Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C1(=O)O[CH2:28][CH2:27][O:26]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][OH:26])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(CC)c1
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OCCO)c(CC)c1
Temperature: 155 °C
Yield: 24.5 %

Procedure:
A solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-4-hydroxy-phenyl)-acetate (400 mg, 1.23 mmol) described in Example 180.1, ethylene carbonate (110 mg, 1.23 mmol) and tetrabutylammonium bromide (264 mg, 1.23 mmol) in DMF (0.6 ml) was heated to 155° C. for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, hexane/EtOAc 9:1). Ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-acetate (111 mg, 24%) was obtained as a yellow oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:39])[CH:27]=3)[C:23](O)=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:43]=1[S:49]([NH2:52])(=[O:51])=[O:50].N12CCCN=C1CCCCC2>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:39])[CH:27]=3)[C:23]([NH:52][S:49]([C:43]3[CH:44]=[CH:45][C:46]([CH3:48])=[CH:47][C:42]=3[O:41][CH3:40])(=[O:50])=[O:51])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(C(C(=O)O)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
1,1′-Carbonyldiimidazole (2.8 kg) was added to a stirred solution of 2-(1,3-benzodioxol-5-yl)-2-(6-methoxycarbonyl-1-methyl-1H-indol-3-yl)acetic acid (from step (a), 5.0 kg) in dry tetrahydrofuran (50 liters) at room temperature under a nitrogen atmosphere. The suspension was heated to reflux for 1.5 h, allowed to cool to room temperature, and treated sequentially with 2-methoxy-4-methylbenzenesulfonamide (see Preparation 11, International Patent Application WO 97/43260; 3.0 kg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 kg). The mixture was heated to reflux for 3.5 h, allowed to cool to room temperature and quenched by the addition of 2M hydrochloric acid (40 liters). The product was extracted from the acidic aqueous solution with dichloromethane (40 liters) and the organic phase was washed with 2M hydrochloric acid (40 liters) and water (40 liters). The organic phase was concentrated to low volume, diluted with acetonitrile (93 liters) and the resulting suspension heated to reflux. The mixture was allowed to cool and the precipitated product collected by filtration to give the subtitle compound as a white crystalline solid (5.34 kg, 71.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:5][CH2:4][CH2:3]1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[Cl:29][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:16]=2[F:25])=[C:7]([C:6]2[C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a solution of 66.53B (0.2574 g, 0.706 mmol) in dry DCM (10 mL) and dry DMF (0.07 mL) was added thionyl chloride (0.11 mL, 1.51 mmol)at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.53C (242.8 mg, 90% yield). 1H NMR (400 MHz, CDCl3) 6 ppm 7.60 (2H, m), 7.40 (1H, m), 7.35 (2H, m), 7.21 (1H, m), 5.52 (1H, td, J=2.4, 0.9 Hz), 4.66 (2H, m), 2.24 (2H, td, J=7.0, 2.3 Hz), 1.68 (2H, m), 0.84 (6H, s).
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:33][N:34]([CH3:38])[C:35]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:36]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)N(C)C)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.12 g, 0.25 mmol, Preparation #K.1) and TEA (0.091 g, 0.9 mmol, Sd Fine Chem) in DCM (15 mL) was added dimethyl carbamoyl chloride (0.033 g, 0.31 mmol, Aldrich). The reaction mixture was slowly warmed to RT and stirred for about 1 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (2×15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted with 2-3% methanol in DCM. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-(dimethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.064 g (50%): LC/MS (Table 1, Method c) Rt=1.83 min; MS m/z: 499.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.I[Si](C)(C)C.C(OC([N:20]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][O:35][CH3:36])[CH2:22][C:21]1([CH3:38])[CH3:37])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:36][O:35][CH2:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:23]1[CH2:22][C:21]([CH3:37])([CH3:38])[NH:20][CH2:25][C:24]1=[O:26]
Reactant: COCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccccc1N1CC(C)(C)NCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
0.58 ml of triethylamine (4.10 mmol) and 0.3 ml of iodotrimethylsilane (2.05 mmol) were added to a solution of 497 mg of 4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.36 mmol) in methylene chloride (14 ml), and the mixture was stirred at 0° C. for 30 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel (NH type) column chromatography (elution solvent: methylene chloride/methanol=20/1) to obtain 310 mg of the title compound (yield: 86%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36](O)=[O:37]>>[CH3:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:37]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: Cc1ccsc1C(=O)O
Agent: Cl
Product: Cc1ccsc1C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3-methyl-2-thiophenecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methyl-2-thiophenecarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 488 (M-H)-.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17].Cl>CO.CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
4-Bromophenyl hydrazine hydrochloride (0.3 g, 1.3 mmol) in MeOH (3 mL) was heated to 60° C. and 1,2-cyclohexanedione (0.16 g, 1.4 mmol), dissolved in AcOH (4 mL) and conc. HCl (1.5 mL) were added while maintaining the temperature at 60° C. After the addition was completed, the reaction mixture was cooled to room temperature and stirred for 12 h during time a solid precipitated out. The mixture was basified with aq NaHCO3 and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography to give the title compound as a pale yellow solid (0.080 g, 22%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.8 (bs, 1H), 7.8 (s, 1H), 7.43 (dd, J=10.0, 2.0 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 2.98 (t, J=8.0 Hz, 2H), 2.63 (t, 8.0 Hz, 2H), 2.24 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[NH2:21][C@H:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:23][OH:24].CCN(C(C)C)C(C)C>CCCCO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:22]([NH:21][C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[N:7]=2)[CH2:23][OH:24])=[CH:30][CH:29]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 85.8 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28; 0.25 g, 0.84 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.15 g, 0.97 mmol) and DIEA (0.16 ml, 0.92 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a yellow solid (0.30 g, 87%). 1H NMR (400 MHz) δ 12.12, 12.10 & 11.61 (s, 1H), 10.94, 10.89 & 10.74 (s, 1H), 9.05, 8.82 & 8.73 (d, J=7.2 Hz, 1H), 8.13 & 8.11 (d, J=9.2 Hz, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 6.32 & 6.07 (d, J=9.2 Hz, 1H), 5.90, 5.83 & 5.79 (s, 1H), 5.23, 5.12 & 4.78 (m, 2H), 4.71, 4.64 & 4.37 (m, 1H), 3.69 (m. 2H), 1.34 & 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 416. Found: [M+H]+ 417.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)(C)(C)C.C(OCC)C.[ClH:30]>>[ClH:30].[CH:21]1([CH2:20][O:19][C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[C@@H:10]2[CH2:11][C@H:9]2[CH2:8][NH2:7])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1c1cc(F)ccc1OCC1CC1
Agent: Cl
Solvent: CCOCC
Product: NC[C@@H]1C[C@H]1c1cc(F)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
The protected amine 11 (5.8 g, 17.3 mmol) was dissolved in a 2 N HCl solution in diethyl ether (43 mL, 86 mmol), and the reaction mixture was stirred at ambient temperature for 48 h. A white precipitate formed after several hours, and the mixture was stirred until the reaction was complete by TLC. The crude precipitate was filtered and purified by recrystallization from ethanol/Et2O to afford the title compound as a white powder (4.3 g, 91.5% yield). HPLC purity: 12.0 min, 99.8%. 1H NMR (400 MHz, MeOD) δ 6.86-6.70 (m, 3 H), 3.91-3.78 (m, 2 H), 3.04 (d, J=7.2 Hz, 2 H), 2.18-2.12 (m, 1 H), 1.32-1.28 (m, 1 H), 1.16-1.02 (m, 2 H), 0.64-0.62 (m, 2 H), 0.39-0.37 (m, 2 H). 13C NMR (100 MHz, MeOD) δ 158.6 (d, 1 J CF=236.9 Hz), 155.4, 132.7 (d, 3 J CF=7.6 Hz), 114.5, 114.2, 114.2, 114.0, 114.0, 75.1, 45.2, 19.8, 18.4, 13.4, 11.4, 4.0, 3.6. MS (ESI) m/z 236.2 [MH+].
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.NC1[NH:77][N:76]=[N:75][N:74]=1>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][C:4]1[NH:77][N:76]=[N:75][N:74]=1)=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: Nc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 22 %

Procedure:
To a solution of 0.20 g (0.41 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.165 g (0.43 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.21 mL (1.24 mmol) N,N-diisopropylethylamine. To the yellow solution 0.037 g (0.43 mmol) 5-amino-1H-tetrazole (commercially available, CAS RN 4418-61-5) was added and the solution was stirred at room temperature for 3.25 hours. Then the solution was heated to 60° C. and stirred at this temperature for 88 hours. After filtration over a syringe micro filter, the reaction mixture was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown solid (0.051 g, 22%). MS (ESI): m/z=551.11 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:14])[N:10]([CH:11]1[CH2:12][CH2:13]1)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of cyclopropyl-carbamic acid benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DMF (20 mL) at 0° C. was added NaH (2.20 g, 91.6 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched at 0° C. by sat. NaHCO3. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc/hexanes) to give cyclopropyl-methyl-carbamic acid benzyl ester (11.32 g, 91%).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate was deprotected with a solution of pTSOH·H2O in acetonitrile as described in the preceding experiment to provide the title compound which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].C1C(=O)N([Br:22])C(=O)C1>C1COCC1>[Br:22][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[C:4]([O:13][CH3:14])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2ccccc2c1OC
Solvent: C1CCOC1
Product: COc1cc(Br)c2ccccc2c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To the solution of 1,2-dimethoxynaphthalene (3.83 g, 20.3 mmol) in THF (100 mL) was added dropwise at 0° C. a solution of NBS (3.62 g, 20.3 mmol) in THF (50 mL). After stirring at 0° C. for 0.5 h, the solvent was removed in vacuo and CCl4 was added. The mixture was filtered and the filtrate was concentrated. Column chromatography yielded the title compound as a yellow oil (3.72 g, 68%). 1H NMR (CDCl3) δ 8.1 (m, 2H), 7.60 (s, 1H), 7.49 (m, 2H), 3.99 (s, 3H) 3.98 (s, 3H); MS m/z 267 (M−H).
Reaction SMILES: S1C=CC=C1[Cl:6].[CH3:7][O:8][CH2:9][CH2:10][N:11]1[C:19]([C:20]([OH:22])=O)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[N:12]1>C1(C)C=CC=CC=1>[CH3:7][O:8][CH2:9][CH2:10][N:11]1[C:19]([C:20]([Cl:6])=[O:22])=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[N:12]1
Reactant: COCCn1nc2ccccc2c1C(=O)O
Reactant: Clc1cccs1
Solvent: Cc1ccccc1
Product: COCCn1nc2ccccc2c1C(=O)Cl
Yield: 102.1 %

Procedure:
Thienyl chloride (2.6 ml; 0.036 mol) was added to a suspension of 2-(2-methoxyethyl)-2H-indazole-3-carboxylic acid (3.6 g; 0.016 mol) in toluene (100 ml) and the reaction mixture was heated under reflux for 24 h. The solvent was removed by evaporation at reduced pressure and the residue was taken up twice in n-hexane. 3.9 g of 2-(2-methoxyethyl)-2H-indazole-3-carbonyl chloride was thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[SH:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C.Cl>CN(C)C=O>[C:31]([CH2:30][S:29][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:33])=[O:32]
Reactant: O=C(O)CS
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CCl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CSCC(=O)O)n1
Yield: 44.3 %

Procedure:
To 5.96 g of 6-(chloromethyl)-4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, methyl ester 0.25 g KI dissolved in 30 ml dimethylformamide, was added a solution of 1.38 g mercaptoacetic acid and 3.04 g triethylamine in 30 ml dimethylformamide. After stirring overnight the formed triethylamne/HCl was filtered off, and the dimethylformamide of the filtrate distilled off in vacuo . The residue was stirred with water/ethylacetate and the pH was adjusted to 2 with 2n HCl. The organic phase was washed with water, dried and evaporated, 6.8 g solid of title compound. Crystallization from ethanol yielded 3.01 g title compound and from the concentrated filtrate another batch of 0.37 g title compound was obtained. M.P. 135° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.ClCCl>[N:15]([CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(CBr)cc1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-bromomethylsalicylate (4.8 g, 18.6 mmoles) was dissolved in dry N,N-di-methylformamide (50 mL) and sodium azide (1.2 g, 18.9 mmoles) was added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (150 mL) and extracted with 1N aqueous hydrochloric acid (100 mL), water (100 mL), and saturated aqueous sodium chloride (50 mL). Finally, the solution was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give ethyl 4-azidomethylsalicylate as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C=O)C>C(Cl)Cl>[C:5]1([CH:11]([CH2:15][CH3:16])[C:12]([Cl:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCC(C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C(=O)Cl)c1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Thionyl chloride (0.12 mol) in 60 mL of CH2Cl2 was added to a stirred solution of 2-phenylbutyric acid (16.4 g, 0.10 mol). A catalytic amount of DMF was added and the reaction was allowed to continue overnight at room temperature. The volatiles were removed under vacuum and the residual liquid was vacuum distilled to yield 12.4 g (68%) of 2-phenylbutyryl chloride. IR (neat) 1798 cm-1 (C=O).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:19][Si](CC)(CC)CC)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:8][CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 0.5 g (1.24 mmol) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine in 2 mL of DMF were added 0.3 mL (2.5 mmol) of benzylbromide and the mixture was stirred overnight at 80° C. After distribution between a 2M aqueous solution of NaOH and Et2O, drying of the combined organic phases over Na2SO4 and evaporation, the resulting crude was dissolved in 5 mL of MeOH, treated with 1 mL of a 2M NaOMe-solution in MeOH and stirred for 30 min. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 95: 5 gave 0.33 g (70%) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow semisolid, MS: 378 (MH+).