Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[O:6][C:7]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[C:9]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[N:8]=1)#[N:2].[OH-].[Li+].S(Cl)(Cl)=O.Cl.[CH3:37][NH2:38].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[O:6][C:7]1[CH:12]=[C:11]([C:13]([NH:38][CH3:37])=[O:14])[CH:10]=[C:9]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[N:8]=1)#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cc(Oc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc(Oc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1
Reaction time: 1.5 h

Procedure:
To 2,6-bis(3-cyanophenoxy)pyridine-4-carboxylic acid, ethyl ester (1.6 g, 4.0 mmol) in tetrahydrofuran/water (50 mL, 1/1) was added lithium hydroxide (0.85 g, 20 mmol). After stirring for 1.5 hours the reaction was partitioned with 1M HCl and ethyl acetate. The organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (50 mL) and thionyl chloride (2.4 g, 20 mmol) was added. After stirring for 2 hours the solvent was removed in vacuo. The residue was dissolved in methylene chloride/water (30/10 mL) and methylamine hydrochloride (0.090 g, 1.3 mmol) and potassium carbonate (0.46 g, 3.3 mmol) were added. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed in vacuo to give 2,6-bis(3-cyanophenoxy)-N-methylpyridine-4-carboxamide; NMR (CDCl3) 7.5 (m,4), 7.3 (m,4), 7.0 (s,2), 6.25 (br s,1), 3.1 (d,3) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:27])[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:11]=2[S:10][C:9]=1[NH:35]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:27])[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:35])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)sc2c1C[C@@H](CN1Cc3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](CN1Cc3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of the above 2-benzyloxycarbonylamino-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (9 mg, 0.014 mmol) in methanol (2 ml) was added 10% Pd/C (4 mg). The mixture was stirred under hydrogen (1 atm.) for 3 hours and then filtered. The filtrate was evaporated in vacuo affording 6 mg (93%) of 2-amino-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: C([S:7][CH2:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])CCCC=C.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1>>[I:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][S:7][CH2:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: BrCc1cccc(I)c1
Reactant: C=CCCCCSC[C@@H](C)C(=O)O
Product: C[C@H](CSCc1cccc(I)c1)C(=O)O

Procedure:
The title compound is prepared similarly to (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid (IIa), using 1-bromomethyl-3-iodo-benzene instead of 6-bromo-hex-1-ene.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C(Cl)Cl>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][N:22]2[C:23]([CH2:25][CH2:26][OH:27])=[CH:24][N:20]=[CH:21]2)=[CH:40][CH:41]=1
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccc(-c2ccccc2CBr)cc1
Solvent: ClCCl
Solvent: CC#N
Product: OCCc1cncn1Cc1ccccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(1-trityl-1H-imidazol-4-yl)ethanol (0.65 g, 1.80 mmol), acetonitrile (9 mL) and CH2Cl2 (12 mL) is added a solution of 2-bromomethyl-4′-fluorobiphenyl (0.478 g, 1.80 mmol) in CH2Cl2 (2 mL). The resulting mixture is stirred at room temperature overnight. The solution is concentrated and the residue is taken up in MeOH and heated to 75° C. for 3.5 h. The solution is then concentrated and the residue is partitioned between CH2Cl2 and aqueous 5% NaHCO3. The aqueous layer is then extracted with CH2Cl2 (3×). The combined organic layers are then washed with brine and dried over Na2SO4. The residue is then purified by flash chromatography (CH2Cl2/MeOH) give 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol. MS (ESI) m/z 297.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=2)=[CH:8][CH:7]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].N1(C(N2C=CN=C2)=O)C=CN=C1>ClCCl>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:34](=[O:35])[CH2:33][C:31]#[N:32])[CH2:23]3)[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(3-fluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (180 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (50 mL), 2-cyanoacetic acid (56 mg, 0.66 mmol, 1.50 equiv), and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (108 mg, 0.67 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature and then diluted with 100 mL dichloromethane. The resulting mixture was washed NH4Cl, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 120 mg (57%) of 3-[(3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([CH3:13])[CH2:11][O:12][C:8]=2[CH:7]=1.[OH-].[BH4-].[Na+].[OH-].[Na+].[CH2:27]([OH:29])[CH3:28]>>[CH2:27]([O:29][C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([CH3:13])[CH2:11][O:12][C:8]=2[CH:7]=1)[CH3:28]
Reactant: CCO
Reactant: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(C)(C)CCCC(C)CCOc1ccc2c(c1)OCC2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.48 g. of 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran in 15 ml. of absolute ethyl alcohol is slowly added dropwise at room temperature to a suspension of 3.81 g. of mercuric acetate in 30 ml. of absolute ethyl alcohol. The mixture is thereupon stirred for one hour at room temperature, cooled by means of an ice bath and 12.8 ml. of 10% by weight aqueous hydroxide followed by 0.24 g. of sodium borohydride in 12.8 ml. of 10% by weight aqueous sodium hydroxide are added dropwise. After stirring for 30 minutes at room temperature, the mixture is filtered through diatomaceous earth, the aqueous phase saturated with sodium chloride and subsequently extracted with pentane. The extracts are washed neutral with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel there is obtained pure 6-[(7-ethoxy-3,7-dimethyl-octyl)-oxy]-3-methyl-2,3-dihydrobenzofuran which is distilled in a bulb-tube at 132° C./0.01 mmHg; nD 22 = 1.4976.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:30][N:28]([CH3:29])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)=[O:31]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(CCl)cc1

Procedure:
4-Chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide using an analogous procedure to that described in Example 37 except that the reaction product was triturated under water rather than under 2N aqueous hydrochloric acid solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.95 (s, 6H), 4.28 (s, 2H), 6.9 (d, 1H), 7.21 (m, 3H), 7.29 (d, 1H), 7.58 (d, 3H), 7.8 (s, 1H), 7.96 (d, 2H), 9.9 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M−H− 420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[N:8](CC1C=CC(OC)=CC=1)[C:7]2([CH3:39])[CH3:38].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[NH:8][C:7]2([CH3:39])[CH3:38].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: COc1ccc(CN2C(C)(C)c3cccc(Cl)c3C23CCN(C(=O)NC2C4CC5CC(C4)CC2C5)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)NC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Cl)cccc21
Temperature: 80 °C

Procedure:
Crude 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide was dissolved in neat TFA (3 mL) and the mixture was heated to 80° C. for 17 h. After this time LC-MS analysis showed complete removal of the p-methoxybenzyl group. The solution was evaporated the amine purified by prep HPLC to afford 7-chloro-N-(2-adamantyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide as its TFA salt. LC-MS Method 1 tR=1.43 min, m/z=428; 1H NMR (CD3OD) δ=7.47 (m, 2H), 7.37 (m, 1H), 4.22 (m, 2H), 3.89 (s, 1H), 3.21 (t, J=12.9, 2H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:9])[CH2:3][O:4][CH2:5][C:6]([Cl:13])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(Cl)COCC(F)(F)F
Yield: 54.6 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (2,2,2-trifluoroethoxy)acetic acid (30.90 g, 0.196 moles) and 250 ml of chloroform under nitrogen. Thionyl chloride (30.20 g, 0.250 moles) was added dropwise and the solution refluxed for 2 hours. The mixture was then concentrated by distillation of the chloroform and excess thionyl chloride. The remaining yellow oil was distilled in vacuo to give 18.9 g of the product as a colorless oil, bp 40°-48° C./20 mm.
Reaction SMILES: C[CH:2]([CH3:9])[CH2:3][CH2:4][C:5](NN)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C@@H:22]([C:24]([N:26]([CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[NH:27][C:28](=[O:48])[C@@H:29]([C@@H:34]([C:44](=[O:47])[NH:45][OH:46])[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.N[C@@H](C(N(C1CCCC1)NC(=O)[C@](C)([C@H](C(O)=O)C/C=C/C1C=CC=CC=1)CCC)=O)C>>[NH2:21][C@@H:22]([C:24]([N:26]([CH:49]1[CH2:50][CH2:51][CH2:52][CH2:53]1)[NH:27][C:28](=[O:48])[C@H:29]([C@H:34]([C:44](=[O:47])[NH:45][O:46][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:9][O:6]1)[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Reactant: CC(C)CCC(=O)NN
Agent: CCC[C@](C)(C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@@H](C/C=C/c1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C[C@H](C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1

Procedure:
In a manner analogous to that described in the first paragraph of Example 5, starting from 0.058 g of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-[tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalero-hydrazide and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalerohydrazide there was obtained 0.048 mg of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide p-toluene-sulphonate and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-(hydroxycarbonyl)-4-phenyl-3-butenyl]-methylvalerohydrazide p-toluenesulphonate in the form of a pale pink solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Br[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][N:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[N:25]=[CH:26][C:21]([C:17]4[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=4)[CH2:14][N:2]([CH3:1])[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:22][N:23]=3)[CH2:28][CH2:29]2)=[N:35][CH:36]=1)#[N:39]
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Br)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C#N)cn4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Under an argon atmosphere, tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and 6-bromonicotinonitrile (124 mg) were dissolved in toluene (6 ml), and tris(dibenzylideneacetone)dipalladium (124 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (169 mg), and cesium carbonate (222 mg) were added thereto, followed by stirring at 100° C. for 6 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (0% to 7% MeOH/CHCl3) to obtain tert-butyl {2-[(3-{2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (122 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:33][C:34]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:53][N:50]1[CH2:51][CH2:52][CH:47]([C:45]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])=[C:34]([NH:33][CH:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[CH:46]=2)[CH2:48][CH2:49]1
Reactant: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Yield: 87.6 %

Procedure:
7.18 mL of 2,2,2-trifluoroacetic acid (93 mmol), 4.11 mg of dihydro-2H-pyran-4(3H)-one (44.5 mmol) and then 14.5 g of tetramethylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino-4-(1-methylpiperidin-4-yl)benzoate in 200 mL of dichloromethane under stirring. The reaction medium is stirred at room temperature for 2 h and then taken up with a 1N soda solution. The organic phase is isolated, dried on magnesium sulfate and then dried concentrated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a 1H soda solution. The organic phase is decanted, dried on magnesium sulfate and dry concentrated to yield 14.6 g of a yellow solid (quantitative yield).
Reaction SMILES: [C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: OC1=CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
1-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C. for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.[Pd].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.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1cc(Cl)cc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(Cl)cc(Cl)c3)cc2)c1C
Yield: 44 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)-palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-dichlorobenzene (0.195 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3,5-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.117 g, 42%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28](=NO)[NH2:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:29]=[C:28]([CH2:27][O:26][CH3:25])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Reactant: COCC(N)=NO
Solvent: CN(C)C=O
Product: COCc1noc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 8 h

Procedure:
A mixture of 6.80 g (20 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. The solution is then evaporated and the residue is partitioned between methylene chloride and water. The organic phase is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 7-chloro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 213°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:14][C:11]=2[CH:12]=O)=[CH:4][CH:3]=1.[S:27]1[CH2:33][C:31](=[O:32])[N:30]([CH2:34][C:35]([OH:37])=[O:36])[C:28]1=[S:29].C(O)(=O)C.N1CCCCC1.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:14][C:11]=2[CH:12]=[C:33]2[S:27][C:28](=[S:29])[N:30]([CH2:34][C:35]([OH:37])=[O:36])[C:31]2=[O:32])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)C(=Cc2cc(OCc3ccc(Cl)cc3)ccc2OCc2ccc(Cl)cc2)SC1=S
Reaction time: 4 h

Procedure:
125 mg (0.323 mmol) of 2,5-bis-(4-chlorophenyl-methoxy)benzaldehyde, 68.3 mg (0.355 mmol) of rhodanine-3-acetic acid, 18 mg (0.125 mmol) of piperidine acetate and 10 ml of toluene were heated on a water separator under a nitrogen atmosphere for 4 hours. Subsequently, the reaction mixture was evaporated, the residue was taken up in ethyl acetate, washed several times with water, dried and again evaporated. The residue was triturated with diethyl ether and filtered off under suction: 125 mg (69%) of the title compound; 1HNMR (DMSO-d6, 250 MHz) δ 7.92 (s, 1H), 7.49 (m, 8H), 7.20 (m, 2H), 7.00 (m, 1H), 5.22 (s, 2H), 5.18 (s, 2H), 4.57 (s, 2H); TLC (toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)): Rf=0.51.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Si:12](OC(CCC)CC(OCC)=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCCCC(O)C(=O)OCC
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Yield: 74 %

Procedure:
Ethyl 2-((tert-butyldimethylsilyl)oxy)hexanoate 5 (2.54 g) was prepared in 74% yield using ethyl 2-hydroxyhexanoate 4 according to the procedures described for compound 2 in above (See Schemes 1 and 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To 1-bromo-4-trifluoromethyl-benzene (1 g), rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g), in toluene (10 mL) was added sodium tert-butylate (0.6 g), 2-(dicyclohexylphosphino)biphenyl (31 mg), and tris(dibenzylideneacetone)Pd—CHCl3 (23 mg). The reaction mixture was then stirred at 80° C. overnight. Ethyl acetate was then added to the reaction mixture. Solids were filtered off. The filtrate was then concentrated in vacuo, and the residue was purified by column chromatography to yield 0.46 g of the title compound. MS (m/e): 345.2 (M+H+, 100%)