Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[C:4]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][CH:17]=[C:18]([Cl:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)[S:5][CH:6]=1.C([Li])CCC.[CH3:54][Sn:55](Cl)([CH3:57])[CH3:56]>C(OCC)C>[CH3:54][Sn:55]([CH3:57])([CH3:56])[C:6]1[S:5][C:4]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17]([Sn:55]([CH3:57])([CH3:56])[CH3:54])=[C:18]([Cl:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:3]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:2]=1[Cl:1]
Reactant: CCCCCCCCCCCCCCc1c(Cl)csc1-c1nc2sc(-c3scc(Cl)c3CCCCCCCCCCCCCC)nc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1c(-c2nc3sc(-c4sc([Sn](C)(C)C)c(Cl)c4CCCCCCCCCCCCCC)nc3s2)sc([Sn](C)(C)C)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL Schlenk flask was added 250 mg (0.32 mmol) of 2,5-bis(4-chloro-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole. The flask was evacuated and refilled with argon three times. After 35 mL of dry THF was added to the flask, the flask was cooled to −78° C. n-Butyl lithium (0.96 mmol) was then added dropwise to the solution. After stirring at −78° C. for 1 hour, 1.1 mL of an 1.0 M solution of trimethyltin chloride was syringed into the reaction mixture. After the solution was allowed to warm up to room temperature, 100 mL of diethyl ether was added to the solution. The solution was washed three times with 100 mL of water and then the organic layer was dried MgSO4. The solvent was removed in vacuo and the desired compound, i.e., 2,5-bis(5-trimethylstannyl-4-chloro-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole, was isolated in quantitative yield. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:25])[C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:18]([C:19]1[C:20]([C:21]([OH:24])([CH3:23])[CH3:22])=[N:2][N:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12)=[O:25])[CH3:16]
Reactant: CCOC(=O)C#CC(C)(C)O
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)(C)O)nn2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a suspension of 1-amino-pyridinium iodide (0.343 g, 1.54 mmol) and potassium carbonate (0.278 g, 2.01 mmol) in 2 mL N,N-dimethylformamide was added 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester (0.262 g, 1.70 mmol) in 1 mL N,N-dimethylformamide dropwise. The mixture was stirred at room temperature for 24 h under nitrogen atmosphere, poured on to ice and filtered, and the solid was washed with water to provide the crude product as a brown solid. The filtrate was extracted with ethyl acetate and the previously filtered solid was combined with the organic extracts, which was dried over magnesium sulfate, filtered and concentrated in vacuo and the residue was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to obtain the product as a yellow solid (0.296 g, 1.19 mmol, 77% yield).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([I:9])=[CH:7][N:8]=2)[CH2:3][CH2:2]1.I[CH3:11]>>[CH:1]1([C:4]2[N:8]([CH3:11])[CH:7]=[C:6]([I:9])[N:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cnc(C2CC2)[nH]1
Reactant: CI
Product: Cn1cc(I)nc1C1CC1

Procedure:
The title compound, MS: m/e=249.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-cyclopropyl-5-iodo-1H-imidazole (example C) and iodomethane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:13]1[C:14](=[O:15])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]1[CH3:16]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.04 g), 1-bromo-3,3-dimethylbutan-2-one (1.53 g), potassium carbonate (1.59 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 26%).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:18])=[CH:12][CH:11]=1>>[ClH:1].[ClH:1].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)N2CCNCC2Cc2cccnc2)cc1
Reaction time: 8 h
Yield: 54 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(4-methoxyphenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate (76.0 mg, 0.141 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 30.5 mg (54%) of the desired product as an off-white solid. LC-MS: RT=2.11 min, [M+H]+=327.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=3)[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:29][C:4]1[CH:3]=[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)[N:10]=[C:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: FC(F)(F)c1cc(-c2cn(-c3ccc(Br)cc3Cl)c(-c3ccccc3Cl)n2)no1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4cc(C(F)(F)F)on4)nc3-c3ccccc3Cl)c(Cl)c2)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
To an 8 mL glass vial was added 3-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)isoxazole (120 mg, 236 μmol), 3-methylsulfonylphenyl boronic acid (52 mg, 260 μmol), PdCl2dppf (20 mg, 10 mol %), K2CO3 (100 mg, 708 μmol), 1,2-dimethoxyethane (6 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (30 mL) and filtered through a celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (40 mL) and aq NaCl (40 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 12 g SiO2 column using a mobile phase gradient of 5% EtOAc to 100% EtOAc to afford 72 mg (53% yield) of the title compound. MS (ESI) 578.0, 580.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 8.13 (d, J=8 Hz, 1H), 8.08 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.71-7.79 (m, 2H), 7.69 (d, J=7 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.48 (m, 1H), 7.36-7.42 (m, 2H), 3.34 (s, 3H) ppm; 19F NMR (400 MHz, DMSO-d6) 6-81.9 ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:32][C:33]1[N:34]=[CH:35][N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=2[O:45][CH3:46])[CH:37]=1>>[Cl:32][C:33]1[N:34]=[CH:35][N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH:42][C:2]3[N:3]=[C:4]([N:18]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:40][C:39]=2[O:45][CH3:46])[CH:37]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Product: COc1cc(Nc2nc3c(c(N4CCC(N(C)C(=O)OC(C)(C)C)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 49.5 %

Procedure:
tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate (Preparation Hm) (148 mg, 0.331 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (74.1 mg, 0.331 mmol) were combined as per Example 26 to give the crude tert-butyl 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate (104 mg, 0.164 mmol, 49.5% yield) which was used without further purification. LC-MS (M+H)+=634.4.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH3:5][N:6]([C@@H:8]1[C:26](=[O:27])[C:25]([C:28]([NH2:30])=[O:29])=[C:24]([OH:31])[C@:23]2([OH:32])[C@H:9]1[CH2:10][C@H:11]1[C:20]([C:21]2=[O:22])=[C:19]([OH:33])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][C:17]=2[OH:34])[CH2:12]1)[CH3:7].[CH2:36]1[CH2:40]OC[CH2:37]1>>[CH:37]1([C:14]2[CH:15]=[CH:16][C:17]([OH:34])=[C:18]3[C:13]=2[CH2:12][C@@H:11]2[C:20]([C:19]3=[O:33])=[C:21]([OH:22])[C@@:23]3([OH:32])[C@H:9]([C@H:8]([N:6]([CH3:7])[CH3:5])[C:26]([OH:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]3=[O:31])[CH2:10]2)[CH2:36][CH2:40]1
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [In+3]
Product: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(C5CC5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1000 mL 2 or 3 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After the flask cooled to ambient temperature and was flushed with argon, anhydrous THF (240 mL) was added. The solution was cooled to −78° C. and c-PrMgBr (244 mL, 122 mmol) as a 0.5 M solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form a clear heterogeneous solution. To the reaction flask was added 7-iodosancycline (19.4 g, 36.0 mmol) and Pd(t-Bu3)2 (0.920 g, 1.80 mmol). The solution was heated to reflux under argon until complete (approximately 1 hour). After cooling to ambient temperature, the solution was quenched with MeOH (1 mL) and poured into a stirring cold solution of 1M HCl (3 L). After 1 hour, the solution was filtered through a pad of Celite, while rinsing with water. The water solution was loaded onto a DVB column for solid phase extraction and the product was isolated by eluting with 1% TFA/CH3CN. The crude product was further purified by preparatory HPLC (C18, linear gradient 20-60% acetonitrile in water with 0.1% TFA, to afford 11.8 g in 72% yield as a yellow solid. 1H NMR (CD3OD) δ 7.18 (d, J=7.4 Hz, 1 H), 6.61 (d, J=7.4 Hz, 1 H), 3.99 (s, 1 H), 3.34 (dd, J=9.1, 2.8 Hz, 1 H), 3.05-2.84 (m, 10 H), 2.32-2.09 (m, 2 H), 0.86-0.75 (m, 2 H), 0.51-0.37 (m, 2 H). LC/MS (MH+) 455.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](O)[CH:32]=1>CN(C)C=O>[N+:37]([C:36]1[CH:31]=[CH:32][C:33]([O:14][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:34][CH:35]=1)([O-:39])=[O:38]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Nα -t-Butoxycarbonyl-D-valine p-nitrophenyl ester is prepared from 5 g., 24 mmol, of Nα -t-butoxycarbonyl-D-valine, 4.8 g., 24 mmol, of dicyclohexylcarbodiimide and 3.4 g., 24 mmol, of p-nitrophenol dissolved in 25 ml. of dimethylformamide and the solution let stand at room temperature overnight. The solids are separated by filtration and the filtrate evaporated to dryness under reduced pressure. The residual oil is purified by chromatography on silica gel in methanol-benzene (5:95); 5 g.; [α]D23 +21° (c 1.0, methanol); ultraviolet in methanol λmax 270 E11 204.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].O.[C:14]1(S(OCC#C)(=O)=O)[CH:19]=CC=C[CH:15]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:14]#[CH:15]
Reactant: NC1CCc2ccccc21
Reactant: C#CCOS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCNC1CCc2ccccc21
Yield: 62 %

Procedure:
To a mixture of racemic 1-aminoindan (64 g), 15% aqueous sodium hydroxide solution (141 g), water (107 mL) and toluene (192 mL) there was added propargyl benzenesulfonate (94.3 g) during 20 minutes at ambient temperature. The resulting mixture was heater to 45° C. for 4 hours, at which time the pH was confirmed to be >12(45% sodium hydroxide added if necessary) and the phases were separated. To the organic phase water (64 mL) was added and the pH was adjusted to 2 with 33% aqueous sulfuric acid. The aqueous phase was separated, diluted with water and mixed with toluene. The pH was adjusted to 6 with 25% aqueous sodium hydroxide and the phases separated. The aqueous phase was extracted again with toluene, ensuring a pH=6. The combined organic layers were concentrated in vacuo to yield 51 g of crude racemic N-propargyl-1-aminoindan as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>C1(C)C=CC=CC=1.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.[Pd].O>[N+:16]([C:4]1[CH:3]=[C:2]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-bromo-2-nitrophenylcarbamate obtained in step IV above (1.0 eq) in toluene, was added 10 mol % of tetrakis Pd, heated to 90° C. for 30 min, then aq K2CO3 and ethanol were added, followed by addition of 2-thienyl boronic acid portionwise and then reaction was refluxed overnight. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired tert-butyl 2-nitro-4-thien-2-ylphenylcarbamate. (Yield=88%)
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([F:9])=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.[C:16](=[O:18])=[O:17]>CCOCC>[F:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[N:4]=1
Reactant: O=C=O
Reactant: Cc1cc(F)nc(C)c1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Cc1cc(F)nc(C)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of 3-bromo-2,4-dimethyl-6-fluoropyridine (1.45 g, 7.10 mmol) in anhydrous Et2O (25 mL) at −78° C. was added t-BuLi (1.7M in pentane, 8.8 mL, 15 mmol) dropwise. After addition the mixture was stirred at −78° C. for 10 min, and CO2 was introduced. After 10 min the cooling bath was removed, and the bubbling of CO2 was continued until the mixture was warmed to 0° C. Water (30 mL) was then added and Et2O was removed. The aqueous layer was washed CH2Cl2 (2×30 mL) and acidified with 6N HCl, resulting in precipitation of a pale brown solid (0.87 g, 73%) which was collected by filtration and dried under vacuum. 1H NMR (CD3OD): δ 2.38 (s, 3H), 2.46 (s, 3H), 6.69 (s, 1H). 19F NMR (CD3OD): δ 0.63.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])[CH:64]=[CH2:65].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:65]=[CH:64]/[CH2:63][NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(=O)NC(C)(C)CO
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=O)NC(C)(C)CO)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To an acetonitrile solution (5.4 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (0.48 g, 0.539 mmol) were added N-allyl-N′-(2-hydroxy-1,1-dimethylethyl)urea (223 mg, 1.29 mmol), palladium(II) acetate (24 mg, 0.108 mmol), tri-O-tolylphosphine (66 mg, 0.216 mmol) and triethylamine (273 mg, 2.69 mmol), and the mixture was stirred at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform and then chloroform:methanol=50:1) to obtain the title compound (210 mg, 40%) as a pale yellow amorphous compound.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([O:13]C)=[O:12])[C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.C1(C)C=CC=CC=1.C(OO)(=O)C>O>[CH2:15]([C:6]12[C:5](=[O:4])[CH2:9][CH2:8][CH:7]1[CH2:10][C:11](=[O:13])[O:12]2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC1=C(OC(C)=O)CCC1CC(=O)OC
Agent: CC(=O)OO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC12OC(=O)CC1CCC2=O
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A 2000 ml three-necked round-bottom flask, equipped with a magnetic stirrer, nitrogen device, thermometer, dropping funnel and a reflux condenser was charged with 591.0 g of crude methyl 3-acetoxy-2-pentyl-2-cyclopentene-1-acetate and 70 g of toluene. At 26° C. 386.9 g (2.04 mol) 40% peracetic acid were added dropwise over a 5.3 h period. Stirring was continued for 2 h. 22.0 g (0.12 mol) of 40% peracetic acid were added over 30 min, and stirring was continued for another 2 h. 350 g of water were added and the water-layer (590.4 g) was separated. Three more washes were made with each 350 ml of water. The organic phase (1273.9 g) was evaporated to give 437.8 g of crude product which was vacuum distilled (0.4 hPa) to furnish 2 fractions, of which the first one (Bp=90-144° C.) was 172.55 g, containing 26.5% of product and the second one was 187.6 g, containing 95% of lactone. 1H-NMR: 0.88 (br t, J=6.7 Hz, Me); 1.15-1.45 (m, 6H); 1.67-1.87 (m, 3H); 2.14-2.63 of overlapping m, 4H); 2.84-2.97 (m, 2H). 13C-NMR: 13.9 (Me), 22.4, 22.6, 25.0, 31.9, 33.0, 35.7, 35.8 (CH2), 38.6 (CH), 89.0 (C), 175.0 (CO2), 210.9 (CO). MS: M+=210 (5): 154 (16), 139 (22), 112 (25), 111 (73), 99 (79), 98 (100), 83 (26), 71 (26), 55 (73), 43 (28).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[C:14]1[C:15]2[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:2][CH3:3].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:6]4[C:7]5[O:11][CH2:10][O:9][C:8]=5[CH:12]=[CH:13][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A70) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 3 product (i.e. N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in dichloromethane (100 ml), hydrochloric acid (36%) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40° C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2×200 ml). The toluene was then completely recovered under vacuum at 50-55° C. to get an oil. Yield=15 gm.