Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH2:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([CH:14]=[CH:15][CH2:16][OH:17])=[CH:12][CH:11]=1)[CH3:5].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>C([O-])(=O)C.[Na+].CCCCCC>[C:23]([O:17][CH2:16][CH:15]=[CH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:4][CH3:5])=[CH:19][CH:18]=1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: CCOCCOc1ccc(C=CCO)cc1
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1
Yield: 90.7 %

Procedure:
36 Milliliters of dichloromethane was added to 12 g of 4-[(1-ethoxy)ethoxy]cinnamyl alcohol, then 60 mg of anhydrous sodium acetate was added thereto. Under refluxing condition, 5 g of diketene was added dropwise to the reaction mixture, and 2 hours later, 0.42 g diketene was further added thereto, the whole reaction mixture was refluxed for 1.5 hours. After the reaction was completed, the dichloromethane was removed by evaporation under reduced pressure, and the residue thus obtained was stirred for 30 minutes with 27 ml of hexane and 1.2 g of activated carbon. The activated carbon was removed by filtration, and the filtrate was concentrated to obtain 15 g of 4-[(1-ethoxy)ethoxy]cinnamyl acetoacetate as in the form of an oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].O[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(#N)C>CCOCC>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:27][CH2:28][NH:29][C:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:31])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C(NCCO)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A reaction of indomethacin (1.79 g, 5.00 mmol) and the product of Example 91 (0.830 g, 5.00 mmol) was carried out, using dicyclohexylcarbodiimide (1.10 g, 5.50 mmol) as the coupling agent and acetonitrile as the solvent. The first two reactants were dissolved completely and the solution was then cooled to 0° C. The dicyclohexylcarbodiimide was added and the mixture was stirred overnight. The reaction was allowed to continue for 48 hours. The precipitate (1.2 g) was removed by vacuum filtration. The solvent was removed from the filtrate under reduced pressure leaving an oily residue. The product was solidified by stirring with anhydrous ether. It was filtered, air-dried and recrystallized from ethanol/ether. The final product was vacuum filtered, washed with ether, and air dried. The product weighed 1.65 g, giving a 65.2% yield: mp 123°-125° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][OH:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: OCc1ccc2c(c1)CCCN2
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCCc2cc(CO)ccc21
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (314 mg) in methanol (4 ml) was dropwise added acetic anhydride (589 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and ethyl acetate and saturated sodium bicarbonate solution was added to the residue. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:2, V/V) to give 1-acetyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (227 mg) as powder.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH:14]=[CH2:15])[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C([O-])(O)=O.[Na+]>[OH:3][CH2:4][C@@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:14]=[CH2:15]
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (4S)-2,2-dimethyl-4-vinyl-1,3-oxazolidine-3-carboxylate (1.90 g, 8.36 mmol) in methanol (83 mL) was added p-toluenesulfonic acid monohydrate (0.80 g, 4.2 mmol) at 0° C. The mixture was slowly warmed to room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution, concentrated, and then diluted with ethyl acetate. The organic layer was washed with sat. NaHCO3 (2×) and brine, dried over Na2SO4, filtered and concentrated to give the desired product as colorless oil (1.187 g, 76%). 1H NMR (400 MHz, CDCl3) δ 5.81 (1H, m), 5.25 (2H, m), 4.90 (1H, m), 4.25 (1H, br s), 3.67 (2H, m), 1.45 (9H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(s1)CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2sccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21](F)=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:8]1>CO>[NH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([O:2][CH3:1])=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:8]1
Reactant: NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 86 h

Procedure:
To a solution of sodium methoxide prepare from sodium (0.2 g) and absolute methanol (9 ml) was added 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was stirred for 86 hours at 140° to 150° C. and then concentrated. Small amount of water was added to the residue, and the solution was adjusted pH 7 with acetic acid and then concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from methanol to give the title compound (40 mg) as pale yellow prisms, mp 225°-228.5° C. (decompd.).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][C:5]=1[O:16][CH3:17].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([C:8]=1[CH3:15])=[CH:6][C:5]([O:16][CH3:17])=[C:4]([OH:3])[CH:13]=2
Reactant: COc1cc2c(C)cc(=O)oc2cc1O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2c(C)c(Br)c(=O)oc2cc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A bromine (2.55 g, 15.96 mmol) solution in acetic acid (8 mL) was added dropwise to a stirred suspension of 7-hydroxy-6-methoxy-4-methyl-chromen-2-one (3.20 g, 15.5 mmol) in glacial acetic acid (31 mL) at room temperature. The mixture was stirred for 10 min, then poured onto crushed ice (400 mL). To the resultant, light, yellow suspension, 1 mL of saturated sodium bisulphite solution was added and the mixture was allowed to reach room temperature. The precipitated solids were filtered off, washed with water, dried and recrystallized from glacial acetic acid. The obtained white powder (3.39 g, 11.88 mmol, 76%) was used without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH3:12])C1C=CC=CC=1.C(Cl)Cl>Br.C(O)(=O)C>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:33])[C@H:11]([CH3:12])[N:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
110 g (0.24 M) of (S)-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate are dissolved in 400 ml of 30-33% hydrogen bromide solution in glacial acetic acid. 30 ml of methylene chloride are added thereto, the mixture is stirred at room temperature for 45 minutes, concentrated, treated with water and extracted 2-3 times with ether. The aqueous solution is cooled in ice, neutralised with solid sodium bicarbonate, extracted with methylene chloride, dried over sodium sulphate, filtered and concentrated. The residue is treated with 50 ml of glacial acetic acid and 500 ml of toluene. The mixture is heated to reflux for 15 to 20 minutes and evaporated. The residual oil is dissolved in methylene chloride and the solution obtained is washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The residue is dissolved in 400 ml of benzene and seeded with rac-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one. The mixture is left to stand at room temperature overnight, 2 g of racemate crystallising out. The mother liquor is concentrated and treated with ether. By crystallisation from ether there is obtained (S)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 130°-134° C.; [α]25D =+377.2° (in methylene chloride; 1%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([C:8](=[O:16])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1.Cl[CH2:20][C:21]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:22]>CN(C)C=O>[O:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][NH:23][C:21]([CH2:20][O:3][C:4]2[CH:18]=[CH:17][C:7]([C:8](=[O:16])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=2)=[O:22])[CH2:31][CH2:30]1
Reactant: O=C(CCl)NCCN1CCOCC1
Reactant: CCOC(=O)NCC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCC(=O)c1ccc(OCC(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
31 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 156 mg of ethyl N-(p-hydroxyphenacyl)carbamate (prepared as described in Preparation 6) dissolved in 10 ml of dimethylformamide. The mixture was then stirred at room temperature for 30 minute, after which 200 mg of 2-chloro-N-(2-morpholinoethyl)acetamide were added, and the mixture was stirred at 100° to 110° C. for 4 hours. The reaction mixture was then poured into ice-water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with ethyl acetate, to give 190 mg of the title compound as pale yellow needles melting at 133°-135° C.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH2:5]O.CCOCC.P(Br)(Br)[Br:18]>N1C=CC=CC=1>[Br:18][CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(C)=CCCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC(C)=CCCBr
Temperature: 25 °C

Procedure:
A solution of 3 g. of 4-methyl-3-nonen-1-ol in a mixture of 20 ml. of ether and 1.25 ml. of pyridine under nitrogen is cooled in an ice-salt bath and stirred while 2.7 ml. of phosphorus tribromide is added slowly. The ice bath is removed and the mixture is allowed to warm to room temperature, then is heated under reflux for about 2.5 hrs. The mixture is then cooled in an ice bath while 10 ml. of water is added slowly. The layers are separated and the ether layer is washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated, giving a residue comprising 1-bromo-4-methyl-3-nonene.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[O:66]=[C:67]([N:80]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:109]=[CH:108][C:107]([C:110]6[NH:114][C:113]([C@@H:115]7[CH2:119][CH2:118][CH2:117][NH:116]7)=[N:112][CH:111]=6)=[CH:106][CH:105]=5)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[CH2:87][C:82]2([O:86][CH2:85][CH2:84][O:83]2)[CH2:81]1)[C@@H:68]([NH:75][C:76](=[O:79])[O:77][CH3:78])[CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1.Cl>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:114][C:110]([C:107]2[CH:108]=[CH:109][C:104]([C:99]3[CH:98]=[CH:97][C:96]4[C:101](=[CH:102][CH:103]=[C:94]([C:91]5[NH:90][C:89]([C@@H:88]6[CH2:87][C:82]7([O:83][CH2:84][CH2:85][O:86]7)[CH2:81][N:80]6[C:67](=[O:66])[C@@H:68]([NH:75][C:76]([O:77][CH3:78])=[O:79])[CH:69]6[CH2:74][CH2:73][O:72][CH2:71][CH2:70]6)=[N:93][CH:92]=5)[CH:95]=4)[CH:100]=3)=[CH:105][CH:106]=2)=[CH:111][N:112]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-oxo-2-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt. MS (ESI) m/z 923.83 [M+H]. (73 mg, 77%).
Reaction SMILES: [C:1]([O:4][CH2:5]Cl)(=[O:3])[CH3:2].[I-].[Na+].[CH:9](=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].C(=O)([O-])[O-].[K+].[K+].C(OCI)(=O)C>CC(C)=O.O>[C:1]([O:4][CH2:5][O:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[CH:9]=[O:17])(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)OCCl
Agent: CC(=O)OCI
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCOc1ccccc1C=O
Reaction time: 24 h
Yield: 81.3 %

Procedure:
20 g (185 mmol) of chloromethyl acetate is dissolved in acetone, to which 35 g (230 mmol) of sodium iodide is added. After stirring for 24 hours, 14.8 g (138 mmol) of salicylaldehyde and 38.20 g (276 mmol) of potassium carbonate are dissolved in 100 mL of acetone. The mixture is stirred at room temperature and freshly prepared suspension of iodomethyl acetate is added. After stirring for 24 hours at 50° C., water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then concentrated. The residue is purified by silica gel chromatography and eluted with a heptane/ethyl acetate mixture, 7/3. 21.79 g of 2-acetoxymethoxy-benzaldehyde is obtained in the form of a yellow oil at a yield of 98%.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)[nH]n1
Yield: 52.8 %

Procedure:
Hydrazine hydrate (0.300 mL, 6.18 mmol) was added to a stirring room temperature solution of 67 (0.1.7484 g, 6.18 mmol) in EtOH (6.2 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (40 min): Upon cooling, a white crystalline solid precipitated from the reaction. The solid was separated by filtration, washed with EtOH, and dried to obtain pure 68 (0.9092 g, 52.7%): 1H (CDCl3, 300 MHz): δ 12.44 (1H, broad s), 7.21 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.1 Hz), 6.58 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.93 (2H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz) ppm. Partial 13C (CDCl3, 75 MHz): δ 139.12, 131.93, 129.67, 128.50, 106.49, 60.94, 34.72, 14.20 ppm. HPLC: 10.269 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: COc1cccc(F)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(F)c1Br
Temperature: -78 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-Bromo-3-fluoro anisole (10 g, 48.77 mmol) was dissolved in DCM (200 mL) and cooled to about −78° C. To the solution was added BBr3 (11.53 mL, 121.9 mmol) in one portion. The mixture was warmed to r.t. and stirred overnight. The mixture was partitioned between water and DCM (50 mL), and the aqueous layer was back extracted with DCM (200 mL). The combined organics were dried (NaSO4), filtered and concentrated to give about 9.32 g of the product as a dark oil. MS found 188.9 (M−1)
Reaction SMILES: C([O:4][C@@H:5]([C@H:21]([O:37]C(=O)C)[C@H:22]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[C@H:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:14]([O:13][C@@H:6]([C@H:5]([OH:4])[C@@H:21]([OH:37])[C@H:22]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(C[C@@H](OCc1ccccc1)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CC(OC)OC)OCc1ccccc1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(C[C@@H](OCc1ccccc1)[C@H](O)[C@@H](O)[C@@H](CC(OC)OC)OCc1ccccc1)OC
Yield: 90.9 %

Procedure:
To 100 ml of methanol were added 9.76 g (17.4 mM) of (3R,4R,5R,6R) 4,5-diacetoxy-3,6-dibenzyloxy- 1,1,8,8-tetramethoxyoctane [20] obtained via the same route as described above and 6.17 g (43.5 mM) of potassium carbonate. The mixture was heated for 2 hours under reflux while stirring. After it was confirmed by thin layer chromatography that the reaction was completed, the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with diethyl ether. After the extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 7.55 g (15.8 mM) of (3R,4R,5R,6R) 3,6-dibenzyloxy-1,1,8,8-tetramethoxyoctane-4,5-diol [21]. Yield, 91%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of intermediate 6, ethyl 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (0.300 g, 0.91 mmol) in ethanol (10 ml) was treated with 3 ml (3.0 mmol) of 1 N sodium hydroxide and stirred at 25° C. for 30 min. The solution was then acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.264 g (96% yield) of the title acid as white crystals; mp 171° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 4.03 (2H, t, J=5.3 Hz, CH2), 4.12 (2H, t, J=5.3 Hz, CH2), 4.73 (2H, s, OCH2), 5.53 (2H, s, OCH2), 7.35-7.42 (3H, m, aromatics), 7.53 (2H, m, aromatics). Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.35; H, 4.69; N, 9.10.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.O1CCOCC1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1C=CC=CC=1>[CH3:22][S:23]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CS(=O)(=O)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
N-Hydroxysuccinimide (11.5 g) and triethylamine (14.0 ml) are suspended into a mixture of benzene (100 ml) and dioxane (50 ml), and thereto is added dropwise a solution of methanesulfonyl chloride (7.8 ml) in benzene (20 ml) with stirring under ice-cooling and the mixture is stirred for 1 hour. After allowing to stand overnight, the solvent is distilled off. To the residue is added water and the resulting crystals are separated by filtration, washed with water and dried to give N-methanesulfonyloxysuccinimide (6.3 g), melting point: 148°-150° C. The product is recrystallized from ethyl acetate-petroleum ether to give crystals having a melting point of 150°-152° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)[CH2:3]1.[CH:35](O)=[O:36].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:30]1([N:27]2[CH2:28][CH2:29][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:10]4[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][CH:35]=[O:36])[CH2:3]5)[N:9]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: O=CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ncc(N2CCC[C@@H](NC=O)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added formic acid (20 μL, 0.5 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (105 mg, 0.2 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.3 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-formamidopiperidin-1-yl)pyrazine-2-carboxamide (437), as HCl salt (24 mg). LC-MS (ESI): m/z (M+1) 492.7. UV: λ=267, 276, 305, 335, 372 nm. Proton NMR (CD3OD): δ 8.06 (1H, s), 7.65 (1H, s), 7.58 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H, m), 3.93 (1H, m), 3.71 (2H, d, J=12.0 Hz), 3.54 (1H, m), 3.46 (1H, m), 3.38 (1H, m), 3.12 (2H, m), 2.86 (1H, m), 2.22-1.66 (16H, m) ppm.