Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:19])[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C.C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ncnc3[nH]ccc23)cc1Cl
Temperature: 95 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (767.9 mg, 5 mmol) and 3-chloro-4-fluoro-phenylamine (873.4 mg, 6 mmol) in 25 mL of dry DMF under nitrogen was added silver trifluoromethanesulfonate (1.54 g, 6 mmol). The mixture was stirred at 95° C. for 15 hours. The cooled reaction was diluted with ethyl acetate (70 mL) and filtered through celite, washed thoroughly with ethyl acetate. The filtrate was washed with brine (5×). The brine was extracted with ethyl acetate which was then washed with brine. The combined ethyl acetate was dried (magnesium sulfate), concentrated and purified to give 1.22 g (93%) of (3-chloro-4-fluoro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine as an off-white solid. m.p. 274-275° C. 1H NMR (360 MHz, DMSO-d6) δ 11.78 (br s, 1H, NH), 9.41 (s, 1H), 8.31 (s, 1H), 8.28 (m, 1H), 7.79 (m, 1H), 7.37 (t, 1H), 7.25 (m, 1H), 6.76 (m, 1H). MS 263.4 [M++1].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9](=[O:21])NC2SC(SCC(O)=O)=CN=2)[CH2:4][CH2:3]1.C([O:33][C:34](=[O:45])[C:35]([S:38][C:39]1[S:43][C:42]([NH2:44])=[N:41][CH:40]=1)([CH3:37])[CH3:36])C>>[CH3:37][C:35]([S:38][C:39]1[S:43][C:42]([NH:44][C:9]([N:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:22][CH2:23][S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:21])=[N:41][CH:40]=1)([CH3:36])[C:34]([OH:33])=[O:45]
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: C[C@H]1CC[C@H](N(CCSc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(CCSc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-methyl-cyclohexyl)-3-(2-phenylsulfanyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C@@H:3]([CH2:11][OH:12])[C@@H:2]1[CH2:13][OH:14].[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:18][O:12][CH2:11][C@@H:3]1[O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][C@H:2]1[CH2:13][OH:14]
Reactant: OC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
(2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyldimethanol (65 g, 321.4 mmol) was dissolved in DMF (500 mL) and cooled in an ice bath. 60% Sodium hydride (15.43 g, 385.7 mmol) was added slowly and the reaction was stirred for 30 minutes in an ice bath then warmed to ambient temperature for 2 hours. Iodomethane (20.05 ml, 321.4 mmol) was added and the reaction was stirred at ambient temperature overnight. The majority of the DMF was removed on a rotary evaporator, and the residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified over 1 Kg of SiO2 (20 to 40% EtOAc in hexanes) to afford ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)methanol (31.3 g, 144.7 mmol, 45.03% yield) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([C@@H:16]([CH3:27])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH2:24][CH2:23][C:22]=3[CH:26]=2)[CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[O:25]1[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([N:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:7][CH2:8]3)[CH2:14][CH3:15])[CH3:27])=[CH:26][C:22]=2[CH2:23][CH2:24]1
Reactant: CCN(CC1CCN(C(=O)CCN)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)CCNS(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To (S)-3-amino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}-methyl)piperidin-1-yl]propan-1-one (0.4 grams, 1.07 mmol) and diisopropylethylamine (0.21 grams, 1.62 mmole) in dichloromethane (10 ml) at 0° C. was added methanesulfonyl chloride (0.16 grams, 1.39 mmole). The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with water, dried over potassium carbonate and concentrated to give a residue which was purified by flash chromatography on silica gel using 3% methanol in dichloromethane containing 0.1% ammonium hydroxide. Appropriate fractions were combined and evaporated to give (S)-N-{3-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-3-oxopropyl}methanesulfonamide as an oil (0.32 grams, 66%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 51.83; H, 7.38; N, 7.87. Requires: C, 51.82; H, 7.56; N, 7.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])(O)[CH3:10])=[CH:4][C:3]=1[F:13].[C:14](#[N:16])[CH3:15].S(=O)(=O)(O)[OH:18].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:16][C:14](=[O:18])[CH3:15])([CH3:12])[CH3:10])=[CH:4][C:3]=1[F:13]
Reactant: CC#N
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(C)(C)Cc1ccc(Cl)c(F)c1
Temperature: 65 °C
Yield: 42.1 %

Procedure:
To a mixture of 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-ol (8.61 g, 42.50 mmol), acetonitrile (13 mL, 255.0 mmol) and acetic acid (80 mL) was added sulfuric acid (13 mL) dropwise and the mixture was heated at 65° C. for 5 h. The mixture was cooled to rt and poured into ice water (400 mL) and the resulting mixture was adjusted to pH>11 with NaOH, and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (150 mL×2), dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (4.38 g, 42.1%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1.CCCCCC>[CH2:26]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Ic1cnc2ccccn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2ccccn12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL three-necked flask, 3-iodoimidazo[1,2-a]pyridine (0.9 g, 3.69 mmol) was dissolved in 50 ml THF at −5° C. using an acetone/ice bath. Isopropylmagnesium chloride (1.3 M, 2.84 ml, 3.69 mmol) was added via a syringe and a light white suspension formed. After 0.5 h, tributylchlorostannane (1.15 g, 0.95 μl, 3.69 mmol) was added. This was stirred at 20° C. for 1.5 h. The reaction mixture was diluted with hexane (100 ml), quenched with a saturated solution of ammonium chloride and the organics were washed with 50% brine/water. The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-tributylstannanyl-imidazo[1,2-a]pyridine as an oil. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, 1H) 7.61 (d, 1H) 7.59 (s, 1H) 7.17 (m, 1H) 6.72 (m, 1H) 0.9-1.55 (m, 27).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:8]([C:6]1[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]=2[C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(=O)c2ccsc2s1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(=O)c2ccsc2s1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, to a stirred solution of 4-oxo-4H-thieno[2,3-b]thiopyran-6-carboxylic acid (10.7 g, 0.05 mol) in tetrahydofuran (50 ml) was added carbonyldiimidazole (8.9 g., 0.055 mol). The mixture was stirred at ambient temperature for 3/4 hour. Anhydrous dimethylamine was bubbled into the thick suspension at 0° C. until an excess was present. The resulting solution was stirred at 0° C. for 3/4 hour and the solvent was removed in vacuo. The residual oil was diluted with H2O (50 ml) and the solid which separated was filtered and dried to give 7.14 g of product, m.p. 126.5°-128° of 97% purity by HPLC. The aqueous filtrate was concentrated in vacuo and the residual gum was chromatographed on silica gel (200 g) using 10% methanol in chloroform. An additional 3.15 g of impure product was recovered. Yield was about 80%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(N(C)C)=O>[C:28]([N:5]1[C:4](=[O:18])[C:3]([C:2]([F:1])([F:19])[F:20])=[CH:16][N:7]([C@@H:8]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]2)[C:6]1=[O:17])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1c(=O)c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
12 Grams of 2'-deoxy-5-trifluoromethyluridine was dissolved in 30 ml of dimethylacetamide. Thereto was added 8 ml of triethylamine, and further to the mixture being cooled with ice-water was added 5.6 g of benzoyl chloride. The whole mixture was stirred overnight. The reaction mixture was subjected to filtration, the resulting filtrate was subjected to evaporation and the residue was dissolved in ether. To the ether solution being stirred was slowly added water. The resulting precipitate was collected by filtration. The precipitate collected was recrystallized from ether-petroleum ether. The yield was 8.0 g. M.p. 144.5° to 146° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[N:19]([CH2:22][CH2:23][NH2:24])=[N+:20]=[N-:21].C(N(CC)CC)C>ClCCl>[N:19]([CH2:22][CH2:23][NH:24][C:3](=[O:5])/[C:2](/[CH3:1])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:20]=[N-:21]
Reactant: C/C(=C\c1ccccc1)C(=O)O
Reactant: [N-]=[N+]=NCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(=C\c1ccccc1)C(=O)NCCN=[N+]=[N-]
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added (E)-2-methyl-3-phenylacrylic acid (0.0.512 g, 3.15 mmol) and dichloromethane (10 mL). Oxalyl chloride (0.400 g, 3.15 mmol) was added dropwise to the reaction mixture and allowed to stir for one hour. Then, the reaction mixture was concentrated de vacuo. To the crude mixture was then added dichloromethane (10 mL), 2-azidoethanamine (0.299 g, 3.47 mmol) and then triethylamine (0.351 g, 3.47 mmol) and allowed to stir for two hours. The reaction mixture was then concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol:dichloromethane) to give (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.698 g, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.39 (m, 6H), δ 7.01 (s, 1H), δ 3.51 (t, 2H), δ 3.45 (t, 2H), δ 2.13 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.5, 136.2, 134.5, 132.0, 130.3, 129.6, 128.9, 128.6, 128.3, 50.9, 39.8, 14.5 ppm; HRMS (ESI) calcd for C12H14N4O (M+) 230.1168. Found 230.1165.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]([CH3:23])([CH2:19][N+:20]([O-])=O)[CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1>[NH2:20][CH2:19][C:15]([S:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:23])[CH2:16][CH2:17][OH:18]
Reactant: CC(CCO)(C[N+](=O)[O-])SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(CN)(CCO)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of lithium aluminum hydride (1.67 g) and tetrahydrofuran (30 ml) was added a solution of 3-(benzylthio)-3-methyl-4-nitrobutan-1-ol (3.00 g) in tetrahydrofuran (10 ml) over 1 hr at room temperature. The reaction mixture was stirred at room temperature for 1 hr, ethanol (10 ml) and water (6.4 ml) were added in this order, and the resulting inorganic salt was removed by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate, dried (MgSO4), and concentrated to give the title compound (2.62 g, yield 99%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:18]Br)=[C:13]([CH2:16]Br)[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[OH-:41].[Na+]>C1C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][O:41][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)N1c2cc(CBr)c(CBr)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)COC3
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-bis-bromomethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 27B) (50 mg, 0.71 mmol) in 0.25 ml benzene was added benzyl tri-n-butylammonium chloride (23 mg, 0.71 mmol) and 30% NaOH (28 μl). The reaction mixture was heated to 80° C. for 4 hours. The mixture was diluted with 0.75 ml ethyl acetate. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2×0.25 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed on silica gel (25% ethyl acetate:hexane) to afford the title product (10 mg, 25%). MS m/z 561 (M+); 1H NMR (CDCl3) δ3.85 (s, 3H), 6.85 (s, 1H).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=O.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14].C(N(CC)CC)C>C(O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3[N:18]=[C:16]([CH2:15][C:13]#[N:14])[S:17][C:2]=3[CH2:10][C:9]=2[CH:8]=1
Reactant: N#CCC(N)=S
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCc1nc2c(s1)Cc1cc(Cl)ccc1-2

Procedure:
1 g (4 mmol) of 2-bromo-5-chloroindan-1-one is stirred with 450 mg (4.5 mmol) of 2-cyanothioacetamide and 0.55 ml (4 mmol) of triethylamine in 10 ml of dry ethanol at room temperature for 4 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography on silica gel with ethyl acetate/n-heptane 1/1. (6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)acetonitrile is obtained with a melting point of 134° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13]O[N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C>CN(C)C=O.[Pd]>[NH2:13][C:8]1[C:7]([NH2:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2
Reactant: Oc1nc2ccc3nonc3c2nc1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc2nc(O)c(O)nc2c1N
Yield: 95.6 %

Procedure:
A solution of 5,0 g (24,5 mmol) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline and 6,B ml (49 mmol) triethylamine in 500 ml dimethylformamide was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water, and the precipitate was fiItered off to give 4,5 g (96%) 5,6-diamino-2,3-dihydroxyquinoxaline, m.p. >300° C. NMR (DMSO-d6) 11.0 (2H, broad m), 6.43 (lH,d), 6.23 (lH,d), 4.5 (4H, broad m).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]=[C:26]([CH3:29])[CH2:25][C@H:24]1[C:30]([OH:32])=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:31][C:30]([C@@H:24]1[CH2:25][C:26]([CH3:29])=[CH:27][CH2:28][N:23]1[C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22])=[O:32])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1=CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(C)=CCN1C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
1,3-Dicyclohexylcarbodiimide (4.3 g, 20.8 mmol) was added to a stirred solution of the product from (f) above (3.35 g, 13.9 mmol), ethanol (4.1 ml, 69.4 mmol) and 4-dimethylaminopyridine (1.7 g, 13.9 mmol) in dichloromethane (40 ml). After 18 hours at room temperature, glacial acetic acid (0.4 ml) was added and the reaction mixture stirred for a further 0.5 hour before being filtered. The residue obtained by evaporation of the filtrate under reduced pressure was partitioned between ether and water, then the organic phase washed successively with 1M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried (MgSO4) and evaporated under reduced pressure to give an oil (5.15 g), which was purified by chromatography on silica gel, using hexane:ether (4:1) as eluent, to furnish the required product (3.4 g) as a clear oil. Rf 0.30 (SS 4). m/e 270 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14])=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[NH:25][N:24]=[N:23][N:14]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccccc1NC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Cc1nnn[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 18.9 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[2-(cyanomethyl)phenyl]butanamide (15 g), sodium azide (14.85 g), ammonium chloride (12.22 g) and dimethylformamide (200 mL) was heated in a 130° C. oil bath under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, water (100 mL) was added and the product was extracted with ethylacetate (3×200 mL). The combined extracts were dried over Na2SO4, filtered and concentrated with a rotary evaporator. The brown residue was purified by high pressure liquid chromatography to give a white solid. The solid was triturated with diethyl ether to give 3.2 g of the title compound, m.p. 117°-178° C.
Reaction SMILES: [C:1]1([C:11]2([CH2:16][C:17]([NH2:19])=[NH:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[C:21]([O:25][C:26](=[O:41])/[C:27](/O)=[C:28](\[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)/[C:29](O)=[O:30])([CH3:24])([CH3:23])[CH3:22].C[O-].[Na+]>CO.CCCCCC.C(OCC)(=O)C>[C:21]([O:25][C:26]([C:27]1[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([OH:30])[N:19]=[C:17]([CH2:16][C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:18]=1)=[O:41])([CH3:24])([CH3:22])[CH3:23]
Reactant: N=C(N)CC1(c2cccc3ccccc23)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 48 %

Procedure:
To a stirred solution of 2-(1-naphthalen-1-yl-cyclopentyl)-acetamidine; hydrochloride (343) (4.5 g, crude) in methanol (30 mL) were added (E,Z)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (5.759 g, 18.7 mmol) and the reaction mixture was cooled to 0° C. in a ice bath. To this reaction mixture was then added sodium methoxide (25% in methanol, 10.1 mL, 46.74 mmol) and the reaction mixture was stirred at room temperature for 18 h (silica TLC, 50% ethyl acetate in hexane; Rf=0.5). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic phase was thereafter dried and concentrated under vacuum to get a crude mass which was purified by CombiFlash eluted with a gradient mixture of ethyl acetate and hexane to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (344) (4.1 g, 48%, 2 steps) as a brown sticky mass.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C([O-])(O)=O.[Na+]>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH:28]([CH3:29])[CH3:30])=[CH:32][CH:33]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(C(C)C)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of enantiomer A of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate, (41 mg, 0.11 mmol) in CH2CL2 (3 mL) was added (4-isopropylphenyl)acetic acid (98 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and DIEA (200 μL, 1.10 mmol). After stirring at room temperature for 18 h, the reaction mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated. Chromatography (10% EtOAc in Hexane) gave butyl 1-{(trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}indane-5-carboxylate. HPLC/MS: m/z=532.3 (M+1), Rt=3.15 min.