Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C@@H:6]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[NH:34])N)[CH2:28][CH2:27]1.C1C=CC2N(O)N=[N:41]C=2C=1.CN1CCOCC1>C(O)(C)C.O>[NH2:41][N:34]=[CH:32][N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][NH:24][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:28]1
Reactant: On1nnc2ccccc21
Reactant: N=C(N)N1CCC(CN)CC1
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CN1CCOCC1
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NN)CC1
Temperature: 0 °C
Yield: 90 %

Procedure:
To a suspension of N-methylsulfonyl-D-phenylalanyl-proline (497 mg, 1.46 mmol), 4-(aminomethyl)-1-piperidinecarboximidamide (470 mg, 1.9 mmol) and HOBt (217 mg, 1.6 mmol) in 1:1 v/v isopropyl alcohol/water (4.5 mL) was added NMM (0.32 mL, 2.9 mmol). The homogeneous solution was cooled to 0° C. and ethyl-3-(3-dimethylamino)-propylcarbodiimide·hydrochloride salt (EDAC·HCl) (308 mg, 1.6 mmol) was added. After 18 hr the reaction was concentrated in vacuo, dissolved in water (10 mL) and washed with ether (2×75 mL). Aqueous NaOH (1 N, 3.8 mL) was added until the aqueous layer attained pH 9.7, the aqueous layer was washed with ether (75 mL) and the process repeated. Aqueous HCl (1N, 3.8 mL) was added until the pH reached 2.0, the aqueous layer was washed with ethyl acetate (3×75 mL), concentrated in vacuo, dissolved in water, and lyophilized to give a foam which was subjected to chromatography on HP-20 polystyrene resin to provide the title compound (629 mg, 84%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(C2CCNCC2)c1F
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.2 g, 1.01 mmol) in acetonitrile (10 ml), was added potassium carbonate (0.28 g, 2.0 mmol) and 1-iodomethane (0.06 ml, 1.0 mmol) and the mixture was stirred at ambient temperature for 1 h. MS m/z (rel. intensity, 70 eV) 211 (M+, 78), 210 (bp), 2140 (8), 127 (12), 97 (11).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CC([O-])(C)C.[Na+]>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(F)c(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture 2-(3,4-difluorophenyl)acetonitrile (25.00 g, 163 mmol) and 2-bromoethyl ether (22.8 mL, 163 mmol) in ether was added dropwise through an addition funnel to a mixture of sodium 2-methylpropan-2-olate (39.2 g, 408 mmol) in DMF (163 mL) at 0° C. The reaction was then allowed to warm to ambient temperature and stirred for 3 hours. The reaction mixture was quenched with 12N HCl, diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 100 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=224 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])[CH2:16][CH2:15]4)=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:34])[CH3:23])[CH2:16][CH2:15]4)=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (30.1 g) was added 4M hydrogen chloride/ethyl acetate (200 mL), and the mixture was stirred at room temperature for 30 min. After stirring, the mixture was concentrated. Pyridine (100 mL) and acetic anhydride (100 mL) were added to the residue, and the mixture was stirred at room temperature for 15 min. After concentration, the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate), and the obtained crystals were recrystallized from hexane/ethyl acetate to give the title compound (17.4 g) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[CH:12][C:11]([OH:25])=[CH:10][CH:9]=2.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>C(#N)C>[CH2:18]([O:17][C:15]([C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:25][CH2:2][C:3]#[N:4])[CH:12]=2)[NH:7][C:6]=1[CH3:5])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1[nH]c2ccc(OCC#N)cc2c1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 51 %

Procedure:
α-Bromoacetonitrile (0.209 mL, 3.00 mmol, 1.0 eq.) was dissolved in dry acetonitrile (30 mL) and treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (0.972 g, 3.46 mmol, 1.2 eq.) and potassium carbonate (0.690 g, 5.0 mmol, 1.7 eq.). The reaction was heated to reflux and followed by TLC (hexane/ethyl acetate 3/2). After 6 hours, the reaction was quenched with water and extracted with ethyl acetate. The resulting organic layers were concentrated, taken up in methylene chloride, and filtered. The filtrate was evaporated to afford a brown solid: 0.490 g (51% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([Cl:11])(=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[Cl:11])/[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 2 L three-necked flask containing TFA (231 mL, 3.01 mol) and acetyl chloride (171.4 mL, 2.41 mol) was added in one portion 2-(4-bromophenyl)-1-(4-butylphenyl) ethanone (Ve) (100 g; 0.301 mol) at RT. The reaction mixture was stirred at room temperature overnight and work-up was then similar with those described above. The title compound (m=100 g) was obtained in a 95% yield. Melting point: 59-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[CH:48]=[CH:47][CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:35][C:36]1[CH:48]=[CH:47][CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:43][CH2:42][CH:41]([NH:44][C:24]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[O:26])[CH2:40]1
Reactant: NC1CCN(Cc2ccccc2Cl)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5Cl)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Chlorobenzyl)-3-pyrrolidinamine (106 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (109 mg, yield 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.[BH3-]C#N.[Na+].CC(O)=O>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:11][C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.075 g, 0.49 mmol), indole-3-carboxaldehyde (0.085 g, 0.58 mmol), NaCNBH3 (0.031 g, 0.49 mmol) and HOAc (0.056 mL, 0.97 mmol) in methanol (3 mL) was stirred at r.t. overnight. The mixture was concentrated in vacuo and the crude product-mixture was used in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:13]=[CH:12][N:11]=2)[CH:5]=1.ClC1N=CN=C(C2C=[C:31](C=CC=2)[C:32]([OH:34])=[O:33])C=1>COCCN>[C:4]([O:34][C:32](=[O:33])[CH2:31][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:21])([CH3:9])([CH3:5])[CH3:3]
Reactant: COCCNc1cc(-c2cccc(C(=O)OC)c2)ncn1
Reactant: O=C(O)c1cccc(-c2cc(Cl)ncn2)c1
Agent: COCCN
Product: COCCNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-[6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(6-Chloro-pyrimidin-4-yl)-benzoic acid (1.0 g, 4.3 mmol) was heated in 2-methoxy-ethylamine (5 ml) to 80° C. for 1 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (25 mL) for 18 h at 50° C. The crude product was purified by chromatography (silica gel, AcOEt-hexane 1:1) to give the methyl ester as light yellow solid (0.67 g).] (0.66 g, 2.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (0.93 g, not pure).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]CCl>CN(C)C=O>[CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([Cl:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a suspension of 3-(3-(benzylsulfamoyl-phenyl)-acrylic acid (5g) (0.16 g, 0.52 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.16 ml, 1.79 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.17 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[N+](C1C=CC(S(O[CH2:23][C@H:24]2[CH2:26][C:25]2([F:28])[F:27])(=O)=O)=CC=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:23][C@H:24]2[CH2:26][C:25]2([F:28])[F:27])=[CH:6][N:7]=1
Reactant: Cc1cc(Br)ncc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ncc1OC[C@H]1CC1(F)F
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a solution of 6-bromo-4-methylpyridin-3-ol (0.50 g) and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (1.077 g) in DMF (50 mL) was added sodium hydride (60% in oil, 0.106 g) under ice-cooling, and the mixture was stirred for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.35 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][C@@H:44]([C:47]([OH:49])=O)[CH2:43][C@@H:42]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:32]2>C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:3]([CH3:4])[CH3:2])=[O:49])[CH2:43][C@H:42]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:32]2
Reactant: CNC
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 72 h
Yield: 118.7 %

Procedure:
Triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) were added to a chloroform suspension (10 ml) of the compound (168 mg) obtained in Example 56, and the mixture was stirred for 72 hours. The solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (methylene chloride:methanol=93:7). The thus-obtained colorless solids (135 mg) were suspended in ethanol (5 ml), to which 1N ethanol solution (0.5 ml) of hydrochloric acid was added. The mixture was stirred for 2 hours, and the solvent was distilled off to obtain the title compound (112 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:23])[CH:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=1)=[O:9])[C:19]2=[O:20])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN=[N+]=[N-])ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (200 mg) and sodium azide (176.8 mg) in anhydrous DMF (7 mL) is heated at 60° C. overnight. The reaction is cooled to room temperature and poured into water to precipitate the product. The solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 0.5% MeOH in CH2Cl2 (1 L), and 1% MeOH in CH2Cl2 (1 L)). Fractions homogenous by TLC were combined and concentrated to afford 182.7 mg (90%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:31][C:32]([F:35])([F:34])[F:33])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:40])C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.CC(OC(C)=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:37][C:2]([F:36])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:31][C:32]([F:33])([F:34])[F:35])[C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:40])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(=O)O
Reactant: CN(c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Ic1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CN(c1ccc(-c2c(O)cc(OS(=O)(=O)C(F)(F)F)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 60 °C

Procedure:
A mixture of 4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyl trifluoromethanesulfonate (360 mg, 0.647 mmol), iodobenzene diacetate (375 mg, 1.164 mmol) and Pd(OAc)2 (7.3 mg, 0.032 mmol) in AcOH (3.0 mL) and Ac2O (3.0 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was basified with aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated. The crude material was loaded onto a SCX column, washed with MeOH and diluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. Compound 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate was obtained as a yellow solid (110 mg, 28%) after flash column chromatography and HPLC purification. MS (M+1)=573.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 650 mg (2.38 mmol) of the compound obtained in Step D are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 450 mg (11.90 mmol) of sodium borohydride are added slowly. After stirring for 30 minutes at room temperature, acetic acid is added and the reaction mixture is filtered over a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.[Br:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([CH3:30])=[O:29]>>[Br-:26].[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N+:3]=1[CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](=[O:29])[CH3:30]
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)C(Br)c1ccccc1
Product: CCCCc1n[n+](C(C(C)=O)c2ccccc2)c(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [Br-]

Procedure:
Reaction of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D) with 1-bromo-1-phenylacetone [A. C. B. Smith and W. Wilson, J. Chem. Soc., 1342 (1955)] according to the procedure of Example 1, Step E, gave an essentially quantitiative yield of the title compound as a yellow oil, suitable for use in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=2[N:6]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:31]([O:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[C:11](=[O:14])[C:12]2[NH:13][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[N:6][C:7]=2[N:8]([CH3:23])[C:9]1=[O:22])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a stirring mixture of (R)-8-(2-chloroethylamino)-1-(5-hydroxyhexyl)-3-methylxanthine (2.2 g, 6.4 mmol), triethylamine (1.94 g, 19.2 mmol) and 4-dimethylaminopyridine (0.39 g, 3.2 mmol) in chloroform (50 ml) at 0-5° C. was added acetic anhydride (1.30 g, 12.8 mmol). The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethylacetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 89% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](C)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].F[C:15]1C=CC=C([N+]([O-])=O)C=1C(O)=O.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH2:30].NC1C=CC=CC=1>>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH:30][C:6](=[O:8])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Nc1c(F)cccc1F
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Solvent: Nc1ccccc1
Product: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1c(F)cccc1F

Procedure:
Compound 118a was prepared following the preparation procedure described above with respect to compound 107, but 2-nitro-5-methylbenzoic acid was substituted for 2-fluoro-6-nitrobenzoic acid and 2,6-difluoroaniline was substituted for aniline.
Reaction SMILES: [Cl-].[Cd+2:2].[Cl-].Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[Mg]>C1COCC1>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([Cd:2][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: [Cd+2]
Reactant: CC(C)Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc([Cd]c2ccc(CC(C)C)cc2)cc1

Procedure:
Ten grams of cadmium chloride was added to a Grignard reagent prepared from 21.7 g of p-bromoisobutylbenzene, 2.5 g of magnesium and 400 ml of THF. The mixture was refluxed for 10 minutes to give a solution of di-(p-isobutylphenyl)cadmium. A solution of 18 g of ethyl α-bromopropionate in 20 ml of THF was added to the reaction mixture which had been cooled. After standing at 20° C. for 24 hours, dilute hydrochloric acid was added to the mixture. The mixture was extracted with diethyl ether. The extract was washed with water, dried, concentrated, and purified by silica gel column chromatography to give 4.05 g (17.4%) of ethyl α-(p-isobutylphenyl)propionate.