Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:41])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][O:32]CC4C=CC=CC=4)=[CH:25][CH:24]=3)=[CH:19][O:20]2)=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][C:10]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:41])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][OH:32])=[CH:25][CH:24]=3)=[CH:19][O:20]2)=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Oc1ccc(-c2coc3cc(OC(=O)COCc4ccccc4)ccc3c2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CO)Oc1ccc(-c2coc3cc(OC(=O)CO)ccc3c2=O)cc1
Reaction time: 22 h

Procedure:
Benzyloxy-acetic acid 4-[7-(2-benzyloxy-acetoxy)-4-oxo-4H-chromen-3-yl]-phenyl ester 42 (1 gram, 1.82 mmol) is dissolved in ethyl acetate (50 ml) in a pressure vessel, Palladium on carbon (5%, 0.5 gram) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 22 hours. The catalyst is removed by filtration, ethyl acetate distilled under vacuum. The crude 43 can be purified by column chromatography on silica gel using benzene: ethyl acetate (8:2) as eluant to get the desired product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5](C(O)=O)[C:4]=2[CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccc(F)cc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Fc1ccc2[nH]c3c4ccccc4nc-3cc2c1
Yield: 64.9 %

Procedure:
2-Fluoroquindoline-11-carboxylic acid from Example 71 (4.50 g, 16.1 mmol) was refluxed at 250° C. in diphenyl ether (40 mL) for 4 hours. The mixture was cooled, diluted with petroleum ether (40 mL), and filtered. The filter cake was washed with petroleum ether (100 mL) and dried. The crude material was added to methanol (250 mL) and filtered, washing with additional methanol (2×75 mL). Concentration of the filtrate afforded 2.47 g (65%) of the title compound as a brown solid, mp >246° C.; 1H NMR (DMSO-d6) δ 11.52 (s, 1H), 8.34 (d, J=8, 1H), 8.28 (s, 1H), 8.24 (dd, J=9.2, J=5.6, 1H), 7.90 (dd, J=10, J=2.8, 1H), 7.50-7.65 (m, 3H), 7.29 (t, J=8, 1H); 13C NMR (DMSO-d6) δ 158.96 (J=244), 145.53, 143.97, 140.42, 132.86, 131.22 (J=10), 129.83, 127.25, 121.31, 120.84, 119.54, 116.23 (J=27), 112.47 (J=5.3), 111.58, 110.01 (J=22); MS (EI, m/z) 236.1 (M+).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].O=C[C@H]([C@H]([C@H](CO)O)O)O>>[C:1]([O:4][C@H:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The same operations as those of Example B1 were carried out with the exception that the half-scale (corresponding to 20 mmol of L-ribose) was used and that diisopropyl ether was not added. As a result, 5.60 g of crude 1,2,3,5-tetra-O-acetyl-L-ribofuranose was obtained in the form of yellow oil. The obtained compound was analyzed by HPLC. As a result, it was found that the crude product contained 3.98 g of 1,2,3,5-tetra-O-acetyl-L-ribofuranose, that the ratio of α-/β-anomers was 21/79, and that the total reaction yield of the β-anomer from L-ribose was 49%.
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([CH2:32][C:33](=O)[CH3:34])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:33]([CH3:34])[CH2:32][C:30]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:23][CH3:22])[CH:31]=2)[CH2:7][CH2:6]1
Reactant: COc1cc(CC(C)=O)ccc1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}propyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion as described for the preparation of EXAMPLE 38 starting from 5-[1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].Cl.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:32]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCSC2=Nc3ccc(Cl)cc3C(c3ccccc3Cl)=NC2)CC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 11.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 100 ml of anhydrous dimethylformamide is added under ice cooling with stirring 2.1 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at 30° C. for 1 hour. To the mixture is added dropwise a solution of 12.5 g of 1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]propane hydrochloride in 50 ml of dimethylformamide over a period of 15 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into iced water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 10.5 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 189°-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1)[CH2:29][OH:30])[CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O1CCOCC1.[Cl-].[NH4+]>[Fe].O>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@H:28]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)[CH2:29][OH:30])=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of (2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol (2.00 g) in a mixed solvent of ethanol (7.5 ml) and 1,4-dioxane (7.5 ml) was added dropwise to a stirred suspension of iron powder (2.00 g) and ammonium chloride (0.24 g) in a mixed solvent of ethanol (5 ml) and water (5 ml) at 85° C. over 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The insoluble solid was filtered off and washed with dioxane, and the filtrate was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to give (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-amino]-1-propanol (1.90 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:20]([OH:21])=[CH:19][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:22]1[O:24][CH2:23]1.[ClH:25]>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:25].[OH:1][C:2]1[C:20]([OH:21])=[CH:19][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH2:22][CH2:23][OH:24])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CSc1ccc(C2CNCCc3cc(O)c(O)cc32)cc1
Reactant: C1CO1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(C2CN(CCO)CCc3cc(O)c(O)cc32)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 4 g sample of 7,8-dihydroxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine is slurred in 25 ml of acetone and 0.8 g ( ~ 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 7,8-dihydroxy-3-(2-hydroxyethyl)-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10]C)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:9]([OH:10])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(F)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(C#N)c(F)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile are dissolved in 60 ml of methylene chloride, treated with 1.1 ml of boron tribromide, stirred at 23° for 1 hour, subsequently treated with an additional 1.0 ml of boron tribromide and stirred at 23° for an additional 80 minutes. Thereupon, the reaction mixture is poured into 100 ml of ice-cold saturated sodium hydrogen carbonate solution, whereupon the mixture is extracted twice with 300 ml of ether, the combined ether phases are washed twice with sodium chloride solution, dried over sodium sulfate, evaporated and the residue is chromatographed on 50 g of silica gel with methylene chloride and methylene chloride/methanol (97:3). There is obtained 2-fluoro-3-hydroxy-p-anisonitrile of m.p. 198°-200°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.[OH-].[Na+]>O.C1COCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ncccc2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
13.0 ml (76.28 mmol) of benzyl chloroformate are added dropwise to a stirred solution, cooled to 0° C. of 10.0 g (69.36 mmol) of 6-aminoquinoline in 160 ml of water and 80 ml of THF in the course of 30 minutes, the pH being kept at 10 by simultaneous addition of a 4N NaOH solution. The mixture is subsequently stirred at 0° C. for a further 2 hours, the THF is evaporated off in vacuo and the residue is extracted with 3×50 ml of ethyl acetate. The combined organic extracts are dried over MgSO4, the solvent is evaporated off in vacuo and the residue is purified by chromatography over 450 g of silica gel (toluene:ethyl acetate 1:4). 11.60 g (60%) of the title compound are obtained as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:6]1[C:7]2[O:8][CH2:26][CH2:25][NH:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2NCCO3)c1=O
Yield: 6.5 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-primidinedione (0.4 g), 1,2-dibromoethane (0.26 g) and potassium carbonate (0.312 g) in acetone (30 ml) was heated at reflux for 6 hours. The insoluble precipitate was removed through Celite and the filtrate was concentrated to an oil. The oily substance was purified by column chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give the title compounds (0.028 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.[OH-].[Na+].CCOC(C)=O.CCCCCC>CC(C)=O.O>[NH2:1][C:2]1[N:3]=[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Nc1nc(Cl)cc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
10 g (61 mMol) 2-amino-4,6-dichloro-pyrimidine and 8.1 g (61 mMol) 5-hydroxyindole are suspended in 250 ml acetone. Then 120 ml 1 N NaOH in water are added and the mixture is stirred at an oilbath temperature of 70° C. for 2 h. The reaction mixture is partially concentrated and the residue diluted with water. Extraction with 3 portions of EtOAc, washing the organic layers twice with water and brine, drying (Na2SO4), addition of 100 g SiO2 and concentration in vacuo gives a powder. This is put on top of a chromatography column (SiO2; EtOAc/hexane 3:7) and eluted with EtOAc/hexane 3:7. Crystallization from hexane gives the title compound: m.p.: 192° C.; MS: [M+1]+=261; HPLC: AtRet=12.4.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][CH:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][S:9]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1SCc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 70.8 %

Procedure:
A solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (4 g, 21 mmol) and 1-Boc-piperazine (8.5 g, 46 mmol) in NMP (20 mL) was heated to 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×300 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1) to provide tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (5 g, 69%). The crude material was purified by chiral separation on chiral HPLC (ODH, 250×20 mm, 100% acetonitrile, 15 mL/min) to give (R)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.016 min) and (S)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.551 min). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 4.83 (m, 1H), 4.18 (m, 2H), 3.73-3.56 (m, 4H), 3.51-3.43 (m, 4H), 1.50 (m, 9H). MS (APCI+) [M+H]+ 337.
Reaction SMILES: Br[CH:2]([CH3:12])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH:2]([CH3:12])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: CC(Br)CCOc1cccnc1
Solvent: CO
Product: CNC(C)CCOc1cccnc1
Temperature: 100 °C

Procedure:
Crude 3-bromo-1-(3-pyridyloxy)butane (2.00 g, 8.69 mmol) from the previous step was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (30 mL) in a heavy-walled glass pressure-tube apparatus. The mixture was stirred and heated at 100° C. (oil bath temperature) for 16 h. After cooling, the mixture was concentrated by rotary evaporation, and the product was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 1.25 g of a pale-yellow oil. Purification by vacuum distillation yielded 0.94 g (60.3%) of a colorless oil, bp 65-67° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1[N:27]=[C:26]([CH2:28]O)[C:25]([CH2:30][NH:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])=[N:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1[N:27]=[C:26]2[CH2:28][N:31]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH2:30][C:25]2=[N:24]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CO)c(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])n2)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc3c(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C3)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 198 %

Procedure:
To a soln of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((4-(hydroxymethyl)-5-((2-nitrophenylsulfonamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (165 mg, 0.237 mmol), and triphenylphosphine (91.6 mg, 0.349 mmol) in THF (11.9 mL) at 0° C. was added DIAD (72 μL, 0.35 mmol), drop-wise. After 3 h, more triphenylphosphine (46.4 mg, 0.177 mmol) was added, whereupon it was cooled to 0° C. followed by addition of DIAD (37 μL, 0.18 mmol). After stirring at rt for 2.5 h it was concentrated in vacuo and purified via silica gel chromatography (EtOAc-Heptane, 0-100%) to afford the title compound (318 mg), which was contaminated with triphenylphosphine oxide. Rt=0.93 min, m/z=678.3 (M+1) Method 2m_acidic.
Reaction SMILES: C(OC(=O)[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C>CCCCCCC.CCOC(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCNc1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 85, intermediate a, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-carbamic acid tert-butyl ester and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless oil (72%). MS (ESI): m/z=263.094 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:16]2[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:34][CH:33]=3)[N:15]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]propenoate (10.0 g), 5% palladium-carbon (20.0 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred for 1 hour under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 3-[3-(4-fluorophenyl)-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (7.15 g, yield 88%) as a colorless oily substance.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.B.[CH:8]1([BH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C#CCCCC>O1CCCC1>[CH:15](/[B:14]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C1=CCCCC1
Reactant: B(C1CCCCC1)C1CCCCC1
Agent: B
Agent: C#CCCCC
Solvent: C1CCOC1
Product: CCCC/C=C/B(C1CCCCC1)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of 64 g (785.0 mmol) of cyclohexene in 20 ml of tetrahydrofuran (THF) is added to 392.5 ml (392.5 mmol) of borane (1 M solution in THF) at -15°, after which the solution is stirred at 0°-5° for 1 hour to prepare dicyclohexylborane. This is cooled to -15° and 32 g (392.5 mmol) of 1-hexyne in 10 ml of THF is added dropwise. After addition is completed the reaction mixture is stirred at 0°-5° for 2.5 hours to yield a solution of (E)-1-hexen-1-yldicyclohexylborane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:23](OC)([O:26]C)[O:24]C>CCOCC.O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:23]([OH:26])[OH:24])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)COc2ccc(B(O)O)cc21
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A stirred, cooled (−78° C.) solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 1.44 g, 6.2 mmol) in 18 mL of anhydrous ether and 5 mL of anhydrous tetrahydrofuran under argon, was treated with a 1.7M solution of t-butyllithium in n-pentane (7.65 mL, 13.02 mmol) and the resulting solution was stirred at the same temperature for 1 h. Trimethyl borate (1.6 mL, 13.02 mmol) was added and the reaction mixture was allowed warm from −78° C. to −30° C. over 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ether. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a foamy solid. Flash column chromatography using 25-100% ethyl acetate in hexane as the eluent afforded 0.57 g, 47.8% of the title compound as a white solid.