Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][Cl:24])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCCc1ccccc1CO)c1ccc([N+](=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1ccccc1CCl)c1ccc([N+](=O)[O-])cc1
Yield: 96.7 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-(2-hydroxymethylphenyl)ethane (15.3 g) was dissolved in 200 ml of chloroform, and with stirring under ice cooling, 15.9 g of phosphorus pentachloride was added gradually. The mixture was stirred at room temperature for 8 hours, and then the solvent was distilled off. The residue was dissolved in benzene, washed in water, and dried, followed by distilling off the solvent. The residue was recrystallized from benzene-n-hexane to afford 15.7 g of 1-(4-nitrobenzoyl)amino-2-(2-chloromethylphenyl)ethane having a melting point of 125.9° to 126.3° C.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]2[CH:7]=[C:8]([CH:10]([OH:30])[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)[O:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[OH:30][CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[O:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:32]=[CH:31][C:6]=2[CH:7]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1cc2ccc(C#N)cc2o1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 4-((6-cyanobenzofuran-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (28 mg, 0.065 mmol) in MeOH (0.65 mL) at room temperature, Cs2CO3 (105 mg, 0.324 mmol) was added and the reaction was stirred at 60° C. After 30 minutes the reaction was cooled to room temperature and quenched with sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc:Heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (br. s., 1H) 8.03 (s, 1H) 7.66-7.78 (m, 1H) 7.58 (dd, J=8.08, 1.39 Hz, 1H) 7.18 (t, J=2.78 Hz, 1H) 6.83 (t, J=1.07 Hz, 1H) 6.76 (s, 1H) 6.41-6.55 (m, 2H) 6.03 (d, J=4.93 Hz, 1H) 3.80 (s, 3H) 2.39-2.47 (m, 3H). HRMS calcd. for C20H16N2O3 (M+H)+ 333.1234. found 333.1237.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O)(=O)C.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:21][CH:18]2[CH2:20][CH2:19]2)[CH2:10][CH2:9]1
Reactant: O=CC1CC1
Reactant: Brc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1ccccc1N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 88 h
Yield: 103.1 %

Procedure:
To a solution of 1-(2-bromophenyl)piperazine (3.0 g, 12.4 mmol) in tetrahydrofuran (30 mL) were added acetic acid (0.71 mL, 12.4 mmol), cyclopropanecarbaldehyde (1.39 mL, 18.66 mmol) and sodium triacetoxyborohydride (4.22 g, 19.9 mmol), followed by stirring for 88 hours at room temperature. Aqueous solution of potassium carbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 3.773 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1
Reactant: COC(=O)C1CCN(c2cc(CO)ccc2Cl)CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)C1CCN(c2cc(C=O)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.3 %

Procedure:
To a solution of methyl 1-(2-chloro-5-(hydroxymethyl)phenyl)piperidine-4-carboxylate 67 (0.198 g, 0.698 mmol) in DCM (3.5 mL) was added MnO2 (0.688 mg, 7.91 mmol). The reaction mixture was stirred at room temperature for 17 h, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave methyl 1-(2-chloro-5-formylphenyl)piperidine-4-carboxylate 68 (0.150 g, 76.3% yield) as a colorless oil. Mass spectrum: calculated for C14H16ClNO3 281.1. found 282.1 (M++1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)=[O:30]>>[C:35]1([CH3:38])[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: Cc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(CC4CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid p-tolyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using p-tolyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 544.2 [M]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B.[O:15]1CCCC1>>[C:1]([C@@H:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH2:8][CH2:7][C@H:6]1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1=CCCc2occc21
Agent: B
Product: CC(C)(C)[C@@H]1c2ccoc2CC[C@H]1O
Temperature: 4 °C
Reaction time: 2.5 h

Procedure:
A flame-dried 2000-mL 3-neck flask fitted with a 250-mL pressure equilibrated dropping funnel, and internal thermometer, and nitrogen inlet is charged with a solution of 4-tert-butyl-6,7 dihydrobenzofuran (24.26 g, 137.8 mmol) in dry tetrahydrofuran (300 mL). The solution is cooled to 4° C. then a solution of borane 1M in tetrahydrofuran, 142 mL) is added dropwise over 20 minutes such that the internal temperature does not exceed 5° C. during the addition. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature and stir for 2.5 hours. The reaction is then quenched by the dropwise addition of water (9.5 mL) followed (after hydrogen evolution was complete) by the addition of 2.5N NaOH (280 mL). Hydrogen peroxide (30% aqueous solution, 16 mL) is carefully added dropwise such that the reaction temperature is about 45° C. upon completion of the addition. An oil bath is added and the reaction mixture maintained at 45°-50° C. for one hour. The reaction mixture is allowed to cool, then diluted with 20% NaCl (500 mL). The layers are separated and the aqueous layer extracted with an additional portion of tetrahydrofuran (300 mL). The combined organic extracts are washed with 20% NaCl (500 mL), dried (MgSO4), and concentrated. Trituration with hexane afforded trans-4-tert butyl-4,5,6,7-tetrahydro-5-benzofuranol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:26])([F:28])[F:27]
Reactant: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2)c1

Procedure:
The title compound was prepared from {3-[3-(2-methylphenyl)-8 (trifluoromethyl)quinolin-4-yl]phenyl}amine and phenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 192-195° C.; MS (EI) m/z 498 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[CH:19][CH:20]=[N:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]2[N:17]4[N:18]=[CH:19][CH:20]=[N:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:25]=[N:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5nccnn45)cc3c2)cn1
Temperature: 135 °C

Procedure:
A mixture of 3-bromo-6-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl-quinoline (69 mg, 0.204 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (51 mg, 0.25 mmol), potassium carbonate (56 mg. 0.41 mml), 1,4-dioxane (2 mL) and water (1 mL) was bubbled nitrogen gas through for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (8 mg, 5 mol %) was added, the vial sealed and heated in a microwave for 1500 seconds at 135° C. The mixture was diluted with dichloromethane and brine, before the organic phase was concentrated onto silica gel and via flash column chromatography (SiO2 4 g, dichloromethane/CH3OH 0-10%) to return the title compound a white solid (11 mg, 16%). Analytical data presented in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(OC)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1([O:15][CH2:14]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:11][C:12]([CH3:14])([OH:15])[CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Yield: 103 %

Procedure:
4-Bromo-3,5-dimethylphenol (4.0 g), isobutylene oxide (2.0 g) and Cs2CO3 (9.7 g) in N,N-dimethylformamide (10 mL) are stirred at 100° C. for 20 h. After cooling the mixture is partitioned between water and EtOAc, the organic layer dried (MgSO4) and concentrated. Purification of the residue by column chromatography (silica gel, n-hexane:EtOAc 100:0 to 50:50 gradient) gives the desired compound (5.6 g, content ca. 97%).
Reaction SMILES: [H-].[K+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][C:18]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[O:19])[C:11](=[O:15])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: O=C1CN(c2ccncc2)CCN1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dispersion of potassium hydride in mineral oil (35% w/w, 0.63 g) was added to a stirred suspension of 4-(4-pyridyl)piperazin-2-one (0.885 g) in DMF (10 ml) and the mixture was stirr-ed at room temperature for 2 hours. To the anion thus formed, was added methyl 4-bromoacetylphenoxyacetate (1.44 g) and the mixture was stirred at room temperature for 20 hours. Solvent was evaporated and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography, the product being eluted with 1/9/0.1 v:v:v methanol/dichloromethane/0.88 S.G aqueous ammonia. Recrystallisation from ethyl acetate gave the title compound, m.p. 164°-165° C.; NMR (d6DMSO) δ 8.2(2H,d), 7.97(2H,d), 7.08(2H,d), 6.83(2H,d), 4.93(4H,d), 4.02(2H,s), 3.71(3H,s), 3.7(2H,m), 3.52(2H,m); m/e 384 (M+H)+ ; calculated for C20H21N3O5 : C, 62.7; H, 5.52; N, 11.0. Found: C, 62.6; H, 5.6; N, 10.9%.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH:16](=[O:18])[CH3:17]>>[OH:18][CH2:16][CH2:17][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: Brc1cccc2cc3ccccc3cc12
Product: OCCc1cccc2cc3ccccc3cc12

Procedure:
For instance, a Grignard reagent prepared from bromonaphthalene is reacted with acetophenone to obtain 1-phenyl-1-naphthylethanol which is then dehydrated to obtain 1-phenyl-1-naphthylethylene. Further, a Grignard reagent prepared from bromoanthracene is reacted with acetaldehyde to obtain hydroxyethylanthracene which is then dehydrated to obtain vinylanthracene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2O[CH:9]=[N:10][N:11]=2)[CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].C1(C)C(C)=CC=CC=1>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:13][CH:9]=[N:10][N:11]=2)[CH:2]=1
Reactant: c1cncc(-c2nnco2)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: Cc1ccccc1C
Product: c1cncc(-c2nncs2)c1
Reaction time: 16 h

Procedure:
A mixture of 5.5 g of the above prepared 2-(3-pyridyl)-1,3,4-oxadiazole, 8.5 g of phosphorus pentasulfide and 70 ml of xylene is stirred for 16 hours at 150°-160° C. To the cooled reaction mixture are added 50 ml of water and stirring is continued for another 5 minutes. The reaction mixture is then filtered. The filter residue is taken up in 100 ml of 10% sodium hydroxide solution. After extraction with chloroform, the organic phase is washed with water, dried and concentrated. After purification by column chromatography over silica gel with a 95:5 mixture of chloroform/ethanol as eluant, the crude 2-(3-pyridyl)-1,3,4-thiadiazole (compound 1) of the formula ##STR8## with a melting point of 64°-67° C., is obtained.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24](O)[CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:24][CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., triethylamine (0.131 ml, 0.942 mmol) and methanesulfonyl chloride (0.0665 ml, 0.856 mmol) were added to a solution of 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (204 mg, 0.544 mmol) in methylene chloride (10 ml). After stirring at 0° C. for 1 hour, the reaction mixture was diluted with methylene chloride, washed successively with a saturated aqueous ammonium chloride solution, water and brine, dried over MgSO4, and then concentrated. The residue was dissolved in tetrahydrofuran (5 ml). After cooling the solution to 0° C., potassium hexamethyldisilazide (a 0.5M toluene solution, 1.30 ml, 0.650 mmol) was added thereto. The resulting mixture was stirred at 0° C. for 3 hours, and saturated ammonium chloride was added thereto. The resulting mixture was extracted with ethyl acetate, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (15% ethyl acetate-hexane). The resulting solid was recrystallized from hexane, whereby the title compound (33.0 mg, 17%) was obtained as colorless needle crystals.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]1([Sn+](C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(O[Hg]C1C=CC=CC=1)=O.C(OO)(=O)C>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: c1ccc([Sn+](c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)OO
Agent: CC(=O)O[Hg]c1ccccc1
Product: CC(=O)Oc1ccccc1
Yield: 58 %

Procedure:
The procedure of Example 1 is repeated except that 5 mmols of triphenyl tin acetate are employed instead of the phenyl mercuric acetate of Example 1, and 30 mmols of peracetic acid is used. After 4 hours of reaction at 75° C. there is obtained phenyl acetate in a yield of about 58%, and in a selectivity of about 68%, at a triphenyl tin acetate conversion of about 85%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26]Br)[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.C1OCCOCCOCCOCCOCCOC1.CN(C=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1])[CH3:22]
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCN(C)CCCN1c2ccccc2CCc2ccccc21
Yield: 88.8 %

Procedure:
A solution of 6.02 g (19.8 mmol) of desipramine hydrochloride was allowed to stir at room temperature for 5 minutes. This was extracted with 6×100 ml of chloroform. The combined organic part was washed with 100 ml of water, dried with anhydrous Na2SO4 and concentrated to give 5.25 g of desipramine free base. A solution of 2.82 g (10.6 mmol) of desipramine free base in 100 ml of anhydrous acetone was added. To this reaction mixture 2.03 ml (15.8 mmol) of ethyl-3-bromopropionate, 3.65 g (26.4 mmol) of anhydrous potassium carbonate, 264 mg (1.76 mmol) of sodium iodide, 5 mg of 18-crown-6 and 0.7 ml of anhydrous DMF were added. The reaction mixture was allowed to reflux under argon overnight. The mixture was filtered and the residue was washed with 20 ml of acetone. The combined filtrate was concentrated and purified by silica gel column chromatography using 4% methanol in ethyl acetate to give 3.45 g (9.41 mmol, 89%) of the ethyl ester (17) as a thick oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:11]([O:15][C:16](=[O:46])[N:17]([C:29]1[CH:30]=[CH:31][C:32]2[NH:33][C:34](=[O:45])[N:35]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:36][C:37]=2[N:38]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])([CH3:14])([CH3:13])[CH3:12].CNCCNC>CCOC(C)=O.[Cu]I>[C:11]([O:15][C:16](=[O:46])[N:17]([C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[C:34](=[O:45])[N:35]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:36][C:37]=2[N:38]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C2CCCCC2)C(=O)N3)c(OC)c1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C2CCCCC2)C(=O)N3c2ccc(Cl)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
Into a reaction tube were placed CsF (211 mg, 1.4 mmol, 2.5 equiv), CuI (21 mg, 0.11 mmol, 0.2 equiv), 1-chloro-4-iodo-benzene (200 mg, 0.85 mmol, 1.5 equiv), (3-cyclohexyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (280 mg, 0.56 mmol, 1.0 equiv) and N,N′-dimethyl-ethylene diamine (60 μL, 0.56 mmol, 1.0 equiv). The tube was sealed, evacuated and back-filled with nitrogen 3 times, then THF (5 mL) was added and the reaction mixture was heated at 80° C. overnight. Further CuI (21 mg, 0.11 mmol, 0.2 equiv) and N,N′-dimethyl-ethylene diamine (30 μL, 0.28 mmol, 0.5 equiv) were added and the heating was continued for 24 h. The reaction mixture was cooled, diluted with EtOAc and the reaction was quenched with saturated ammonium chloride. The products were extracted with ethyl acetate, the combined organic extracts were washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-500%) to afford [1-(4-chloro-phenyl)-3-cyclohexyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (224 mg). MS: [M+H]+=606.