Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][CH:10]2[CH2:13][N:12]([C:14]([CH3:33])([CH3:32])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]#[N:19])[CH2:11]2)=[CH:7][CH:6]=1>CC(O)(CC)CC>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]2[CH2:11][N:12]([C:14]([CH3:32])([CH3:33])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:18]([NH2:19])=[O:1])[CH2:13]2)=[CH:34][CH:35]=1
Reactant: [OH-]
Reactant: COc1ccc(OC2CN(C(C)(C)CCC(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Agent: CCC(C)(O)CC
Agent: [K+]
Product: COc1ccc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Potassium hydroxide (135 mg, 2.41 mmol) was added to a solution of the product of example 105 (53 mg, 0.12 mmol) in 3-methyl-3-pentanol (5 mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (5 mL). The aqueous layer was separated, extracted with ethyl acetate (2×20 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give a colourless oil in 96% yield, 53 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@H:6]([OH:19])[C@@H:5]1[NH2:20].[C:22]([O:26][C:27]([NH:29][CH:30]([C:39](O)=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.O>[NH2:18][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[C:15]=1[N:16]=[CH:17][N:9]2[C@@H:7]1[O:8][C@H:4]([C:3]([O:2][CH3:1])=[O:21])[C@@H:5]([NH:20][C:39](=[O:40])[CH:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:6]1[OH:19]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of methyl-1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (294 mg) prepared in Example 62, N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanine (300 mg) and N,N'-dicyclohexylcarbodiimide (206 mg) in tetrahydrofuran (15 ml) and water (5 ml) was stirred overnight. The mixture was diluted with water (50 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness. The residue was subjected to column chromatography on silica gel. The elution was carried out with a mixed solvent (chloroform/methanol=97/3). The eluate was evaporated to dryness to give methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (203 mg), mp. 120°-125° C.
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12].C(O)(=O)C>O>[CH3:12][CH:11]([CH3:13])[CH2:10][CH:9]=[C:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[O:8]
Reactant: O=C1CCCC1
Reactant: CC(C)CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC=C1CCCC1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Water (1.9 L) and sodium hydroxide (NaOH, 40 g, 50% caustic) were charged in a flask and heated to 80° C. A premix of cyclopentanone (840 g, 10 mol) and isovaleraldehyde (1.05 Kg, 12 mol) was slowly fed for over 5 hours. The reaction mixture was aged at 80° C. for another 30 minutes, cooled to room temperature, and quenched with acetic acid (120 g, 2 mol). A rushover process provided the crude product 2-[3-methyl-butylidene]-cyclopentanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Amino-2-nitro-benzoic acid (compound A′) (910 mg) was dissolved in methanol (50 ml). Thionyl chloride (0.74 ml) was added dropwise to the solution on an ice bath, and a reaction was allowed to proceed under reflux with heating for 12 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling to room temperature and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-amino-2-nitro-benzoic acid methyl ester (410 mg, yield 42%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:27]=[CH2:28])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:2]([F:14])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([P:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH:27]=[CH2:28])[CH:18]=2)(=[O:13])[O:10][CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: CCO[PH](=O)c1ccc(C(F)(F)F)cc1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(P(=O)(OCC)c2ccc(C(F)(F)F)cc2)ccc1OC(C)C
Temperature: 70 °C
Yield: 8.6 %

Procedure:
To a degassed solution of ethyl 4-(trifluoromethyl)-phenylphosphinate (1.00 g, 4.20 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (921 mg, 3.81 mmol) in DMF (40 mL) were added the triethylamine (1.1 mL, 7.62 mmol) and tris(dibenzylideneacetone)dipalladium (698 mg, 0.762 mmol). The mixture was warmed at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography using 5 to 100% ethyl acetate in petroleum ether to afford compound BA1 (130 mg) as a dark green oil in 8.6% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[Cl:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.[C:57]([O:60][CH2:61]C)(=[O:59])C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:49][C:48]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[C:37]1[CH:38]=[C:39]2[C:31]([C:57]([O:60][CH3:61])=[O:59])=[C:32]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)[O:33][C:34]2=[N:35][CH:36]=1
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3Cl)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (28 mg, 0.067 mmol) was added to a stirring solution of palladium(II) acetate (7.5 mg, 0.034 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (75 mg, 0.17 mmol) in MeOH (0.6 mL) and DMSO (1.1 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (75 mg, 0.113 mmol, 67% yield) by LCMS. LC-MS retention time: 2.28 min; m/z (MH+): 427. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), (R)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown foam (69%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[O:36]1[CH2:40][CH:39](O)[CH:38]([OH:42])[CH2:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:42][C@H:38]3[CH2:37][O:36][CH2:40][C@H:39]3[O:35]2)[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OC1COCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), tetrahydrofuran-3,4-diol (0.48 g), p-toluenesulfonic acid monohydrate (0.028 g) and toluene (25 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 90%).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N+:16]([O-])=O)[CH:15]=1)[NH:12][C:11]([C:19]1[S:20][CH2:21][C@@H:22]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:23]=1)=[CH:10]2)=[O:4].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:16][C:14]2[CH:15]=[C:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:33])([CH3:32])[CH3:1])[CH:8]=[C:9]3[C:13]=2[NH:12][C:11]([C:19]2[S:20][CH2:21][C@@H:22]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:23]=2)=[CH:10]3)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCCC1
Reactant: CC(C)(C)C(=O)OCc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1
Product: CC(C)(C)C(=O)OCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1

Procedure:
2,2-Dimethyl-propionic acid (R)-2-[5-(2,2-dimethyl-propionyloxymethyl)-7-nitro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl-methyl ester prepared in Preparation 43 and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].O=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][C:13]#[N:14]>CCO>[C:2]([N:6]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a slurry of tert-butylhydrazine hydrochloride (12.8 g, 102.9 mmol) in 350 mL of EtOH was added sodium hydroxide (3.5 g, 88.2 mmol). After 1 hr of stirring, a solution of 3-oxo-3-phenyl-propionitrile (10.6 g, 73.5 mmol, in 50 mL of EtOH) was added and the resulting slurry was heated to reflux. After 12 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting solid was washed with hexanes and dried under reduced pressure to give the title compound (13.1 g, 83% yield) as yellow-colored solid, which was used without further purification. LRMS m/z /(APCl) 216 (M+1); 500 MHz 1H NMR (CD3OD) δ 7.67 (d, J=7.5 Hz, 2H), 7.35-7.29 (m, 2H), 7.25-7.20 (m, 1H), 5.86 (s, 1H), 1.65 (S, 9H).
Reaction SMILES: Cl.[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.C1COCC1>[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CN)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 3-acetyl-2-(4-aminomethylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one hydrochloride (100 mg) and triethylamine (0.09 ml) and 4-dimethylaminopyridine (24 mg) in THF (5 ml) was added acetic anhydride (0.08 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (93 mg, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[CH2:2]([C:3]1([CH2:7][OH:8])[NH:4][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:6][CH2:5]1)[OH:1]
Reactant: O=C1CCCCC1
Reactant: NC(CO)(CO)CO
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1(CO)COC2(CCCCC2)N1

Procedure:
Tris-(hydroxymethyl)-aminomethane (24.23 grams; 0.2 mole) and cyclohexanone (19.63 grams; 0.2 mole) were refluxed overnight in 150 mls of toluene, using a water separator to remove approximately 3.6 mls of water. The toluene was then removed by distillation and the residue was recrystallized from acetone to obtain 32 grams (79.5% of theoretical; m.p. 117°-119° C.) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.CCCCCC.C([Li])CCC.[Cl:27][Si:28](Cl)([Cl:30])[Cl:29]>C(OCC)C>[Cl:27][Si:28]([Cl:30])([Cl:29])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (175 mL) of 1-bromo-3,5-di-tert-butylbenzene (35.00 g, 130.00 mmol), a 1.65 M hexane solution of n-butyllithium (88.67 mL, 143.00 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 2 hours. The resultant mixture was added dropwise to a solution of tetrachlorosilane (66.26 g, 390.00 mmol) dissolved in diethyl ether (58 mL) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Purification by distillation under reduced pressure afforded trichloro(3,5-di-tert-butylphenyl)silane (24.11 g, yield 57.3%).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNc1ccccc1
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(-c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
1-phenyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 200 mg (1.2 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and phenylhydrazine (767 mg, 7.1 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 77 mg (23%) of the compound as an orange coloured solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(N)[C@@H:22]([NH2:28])[CH2:23][O:24][CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:28][C@@H:22]([CH2:23][O:24][CH2:25][O:26][CH3:27])[C:21]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[N:2]=2)[N:8]=1)=[O:10])[CH3:13]
Reactant: COCOC[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(C#N)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)[C@H](COCOC)N2)n1
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
2-Cyano-4-ethoxycarbonylpyrimidine (207.3 mg) and scandium trifluoromethanesulfonate (48.8 mg) were added to a solution of (2R)-1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine (303.5 mg) in toluene (2.0 mL), and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1→1:2) to give (5R)-2-(4-ethoxycarbonyl-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (279 mg). The obtained ester compound was dissolved in methanol (2 mL), and ammonia gas was passed through the solution at −78° C. for 20 minutes. Then the solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1→chloroform:methanol=9:1) to give the corresponding amide compound (273 mg). Triethylamine (0.75 mL) and trifluoroacetic anhydride (0.26 mL) were added at −78° C. to a solution of the obtained amide compound in tetrahydrofuran (2 mL), and the temperature of the mixture was raised up to room temperature, followed by stirring for 7 hours. Water was added to the reaction mixture, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. Then the organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1→1:2) to give the corresponding cyano compound (178 mg). The obtained cyano compound was dissolved in tetrahydrofuran (6 mL), and 6N hydrochloric acid(6 mL) was added to the solution. Then the mixture was stirred at room temperature for 5 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture carefully, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. The organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (C-300; chloroform:ethyl acetate=2:1) to give the title compound (74.7 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 3-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 36 mg (46%) of the title compound as light brown powder.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[NH:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:24]([NH2:26])=[NH:25]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:26]=[C:24]([NH:23][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:25]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccccc3F)C4)cc2)CC1

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and benzyl 4-(4-guanidinophenyl)piperazine-1-carboxylate as described in general procedure 1. LCMS m/e 586 (M+H).