Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:44]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:45])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CC(C)N=C=O
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 12.2 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (52 mg, 0.6 mmol) in dichloromethane (1 mL) was added isopropylisocyanate (36.5 mg, 0.51 mmol). Triethylamine (60 mg, 0.60 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 40.8 mg (52%) of the title compound as off white solid. MS (ES) m/e 654.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[N:11]1([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1csc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperazinecarboxylate (1.0 g, 3.4 mmol) (i.e. the product of Example 30, Step A) in 10 mL of dichloromethane was treated with 2 M hydrogen chloride in diethyl ether (10 mL) and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was evaporated in vacuo to give 1.0 g of the title compound as a white solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]2[CH3:17])=[O:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23]([Cl:25])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]3[CH3:17])=[O:9])=[CH:6][N:7]=2)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (6-aminopyridin-3-yl)((3R,5S)-3,5-dimethylmorpholino)methanone 320a (235 mg, 1.0 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (232 mg, 1.05 mmol), cesium carbonate (652 mg, 2.0 mmol), and 1,4-dioxane (6.0 mL). After bubbling nitrogen through the suspension for 10 minutes, Xantphos (116 mg, 0.20 mmol) and tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.10 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×10 ml). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:10) to afford 321a (140 mg, 37%) as a yellow solid. MS-ESI: [M+H]+ 378.3
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].Cl.[N:11]([O-])=O.[Na+]>O>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][NH2:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1ccc(NN)cc1
Temperature: 0 °C

Procedure:
To a suspension of 4-ethylaniline (90g.) in water (280ml.) was added concentrated hydrochloric acid (38% w/w, 280ml.), and the mixture was warmed on a steam bath. The suspension obtained was stirred and cooled to 0°C., and a solution of sodium nitrite (52.1g.) in water (180ml.) was added during 45 minutes, the temperature being maintained at -10° to -5°C. by cooling. The dark solution was stirred at 0° C. for a further 30 minutes, and then filtered through celite. The filtered diazonium salt solution (stored at 0°C.) was added in portions to a stirred fresh mixture of sodium dithionite (500g.) in ice-cold water 1 l.) keeping the temperature at 5°-10°C. After the addition of each batch of the diazonium salt solution, further dithionite (total 500g.) was added in portions. After the addition was complete (45 minutes), the mixture was stirred at room temperature overnight. The mixture was separated by filtration and the filtered solid was suspended in water (1 l.), basified with sodium hydroxide solution, and the mixture extracted with ethyl acetate (3 × 250ml.). The combined extracts were washed with a minimum of water, dried (MgSO4), and evaporated to give 4-ethylphenylhydrazine as a low melting solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32]([C:29]2[N:26]3[C:25]([S:24][CH:28]=[CH:27]3)=[N:31][CH:30]=2)=[O:33])=[O:10])[N:12]=1
Reactant: O=C(O)c1cnc2sccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=478.3.
Reaction SMILES: [CH:1](=[C:5]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].CO>[Ir].ClCCl>[CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=C1CCCNC1=O
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: CCCCC1CCCNC1=O
Yield: 90.2 %

Procedure:
This example describes the preparation of I where n=2 and R1=n-propyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (8 mg, 0.010 mmol) and 3-(butylidene)-2-piperidone (150 mg, 1.0 mmol). Methanol (2 mL) and dichloromethane (2 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 Mpa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-butyl-2-piperidone (140 mg, 93%) as a white crystalline solid. Chiral gas chromatographic analysis (Rt-GammaDex SA column, 130° C. for 5 min, then programmed to 200° C. at 10°/min) indicated that conversion was 95% and the enantiomeric excess was 90%. 13C NMR: δ 14.24, 21.27, 22.85, 26.04, 29.25, 31.36, 40.96, 42.38, 176.02; 1H NMR: δ 0.91 (t, J=7, 3H), 1.22-1.58 (m, 6H), 1.70 (m, 1H), 1.79-2.00 (m, 3H), 2.24 (m, 1H), 3.29 (m, 2H), 7.25 (br s, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:32][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[O:30][CH3:31])[C:9]=2[C:8]=1[CH3:33])=[O:6].Cl>CO.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:9]3[C:8]([CH3:33])=[C:7]([C:5]([OH:6])=[O:4])[S:32][C:10]=3[N:11]=[CH:12][N:13]=2)=[C:17]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH3:31])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3OC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12

Procedure:
7 ml sodium hydroxide solution (2M) were added to a mixture of 1.270 g 4-[4-fluoro-2-((1S,2S)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 42.1) in 10 ml MeOH/THF (1:1). The reaction mixture was stirred at reflux for 15 minutes, then cooled and acidified with 2 M aq. HCl. The solvent was removed in vacuo, the residue suspended in water, filtered and dried.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:19]=[C:18]([N:20]2[C@@H:26]([CH3:27])[C@H:25]([OH:28])[C:22]3([CH2:24][CH2:23]3)[C:21]2=[O:29])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:19]=[C:18]([N:20]2[C@@H:26]([CH3:27])[C:25](=[O:28])[C:22]3([CH2:24][CH2:23]3)[C:21]2=[O:29])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1C(=O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A solution of oxalyl chloride (0.050 mL) in methylene chloride (2.0 mL) was cooled to −60° C., dimethyl sulfoxide (0.062 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 min. A solution of 2-chloro-4-[(6S,7R)-7-hydroxy-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]benzonitrile (40.1 mg) in methylene chloride (2.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at −40° C. for 1 hr. Triethylamine (0.202 mL) was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/1) to give the title compound as a pale-yellow oil (yield: 35 mg, 88%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[N:8]=1.Cl>C(O)C>[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[N:8]=1
Reactant: CCOC(=O)c1noc(Cc2cc(F)ccc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1noc(Cc2cc(F)ccc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of sodium hydroxide 1M (2 mL, 2 mmol) was added to a mixture of ethyl 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.150 g; 0.559 mmol) in ethanol (1 mL) and the reaction was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 1 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure to afford 0.124 g (92%) of 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylic acid as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[Br:23][C:24]1[CH:25]=[C:26]([C:36](O)=[O:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]([C:36]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]([CH3:20])[C:13]4=[O:21])[CH:8]=2)=[O:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:28]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(Br)nn2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
6-(5-Amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (30 mg, 0.08 mmol) was dissolved in DMF (5 mL) with 5-bromo-2-(4-fluoro-phenyl)-2H-pyrazole-3-carboxylic acid (45 mg, 0.16 mmol) at RT. HATU (60 mg, 0.16 mmol) was added, followed by DIEA (0.14 mL, 0.8 mmol). The mixture was stirred for 20 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 30 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 549.0.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:13]([OH:21])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[Cl-].[Na+]>CC(O)(C)C.CCOC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][N:1]2[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][C:13]([OH:21])=[O:20])[N:3]=[N:2]2)=[CH:6][CH:7]=1
Reactant: C#CCCCCC(=O)O
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Cn2cc(CCCCC(=O)O)nn2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(Azidomethyl)-4-methoxybenzene (259 mg, 1.585 mmol) was solubilised in t-BuOH (15.9 ml). Hept-6-ynoic acid (201 μl, 1.585 mmol) was added followed by water (15.9 ml) copper acetate (28.2 mg, 0.159 mmol) and sodium L-ascorbate (63 mg, 0.317 mmol). The reaction mixture was stirred at RT for 72 hrs. Sodium chloride was added and the mixture was stirred vigorously. EtOAc was added and the phases were separated. The aqueous layer was re-extracted with EtOAc and the combined organics were treated with charcoal & MgSO4 (anh), stirring for 5 minutes. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to afford the title compound;
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.0 g), DMAP (1.55 g) and triethylamine (2.34 g) in DCM (80 mL) was cooled to 0° C. A solution of acetic anhydride (2.35 g) in DCM (20 mL) was added dropwise over 20 minutes and the reaction mixture was stirred at room temperature for 1 hour. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ether and washed with 10% aqueous citric acid solution and brine, dried (MgSO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl 3-acetoxyazetidine-1-carboxylate (2.34 g) as a clear oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:13][NH2:14])=[O:10]
Reactant: NN
Reactant: COC(=O)Cc1cnccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1cnccn1
Temperature: 120 °C
Yield: 80 %

Procedure:
In a 25 mL sealed tube, methyl 2-(pyrazin-2-yl)acetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.33 g, 4 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-(pyrazin-2-yl)acetohydrazide (0.2 g) which was used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
A mixture of 4-methyl-1H-imidazole (18.0 g, 53.5 mmol), 1-chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol), and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (330 g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 20% yield) as a yellow/orange solid. LC-MS (M+H)+=234.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.97-8.00 (m, 1H) 7.93-7.97 (m, 2H) 7.45 (d, J=8.85 Hz, 1H) 7.02 (s, 1H) 4.02 (s, 3H) 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:31][CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC(F)(F)F)cc1

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (4.50 g), which is the product of Reference example 1(b), 4-trifluoromethoxyphenol (2.33 ml), triphenylphosphine (4.71 g) and solution of diethylazodicarboxylate in toluene (40%, 8.15 ml) and the reaction mixture was treated to afford the desired compound (4.19 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[NH:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>CN(C)C=O>[CH2:3]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([C:22]([O:24][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:23])=[CH:18][CH:19]=2)[NH:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC1Cc2ccc(C(=O)OCC(O)CO)cc2N1
Yield: 60.3 %

Procedure:
Sodium hydride (0.32 g of a 50% oil dispersion) was added to a stirred solution of (RS)-2-(n-decyl)indoline-6-carboxylic acid (2 g; prepared as described hereinbefore in Example 57) in dry dimethylformamide (50 ml). When the addition was complete, the mixture was warmed on the steam bath for 1 hour with stirring, and 3-chloro-1,2-propanediol (0.8 g) was added. The mixture was warmed on the steam bath for 20 hours with stirring. The solvent was then evaporated to dryness and the residue was dissolved in dichloromethane. The solution in dichloromethane was washed with water, dried over magnesium sulphate and filtered, and the solvent evaporated to dryness to give an oil which slowly solidified. This solid was washed with petroleum ether (b.p. 60°-80° C.), filtered off and dried in air to give (RS)(RS)-2,3-dihydroxyprop-1-yl 2-(n-decyl)indoline-6-carboxylate (1.5 g), in the form of an off-white powder m.p. 102°-110° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:76])[C@@H:40]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:68])[C@H:47]([CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@H:47]([C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@H:40]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11]1)[OH:76])=[O:68])[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 96.5 %

Procedure:
By using an analogous procedure to that described for Example 2, tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[3-(tert-butoxy)-3-oxopropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (94 mg, 0.086 mmol, obtained from Example 20) was hydrogenated in methanol (3 ml) using 10% palladium on carbon (24 mg) to provide tert-butyl (4S)-4-amino-5-[(3-{[(1S,2R)-2-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-1-(tert-butoxycarbonyl)-2-hydroxyethyl]amino}propyl)amino]-5-oxopentanoate (80 mg, 96%) as a white solid.