Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@H:15]2[C:21](=[O:22])[N:20]3[C@@H:16]2[CH2:17][C:18](=O)[C@@H:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[SH:63][C@@H:64]1[CH2:68][N:67]([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=2)=[O:70])[C@H:66]([CH2:82][S:83][C:84]2[CH:89]=[CH:88][N:87]=[CH:86][CH:85]=2)[CH2:65]1>ClCCl>[N+:79]([C:76]1[CH:75]=[CH:74][C:73]([CH2:72][O:71][C:69]([N:67]2[CH2:68][C@@H:64]([S:63][C:18]3[CH2:17][C@H:16]4[N:20]([C:21](=[O:22])[C@@H:15]4[C@H:13]([O:12][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:38][CH:37]=4)=[O:11])[CH3:14])[C:19]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:65][C@H:66]2[CH2:82][S:83][C:84]2[CH:89]=[CH:88][N:87]=[CH:86][CH:85]=2)=[O:70])=[CH:78][CH:77]=1)([O-:81])=[O:80]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSc1ccncc1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4ccncc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.2 g) in dry dichloromethane (40 ml) were added N,N-diisopropyl-N-ethylamine (0.44 ml) and trifluoromethanesulfonic anhydride (0.40 ml) at -40° C., and the solution was stirred at the same temperature for 15 minutes. To this solution were added N,N-diisopropyl-N-ethylamine (0.63 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-(pyridin-4-ylthiomethyl)pyrrolidine (1.38 g) in dry dichloromethane (5 ml) successively at the same temperature under an atmosphere of nitrogen, and stirred at ambient temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (4:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(pyridin-4-ylthiomethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.CC(=O)OCC.O.[CH3:20][N:21](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:21]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 4-hydroxy-3-iodobenzoate (2.78 g) and Zn(CN)2 (1.409 g) in N,N-dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (1.155 g). The reaction mixture was stirred at 140° C. for 12 h. After cooling the reaction, EA (100 mL) and water (40 mL) were added to the solution. After filtration, the filtrate was washed with water and brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (D21) (1.3 g) as a white solid. MS (ES): C9H7NO3 requires 177. found 178.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:17]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 3'-bromo-4'methyl-1,1'-biphenyl-2-nitrile (Step C) in 15 mL of carbon tetrachloride under a nitrogen atmosphere was treated with 0.720 g (4.04 mmol) of N-bromosuccinimide followed by 60 mg (0.37 mmol) of azobisisobutyronitrile (AIBN). The reaction mixture was heated at reflux for four hours, cooled to room temperature and filtered through Celite. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and treated with decolorizing carbon. The solids were filtered through Celite and the solvent removed under vacuum. The resulting solid was triturated with cold ether, filtered and air dried to afford 920 mg (71 %) of the product as an off-white solid. 1H NMR (200 MHz, CDCl3): δ 4.64 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C14H9Br2N 351; found 351 (M+, 20%); 271 (M-Br, 100%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([O:13][CH3:14])[N:4]=1)[NH2:2].[C:15]1([CH2:21][CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([NH:1][N:2]=[CH:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1
Reactant: O=CCc1ccccc1
Reactant: COc1cc(C(F)(F)F)cc(NN)n1
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(NN=CCc2ccccc2)n1
Yield: 64.7 %

Procedure:
A mixture of 2-hydrazinyl-6-methoxy-4-(trifluoromethyl)pyridine [261360-23-0] (0.11 g, 0.55 mmol) and 2-phenylacetaldehyde (0.57 g, 0.66 mmol) in toluene (5 ml) was heated at reflux for 6 h using a Dean-Stark apparatus. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (5% EtOAc in hexane) to yield the title compound (0.11 g, 63%). [LCMS RtD=3.75 min; [M+H]+=310.1]
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:20])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2(COc3ccc(N)cc3OC2)OC1=O
Reactant: CS(=O)(=O)Cl
Product: CC(C)N1CC2(COc3ccc(NS(C)(=O)=O)cc3OC2)OC1=O

Procedure:
By reacting the oxazolidinone obtained in Step A with methanesulfonyl chloride and employing the other reaction conditions and procedure described in Example 87, Step A, there is obtained 3'-isopropyl-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)(=O)=O.[C-:36]#[N:37].[Na+]>CS(C)=O.C(Cl)Cl>[C:36]([CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)#[N:37]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (525 mg, 1.00 mmol, 1.00 equiv) in DMSO (20 mL) was added NaCN (294 mg, 6.00 mmol, 6.00 equiv) and the resulting solution was stirred for 2 h at 70° C. under nitrogen. After cooling, the mixture was diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield 380 mg (83%) of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13][CH:14]2[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](O)[CH:32]=[CH:33][C:34]=1[F:35].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>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13][CH:14]2[CH2:16][O:17][C:32]2[CH:31]=[CH:30][C:29]([F:28])=[C:34]([F:35])[CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of alcohol 77 (0.84 g, 2.2 mmol) in benzene (15 mL) was treated with 3,4-difluoro-phenol (402 mg, 3.1 mmol) and triphenylphosphine (864 mg, 3.3 mmol). To this solution was added DIAD (0.65 mL, 3.3 mmol) and the reaction mixture was stirred at ambient temperature. After 16 h, the solution was concentrated, diluted with DCM, washed with 1M NaOH, dried over anhydrous Na2SO4, filtered and concentrated. The aqueous phase was back-extracted with Et2O and the combined organic extracts were absorbed on SiO2 and purified by flash chromatography (3:1 hexane/EtOAc to 1:1 hexane/EtOAc) to afford 78 (0.86 g) which was contaminated with DIAD-related impurities and used without further purification.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O1CCCC1>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@H](C(=O)c2ccc(-c3ccccc3)cc2)N1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CC[C@H](Cc2ccc(-c3ccccc3)cc2)N1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
14 g of (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one are suspended in 80 ml tetrahydrofuran. Subsequently 331 mg of concentrated sulphuric acid are added and the reaction vessel is purged with argon. 1.4 g of palladium on carbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) is added and the mixture is stirred under an atmosphere of hydrogen (3 bar) at 30° C. for 20 h. The black suspension is filtered and the filter cake is washed with tetrahydrofuran. After the addition of 50 ml water, the pH of the emulsion is adjusted to pH 5.5 using sodium hydroxide solution (2M). Under reduced pressure, the organic solvent is removed and 100 ml of isopropyl acetate are added. The aqueous layer is then separated and the remaining organic layer is concentrated to approx. half of its original volume. The suspension is cooled to −5° C. and filtered. The filter cake is washed with cooled isopropyl acetate and is dried under reduced pressure to give (R)-5-biphenyl-4-ylmethylpyrrolidin-2-one as colourless crystals. 1H-NMR (CDCl3): 1.93 (1H); 2.37 (3H); 2.80 (1H, dd, J=8.5, 13.5); 2.92 (1H, dd, J=5.4, 13.5); 3.95 (1H); 5.70 (1H); 7.29 (1H, d, J=7.5); 7.38 (1H); 7.47 (2H); 7.59 (4H). MS (ESI, m/e) 252 [M+H]+; 503 [2M+H]+. IR (solution in CH2Cl2, □/cm−1): 3191; 3055; 2930; 1692; 1489; 1272; 762; 692.
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][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]3[O:28][CH2:29][CH2:30][C:26]=3[CH:25]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1ccc2c(c1)CCO2
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (2.3 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (2.0 g), triethylamine (2.3 ml) and methanol (23 ml) was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (8 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with diethyl ether to give the title compound (1.98 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[C:25]([F:26])=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33](=[O:34])/[CH:32]=[CH:31]/[C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[C:25]([F:26])[C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)c(F)c1F
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)c(F)c3F)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-difluoro-4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=440.1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29].CO>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[C:11]1=[CH:27][N:28]([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)CC2=O)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C(=CN(C)C)C2=O)c(=O)[nH]c1=O
Temperature: 50 °C
Yield: 56.3 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-5-methyl-2'-oxo-uridine (3.854 g, 10.9 mmol) from Step 3 was dissolved in 50 mL of dry dimethylformamide (DMF) and 1.74 mL (1.56 g, 13.1 mmol) of N,N-dimethylformamide dimethylacetal was added. The reaction mixture was heated in an oil bath at 50° C. for 40 min. The solvent was evaporated in vacuo and the residue purified on a silica gel column, the product eluting with 5% methanol in methylene chloride to give 2.512 g (56.3% yield) of the title compound, [α]D23 =-84.2° (c, 1.44, MeOH). DCI MS M/Z: (M+H)+ 410.
Reaction SMILES: [CH2:1]([C:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO>[CH2:1]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=Cc2ccc([C@H]3CC[C@]4(COC(=O)N4)C3)cc2CC1
Solvent: CO
Product: CCCCCCC1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Reaction time: 16.67 h
Yield: 83.7 %

Procedure:
A mixture of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2A, 760 mg, 2.15 mmol) and (−)-2,3-bis[(2R,5R)-2,5-dimethylphospholanyl]-N-[3,5-bis(trifluoromethyl)phenyl]maleicimide (1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (273 mg, 0.43 mmol) in MeOH (27 mL) was hydrogenated at 850 PSI for 1000 minutes using a 100 mL HEL autoclave. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-100% EtOAc over 20 minutes) to afford 640 mg of (5R,7S)-7-(6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one in a 1:2 ratio of the two isomers. The desired major isomer was separated using a CHIRALPAK® AS-H column under SFC conditions (35% MeOH in CO2). Retention time=5.14 min. Recovered 400 mg of (5R,7S)-7-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one. 1H NMR (400 MHz, methanol-d4) δ 7.02-6.91 (m, 3H), 4.47-4.20 (m, 2H), 3.02 (tt, J=11.0, 7.2 Hz, 1H), 2.87-2.74 (m, 3H), 2.41-2.24 (m, 2H), 2.17-2.03 (m, 2H), 2.00-1.89 (m, 3H), 1.86-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.51-1.28 (m, 11H), 0.99-0.88 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NC(CO)CO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NC(CO)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.0 g of 2-amino-1,3-propanediol are boiled under reflux for 3 h in 8 ml of ethanol. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxy-1-hydroxymethylethyl)acetamide remains as colorless less crystals of m.p. 212-214° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[OH:18])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>C(Cl)Cl>[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[O:18][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CC(O)C1CC2C=CC1C2
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CC(=O)OC(C)(C)C)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 81 %

Procedure:
66 g of diisopropyl ethyl amine was dropped to a solution prepared by dissolving 100 g of 3-bicyclo[2.2.1]hept-5-en-2-yl-3-hydroxy-propionic acid tert-butyl ester (BHP) i and 44 g of chloromethyl methyl ether ii in 1 L of methylene chloride while stirring at room temperature. The mixture was stirred at room temperature for 4 hours, and reaction was evaluated by thin-layer chromatography (TLC) and terminated. This was followed by workup twice with 400 ml of each of a 1 N HCl solution and a 10% Na2CO3 solution, the resultant was washed with 400 ml of distilled water, and an organic layer was collected. Methylene chloride was removed from the organic layer at reduced pressure to obtain 96 g of 3-bicyclo[2,2,1]hept-5-en-2-yl-3-methoxymethoxy-propionic acid t-butyl ester iii (Yield: 81%). The structure was identified using 1H NMR.
Reaction SMILES: [CH2:1]([C:3]1[C:13]2[NH:12][C:11](=[O:14])[CH2:10][N+:9]([O-])=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([O:26][CH:10]1[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:13]=2[NH:12][C:11]1=[O:14])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc2c1NC(=O)C[N+]([O-])=C2c1ccccc1F
Solvent: ClC(Cl)Cl
Product: CCc1cccc2c1NC(=O)C(OC(C)=O)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of 9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (9.0 g) and acetic anhydride (32 ml) in chloroform (32 ml) was stirred at room temperature overnight. The reaction mixture was evaporated to remove chloroform. Diisopropyl ether was added to the residue to afford powder, which was collected by filtration and washed with diisopropyl ether to give (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.30 g, 61.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)=[C:4]([O:22][CH3:23])[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1CCCOC1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCCOC1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)pyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 90 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Chiral chromatography on a Ciralpak AD column with a gradient of ethanol (containing 0.05% formic acid): n-heptane (40:60) furnished both enantiomers, with the desired enantiomer eluting second. Colorless solid (19%). MS (ESI): m/z=567.158 [M+H]+.