Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:44](=[O:62])[CH:45]=[C:46]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)CCC>>[Br:61][C:58]1[CH:59]=[C:60]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:46]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)[CH:45]=[C:44]2[OH:62]
Reactant: CCCCOC(=O)C=C(Nc1ccc(Br)cc1)c1cccc(F)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 250 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a 3 L three-neck flask, equipped with mechanical stirrer, Claisen adapter holding a thermocouple probe and reflux condenser with nitrogen inlet was added 0.75 L of Dowtherm A (a eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide) and the solvent was heated to 250° C. To this was cautiously added in small portions 77.0 grams (0.215 moles) of 3-(4bromo-phenylamino)-3-(3-fluorophenyl)-acrylic acid butyl ester over the course of 0.25 hours. The mixture was maintained at 250° C. for 1.5 hours and then allowed to cool to 90° C. over the course of 2 hours. The mixture was treated with 1.0 L of hexanes, and allowed to cool to room temperature while stirring overnight. The tan solids were collected by suction filtration and washed with three 0.15 L portions of hexanes. The solids were dried under vacuum at 50° C. overnight to yield 58.63 grams (96.0%) of the title compound.
Reaction SMILES: [N+:1](/[CH:4]=[C:5](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH3:6])([O-:3])=[O:2].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])([O-:3])=[O:2]
Reactant: C/C(=C\[N+](=O)[O-])c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C[N+](=O)[O-])c1ccccc1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
In a 10 mL Schlenk-flask, 6.8 mg of cuprous tert-butoxide and 37.3 mg of (S)-p-tol-BINAP were dissolved in 5 ml of toluene. After stirring for 30 minutes at room temperature to give an asymmetric copper complex. One hundred microliters (100 μL) of this solution (containing 1 μmol of the asymmetric copper complex) were mixed with 4.9 ml of toluene, and 90 μL (1.5 mmol) of poly(methylhydrosiloxane) (15-40 mPas (20° C.), d=1.004 g/mL, nD20=1.398, produced by Fluka) and 221 mg (1.2 mmol) of diphenylsilane were added thereto. After stirring for 5 minutes, 1 mmol of (E)-1-nitro-2-phenyl-1-propene was added, and the mixture was further stirred for 24 hours at room temperature. Four milliliters (4 mL) of a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L) were added to the reaction mixture and stirring was continued for 3 hours. Water was added and the mixture was extracted with diethyl ether (30 mL×2). After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide optically active 1-nitro-2-phenylpropane.
Reaction SMILES: N[C:2]1[C:3]([O:29][CH3:30])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:37]>O>[CH2:12]([N:9]1[CH2:8][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:6]2[C:11](=[C:2]([Cl:37])[C:3]([O:29][CH3:30])=[CH:4][CH:5]=2)[CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3N)cc1OC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC

Procedure:
##STR57## 2.02 g of 8-amino-2-benzyl-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 20% hydrochloric acid; and to the solution was added dropwise a solution of 0.38 g of sodium nitrite in 1.9 ml of water, under cooling. To the mixture was added dropwise a solution of 0.55 g of cuprous chloride in 11 ml of 20% hydrochloric acid. After the reaction was over, 4.84 g of sodium hydroxide was added to the mixture, and the mixture was extracted with chloroform 2 times. The chloroform layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, giving 1.23 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, m.p. 88°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16]([O:18]CC)=O)=[O:5].[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16](=[O:18])[N:27]([CH3:28])[CH3:26])=[O:5]
Reactant: CCOC(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CNC
Product: CN(C)C(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
The original compound (II) can be prepared by ammonolysis, aminolysis, or by ester exchange from, for example, 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-ethoxycarbonylmethylene)hydrazine (IIa) [Japanese Patent Kokai 101396/1974]. For example, IIa is reacted with dimethylamine to give 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-dimethylcarbamoylmethylene)hydrazine (IIb): ##STR20## Still, another original compound (II), in particular 1-(2-benzoyl-4-chlorophenyl)-2-(1-amino-1-dimethylcarbamoyllmethylene)hydrazine (IIc) is prepared as follows: ##STR21## Thus, the compound (IIc) is prepared by reacting a diazonium salt of 2-amino-5-chlorobenzophenone with the compound (XIV), brominating the resulting compound (XI) and treating with aqueous ammonia; or reacting a diazonium salt of 2-amino-5-chlorobenzophenone with the compound (XV) and treating the resulting product (XIII) with aqueous ammonia.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH3:5][C:4](=[O:6])[CH2:3][CH2:2][CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(C)=O
Temperature: 95 °C
Yield: 95 %

Procedure:
To a 2 L two-necked round bottom flask equipped with water condenser, calcium chloride guard tube and mechanical stirrer, 100 g of 2,4-pentanedione, 600 g of 1-bromooctadecane, 10 g of 18-crown-6, anhydrous potassium carbonate 125 g and 550 ml of absolute ethanol were added with stirring. The mixture was refluxed at 95° C. with continuous stirring for 24 hrs, after refluxing at the said temperature, the mixture was cooled to ambient temperature (25° C.), 550 ml of water was added to it and the 2-heneicosanone was extracted with dichloromethane from the mixture. On distillation of dichloromethane, 2-heneicosanone was obtained.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.O>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)CCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1-Chloro-4-(4-chlorophenyl)-2-butanone (110 g.) was added portionwise over half an hour to a stirred suspension of imidazole (175 g) in dimethylformamide (150 ml) at 0° C. and the mixture stirred overnight at ambient temperature. The resulting solution was poured into water (1500 ml) with seeding at the first sign of turbidity, and the precipitate filtered off and washed well with water and hexane. Chromatography of the product on silica gel (1 Kg.), eluting with 7% methanol in methylene chloride gave 100 g of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]([N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C@:20]([CH2:23][CH2:24][CH2:25][CH3:26])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[NH:10][CH2:11][CH2:12][Cl:13])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C@:20]([CH2:23][CH2:24][CH2:25][CH3:26])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[N:10]([CH2:11][CH2:12][Cl:13])[N:1]=[O:3])([CH3:6])[CH3:7]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Yield: 62.3 %

Procedure:
Sodium nitrite (0.74 g) was slowly added to a solution of 3-isopropyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.43 g, 8.96 mmol), obtained in the above way, in 40% aqueous acetic acid with well stirring at 0° to 5° C. After continuation of stirring for four hours at the same temperature, an ion exchange resin (13 ml, the same type as used in Example 65) was added to the resulting solution, and the mixture was stirred for 30 minutes. The ion exchange resin was filtered off, and the filtrate was vacuum-concentrated at 25° C. and purified by column chromotography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1). Thus, 2.39 g of 3-isopropyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 64.8%, m.p. 70°-72 C., [α]D20 +69.8° (C 1.0, methanol).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=1[CH3:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][S:6][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:15]([CH3:22])[CH:16]=1)#[N:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1csc(Br)c1-c1ccc(C#N)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of ethyl 3-(5-bromo-4-(4-cyano-2-methylphenyl)thiophen-3-yl)propanoate (35 mg, 0.09 mmol), 4-methoxyphenylboronic acid (16 mg, 0.10 mmol), Na2CO3 (19 mg, 0.18 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in a mixture of dioxane and H2O (5 mL, 4:1) was stirred at 100° C. overnight under nitrogen. The mixture was neutralized to pH=5, and extracted with EtOAc. The organic layer was concentrated, and purified by preparative TLC to give 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, yield 86%) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11](O)[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:23])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CSc1nc(O)cc(-c2ccccc2)n1
Product: CCOC(=O)CSc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
A solution of 18.0 g of (4-hydroxy-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester in 200 ml. of phosphorus oxychloride was heated under reflux for 17 hr. The excess phosphorus oxychloride was removed in a rotary evaporator. The residual oil crystallized on standing. Recrystallization from petroleum ether afforded 8.7 g of the title compound, mp. 82°-84°C.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][O:13][S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCOc1ccc(-n2ccnc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)OCCOc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.0 g (0.074 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol in 100 mL of N,N-dimethylformamide (DMF) was added 3.8 g (0.1 mol) of sodium hydride (60% oil dispersion) portionwise and the mixture was stirred at ambient temperature for 3 h. To this mixture was added 13.7 g (0.1 mol) of dimethylsulfamoyl chloride and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 1.2 L of water and its pH was adjusted to 10 with sodium carbonate. The mixture was extracted with three 400-mL portions of ethyl acetate. The combined organic layers were washed twice with 400-mL portions of water, dried (MgSO4), and the solvent was evaporated under reduced pressure to give a viscous residue. The residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500 A; PrepPAK 500 silica; ethyl acetate; flow rate 150 mL/min). Fractions containing the product were combined and the solvent was evaporated under reduced pressure to give the title compound, a viscous oil. The oil was converted to the hydrochloride (2-propanol; ethereal HCl) and the white solid was collected by filtration to yield 5.9 g (26%), mp 120°-123° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:12][C:13]2[C:18]([N:19]=1)=[C:17]([NH2:20])[N:16]=[CH:15][N:14]=2.Br[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:20][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[C:18]=1[N:19]=[C:11]([S:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[I:1])[N:12]2[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)NCCCBr
Reactant: COc1ccc(I)c(Sc2nc3c(N)ncnc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(I)c(Sc2nc3c(N)ncnc3n2CCCNC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of 8-((2-iodo-5-methoxyphenyl)thio)-9H-purin-6-amine (200 mg, 0.5 mmol) in DMF (3 mL) was added N-(3-bromopropyl)pivalamide (445 mg, 2 mmol) and Cs2CO3 (326 mg, 1 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS64 as a white solid (53 mg, 20%). 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.43 (br s, 1H), 6.66 (s, 1H), 6.50 (d, J=8.7 Hz, 1H), 5.86 (br s, 2H), 4.20 (t, J=6.1 Hz, 2H), 3.61 (s, 3H), 2.78 (m, 2H), 1.82 (m, 2H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.8, 160.5, 155.0, 153.2, 152.0, 145.0, 140.6, 137.7, 120.1, 117.2, 115.4, 88.4, 55.5, 40.7, 38.8, 34.8, 29.1, 27.7; HRMS (ESI) m/z [M+H]+ calcd. for C20H26IN6O2S, 541.0883. found 541.0898.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[O:33])[CH2:31][CH2:30]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and cyclopropanecarbonyl chloride in the same manner as in Example 32.
Reaction SMILES: [CH:1]1[C:2]2[C:15]3=[CH:16][C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([OH:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.CO.O.C([O-])(=O)C.[Mg+2:33].C([O-])(=O)C.C([O-])(=O)C>O>[CH:1]1[C:2]2[C:15]3=[CH:16][C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([O-:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([O-:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.[Mg+2:33]
Reactant: O=C1N[C@@H]2C(=C[C@H](O)[C@H]3OP(=O)(O)O[C@H]32)c2cc3c(c(O)c21)OCO3
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: O=C1N[C@@H]2C(=C[C@H](O)[C@H]3OP(=O)([O-])O[C@H]32)c2cc3c(c([O-])c21)OCO3
Reaction time: 72 h

Procedure:
To a mixture of phosphoric acid (3b, 50 mg, 0.135 mmol) and methanol-water (3:2) was added a solution of magnesium acetate (15 mg, 0.0675 mmol. 0.5 equiv) in water (1 ml). The mixture became opaque immediately upon addition of the metal acetate and was stirred for 3 days while further precipitation occurred. The solution was concentrated to a white residue and water-methanol was added (1.4 ml). The precipitate was collected and dried; grey solid, m.p. 210° C. dec. very insoluble in water, soluble in DMSO; 1H-NMR (DMSO-d6, 300 MHz) δ 13.69 (s, 1H), 8.73 (s, 1H), 6.99 (s, 1H), 6.43 (s, 1H), 6.14 (m, 1H), 6.05 (s, 2H), 5.82 (bs, 1H), 4.41-4.31 (m, 2H), 4.03-3.95 (m, 2H). Each of the divalent cation salts proved to be only sparingly soluble in water.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
29.0 g (0.111 mol) of 7-amino-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 200 ml of acetic acid. A spatula tip of 4-(N,N-dimethylamino)pyridine was added and then 11.4 g (0.111 mol) of acetic anhydride were added dropwise. The mixture was stirred at room temperature for 30 minutes and then poured into ice-water, and the precipitate was filtered off with suction and dried to yield 22.5 g (67%) of the product.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH:8]([CH3:10])[CH3:9])[C:3](OCC)=[O:4].Cl.[NH2:13][C:14](N)=[NH:15].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:15][C:14]1[O:1][C:2]([CH:8]([CH3:10])[CH3:9])([CH3:11])[C:3](=[O:4])[N:13]=1
Reactant: CCOC(=O)C(C)(O)C(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)C1(C)OC(N)=NC1=O

Procedure:
A mixture of ethyl 2-hydroxy-2,3-dimethylbutanoate (2.92 g, 18.2 mmol), guanidine hydrochloride (1.74 g, 18.2 mmol), and K2CO3 (2.52 g, 18.2 mmol) in 99.5% ethanol (40 mL) was stirred under reflux for 20 h. The solvent was removed, and the residue was purified by silica gel flash chromatography (ethyl acetate/methanol 9:1) to give the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][O:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:23]2[CH2:24][CH2:25][C:20]3([CH2:17][O:18][CH2:19]3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CC2(CCN1)COC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCC3(CC2)COC3)cc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.26 g, 1.04 mmol), triethylamine (0.21 mL, 2.07 mmol) and 2-oxa-7-azaspiro[3.5]nonane (0.50 g, 2.07 mmol) in THF (20 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate was concentrated under reduced pressure. The resultant residue was loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in MeOH to afford the title compound (0.30 g, 97%). 1H NMR (CDCl3, 300 MHz): 7.47-7.41 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 4.40 (s, 4H), 3.45-3.40 (m, 2H), 2.38-2.28 (s, 2H), 1.92-1.86 (s, 4H). LCMS (Method B): RT=1.89 min, M+H+=296/298.
Reaction SMILES: C(OC(=O)[NH:7][S:8]([O:11][CH2:12][C@@H:13]1[CH2:17][C@@H:16]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C@H:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[C:21]=3[CH:20]=[CH:19]2)[CH2:15][C@@H:14]1[OH:37])(=[O:10])=[O:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[S:8](=[O:10])(=[O:9])([O:11][CH2:12][C@@H:13]1[CH2:17][C@@H:16]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C@H:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[C:21]=3[CH:20]=[CH:19]2)[CH2:15][C@@H:14]1[OH:37])[NH2:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
tert-Butyl{[((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate (31.0 mg, 0.0570 mmol) was dissolved in DCM (0.803 mL) and trifluoroacetic acid (0.803 mL, 10.4 mmol) was added. The solution was stirred at rt for 15 min before being concentrated in vacuo. The residue was taken up in MeOH (5.00 mL), treated with solid sodium bicarbonate (300 mg) and stirred for 10 min. Filtration and silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (7.20 mg, 58%). 1H NMR (400 MHz, CD3OD, δ): 8.17 (s, 1H), 7.27-7.14 (m, 5H), 6.64 (d, J=3.5 Hz, 1H), 5.86 (t, J=7.5 Hz, 1H), 5.49-5.42 (m, 1H), 4.51-4.48 (m, 1H), 4.38 (dd, J=7.5, 9.8 Hz, 1H), 4.21 (dd, J=7.3, 9.8 Hz, 1H), 3.10-3.03 (m, 1H), 2.97-2.88 (m, 1H), 2.86-2.76 (m, 1H), 2.68-2.60 (m, 1H), 2.37-2.21 (m, 3H), 2.08-1.97 (m, 2H) ppm. LC/MS: Rt=1.16 min, ES+ 444 (FA standard).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH2:17])([O-])=O>CCO.[Pd]>[F:15][C:13]([F:14])([F:16])[S:10]([C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:17])=[CH:6][CH:7]=1)(=[O:11])=[O:12]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1N

Procedure:
Dissolve 2-nitro-4-trifluoromethylsulfonyl-phenylamine (530 mg) in EtOH (50 mL) and hydrogenate over Pd/C (10%) for 6 hours. Filter the mixture and concentrate the filtrate in vacuo to obtain 4-trifluoromethylsulfonyl-benzene-1,2-diamine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[CH:8]=[CH:7][N:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:10]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccnc(OCC(F)(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccnc(OCC(F)(F)F)c1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (0.52 g, a white solid) from 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethanone (0.47 g, 2.14 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.