual solid is recrystallized from cyclohexane to give 22 g (86% yield) of the title compound, which has a melting point of 88°-9° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.[ClH:20]>CCOC(C)=O>[ClH:20].[ClH:20].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: Cn1ccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ccnc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (132 mg) in EtOAc (1.3 ml) was added 4N hydrogen chloride in EtOAc (1.3 ml) and the mixture was stirred at room temperature for 2 hours. Solvent was removed in vacuo to give 4-(1-methyl-1H-imidazol-2-yl)piperidine dihydrochloride (108 mg) as a colorless powder. The obtained crude product was used in next reaction without further purification.