Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:32][NH:33][S:34]([CH:37]1[CH2:39][CH2:38]1)(=[O:36])=[O:35].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:33]([CH3:32])[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)C1CC1
Reactant: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 70 °C

Procedure:
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (147 mg, 0.319 mmol; Example 202, Step B) and N-methylcyclopropanesulfonamide (129 mg, 0.958 mmol) were dissolved in toluene (2 mL). The mixture was evacuated and backfilled with argon (5×). Cyanomethylenetributylphosphorane (0.251 mL, 0.958 mmol) was added. The mixture was evacuated and backfilled with argon (5×). The mixture was heated at 70° C. for 2 hours. The mixture was loaded onto silica gel and the product was eluted with 5 to 75% ethyl acetate/hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29]O)[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:22][CH2:21][C:5]1[C:4]([CH2:29][N:35]2[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]2=[O:36])=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(CN4C(=O)c5ccccc5C4=O)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (210 mg, 0.49 mmol), phthalimide (144 mg, 0.98 mmol), and PPh3 (385 mg, 1.47 mmol) in THF (5 mL) was added DIAD (0.29 mL, 1.48 mmol) at 0° C., and then the mixture was stirred at room temperature for 3.5 h. The reaction was then concentrated and partially purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 6/4). A solution of the resulting residue and 4M HCl in dioxane (4 mL) in MeOH (10 mL) was stirred at room temperature for 0.5 h. The reaction mixture was poured into 5% aq. NaHCO3. The basic mixture was extracted with CH2Cl2. The organics extract was washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue which was purified by SiO2 column chromatography (heptane/EtOAc=6/4 to 3/7) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.95 (m, 5H), 7.59 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.06 (d, J=4.04 Hz, 1H), 6.90 (s, 1H), 5.08 (t, J=5.31 Hz, 1H), 4.91 (s, 2H), 4.85 (d, J=5.31 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=O.B.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([CH2:2][OH:1])[CH2:12][CH2:11]2
Reactant: COc1ccc2c(c1)CCC(=CO)C2=O
Agent: B
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(CO)C2
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Hydroxymethylene-6-methoxy-1-tetralone (2) (4.81 g, 0.024 mole) and borane:t-butylamine complex (10.25 g, 0.12 mole) were dissolved in about 250 mL of methylene chloride and the solution was cooled to about -78°. Boron trifluoride etherate (14.5 mL, 0.12 mole) was added dropwise and the mixture was stirred for about 1 hour then warmed to about 23° and stirred for an additional 2 hours. The reaction mixture was quenched with about 1N HCl and extracted with methylene chloride. The methylene chloride extracts were dried (MgSO4) and concentrated in vacuo. The crude oil was purified by flash chromatography [gradient 3:1 to 1:2 Hexanes:Ether] to yield the title compound as a light yellow oil (3.41 g, 0.018 mole, 75% yield): IR (Film) 3362, 2996, 2918, 1610, 1504, 1464, 1264, 1234, 1040 cm-1 ; 1H NMR (CDCl3) δ1.40 (m, 1H), 1.47 (s, 1H), 1.95 (m, 2H), 1.39,1.45 (d of d, J=10.6,16.1 Hz, 1H), 2.81 (m, 2H), 3.62 (d, J=6.3 HZ, 2H), 3.77 (s, 3H), 6.62 (d, J=2.6 Hz, 1H), 6.68 (d of d, J=8.4,2.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H); MS m/e 193 (MH+).
Reaction SMILES: FC(F)(F)C(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=O.[Br-:23].[Li+]>C1COCC1.C(#N)C>[Si:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][Br:23])=[CH:8][CH:9]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(COC(=O)C(F)(F)F)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1
Yield: 88 %

Procedure:
The benzyl trifluoroacetate 8 (17.9 g) was dissolved in dry THF, and dry lithium bromide (5.06 g) was added with stirring. The mixture was refluxed overnight, cooled, diluted with acetonitrile, and extracted three times with hexane. The hexane layers were combined, dried, filtered, and concentrated, thereby leaving the product 10 as a white oil in 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=O)[C:6](=[O:15])[N:7]2[CH:12]([CH3:14])[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH2:34][CH2:33]1)=[O:18])[C:6](=[O:15])[N:7]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Reactant: NCC1CCN(CC2(O)CCOCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c(C(=O)NCC2CCN(CC3(O)CCOCC3)CC2)cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (111 mg, 0.418 mmol, step 4 in preparation 1) in dichloromethane (1 mL) was added oxalyl chloride (0.11 mL, 1.26 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 0.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL), 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (191 mg, 0.837 mmol, step 2) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL), and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropanol to give 156 mg (78%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.BrCCCCCC[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][C:25]2[CH:24]=[CH:23][CH:22]=[C:19]3[C:20]([NH:16][C:17](=[O:26])[C:18]=23)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCSc3ccc(Cl)cc3)cccc21
Temperature: 90 °C
Reaction time: 23 h

Procedure:
4-Chlorothiophenol (2.89 g, 20 mmol), N-(6-bromohexyl)-phthalimide (6.20 g, 20 mmol) and K2CO3 (5.53 g, 40 mmol) were suspended in DMF (50 mL) under an atmosphere of argon and stirred at 90° C. for 23 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (100 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL), the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound, pure enough for further reactions.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.S(=O)(=O)(O)O.[F:22][C:23](I)([F:25])[F:24].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:22][C:23]([F:25])([F:24])[C:15]1[C:13]([NH2:14])=[N:12][C:10](=[O:11])[N:9]([CH:16]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: FC(F)(F)I
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 11 %

Procedure:
0.15 g (1.0 mmol) of 2′-deoxycytidine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl-2′-deoxycytidine (19F-NMR yield: 11%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethyl-2′-deoxycytidine was obtained as a white solid (0.01 g, yield: 3.3%) by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:3]3[C:2]([CH3:1])=[N:6][N:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:4]=3)=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 1 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H20N6O2 (m/e) 364, obsd 365 (M+H).
Reaction SMILES: C(=[N:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)=[CH:27][N:28]=[C:23]3[NH:22][C:21]2=[O:41])=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([C:29]4[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=4)=[CH:27][N:28]=[C:23]3[NH:22][C:21]2=[O:41])=[CH:17][CH:16]=1
Reactant: COc1cc(-c2cnc3[nH]c(=O)n(Cc4ccc(N=C(c5ccccc5)c5ccccc5)cc4)c3n2)cc(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]c(=O)n(Cc4ccc(N)cc4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
1-[4-(Benzhydrylideneamino)benzyl]-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (10 mg, 0.0175 mmol) was dissolved in THF (0.5 mL) and 4N aq. HCl (0.3 mL) was added. The mixture was stirred overnight at room temperature, concentrated under reduced pressure, and the resultant residue was purified by silica gel chromatography [EtOAc] to afford 1-(4-aminobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (1.8 mg, 20% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.90 (br, 1H), 8.32 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.19 (s, 2H), 6.62 (d, J=8.1 Hz, 2H), 5.08 (s, 2H), 3.99 (s, 6H), 3.92 (s, 3H). MS: 408.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]=[O:12])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of 1.10 g (4.0 mmol) tert-butyl N-(tert-butoxycarbonyl)-L-homoserinate (prepared according to J. Org. Chem. 1988, 53, 1900-1903) in dichloromethane (50 mL) was added pyridine (0.97 mL, 12.0 mmol), followed by 2.55 g Dess Martin periodinane (6.0 mmol), at room temperature. The mixture was stirred 90 min at room temperature prior to being diluted with ethyl acetate (40 mL). The mixture was washed with 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and then evaporated. The crude product (1.09 g, quantitative yield) was used immediately without further purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.[OH-].[Na+].Cl>O1CCCC1>[CH:30]1([N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:36])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was dissolved in tetrahydrofuran (1 mL) and 1N sodium hydroxide (1 mL) was added. Stirred at room temperature for 2 h then acidified with 1N hydrochloric acid. White precipitate filtered and dried to give the title compound (73 mg)
Reaction SMILES: [OH:1][P:2]([OH:5])([OH:4])=[O:3].O[P:7]([OH:10])([OH:9])=[O:8].[Ca+2].[P:12](=[O:16])(O)([OH:14])O.[P:17]([O-])([O-])([O-])=[O:18].[P]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:14][P:17]([O:9]3)([O:4]1)=[O:18])(=[O:16])[O:1]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [P]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
Concentrated superphosphate is manufactured by reacting thermal phosphoric acid with finely ground phosphate ore. The thermal phosphoric acid is made by burning elemental phosphorus to obtain P2O5 and combining P2O5 with water to make phosphoric acid. A porous monolithic mass is formed which is reduced to small sized particles for storage and completion of the chemical reactions. Electric furnace feedstock can be prepared by reducing the monolithic mass to a size suitable for smelting in electric furnaces. The P2O5 content of concentrated superphosphate fertilizer is in the range 48 to 50 percent.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][C:24]2([CH3:23])[CH2:27][O:26][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC1(N)COC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)COC1
Temperature: 100 °C
Yield: 38 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 47 mg, 0.159 mmol), 3-methyloxetan-3-amine (27.6 mg, 0.317 mmol; Synthonix, Wake Forest, N.C.), and DIPEA (83 μl, 0.476 mmol), heating at 100° C. for 2.5 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(2-methyl-3-((3-methyloxetan-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (s, 3H) 2.57 (s, 3H) 2.89 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 4.60 (d, J=6.26 Hz, 2H) 4.87 (d, J=6.26 Hz, 2H) 6.95 (br. s., 1H) 7.06 (d, J=2.35 Hz, 1H) 7.34-7.41 (m, 2H) 7.61 (dd, J=8.02, 1.37 Hz, 1H) 7.82 (dd, J=7.63, 1.37 Hz, 1H) 11.66 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][N:13]([CH3:15])[CH3:14]>[Fe].C(O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cc(N)ccc1Cl
Yield: 54.6 %

Procedure:
Iron (1.36 g, 21.9 mmol) and concentrated hydrochloric acid (0.15 mL) was added to ethanol/water (20 mL/20 mL), followed by refluxing for 1 hour. The mixed reaction solution was added with 1-(2-chloro-5-nitrophenyl)-N,N-dimethylmethanamine (940 mg, 4.38 mmol) obtained in <Step 1> above, and refluxed for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (chloroform:methanol=30:1→15:1 (v/v)) to obtain the title compound (442 mg, 55%).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]([N+]([O-])=O)=[CH:11][CH:12]=1)=[O:7])[CH3:4].[CH3:16][S-:17].[Na+].[NH4+].[Cl-]>CS(C)=O>[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]([S:17][CH3:16])=[CH:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])o1
Reactant: C[S-]
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(SC)o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-nitro-furan-2-carboxylic acid ethyl ester (5.00 g, 27.01 mmol) in DMSO (34.5 mL) was treated at rt with sodium methanethiolate (2.05 g 27.82 mmol). The mixture was then stirred at 100° C. overnight, cooled down to rt and treated with sat. aq. NH4Cl (250 mL). The aqueous layer was extracted with EA (3×100 mL). The combined org. extracts were washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound. TLC: rf (70:30 hept-EA)=0.52. LC-MS-conditions 02: tR=0.96 min; [M+AcCN+H]+=228.23.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:10]=[CH:11][C:12](O)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]3[NH:22][NH:21][C:12](=[O:13])[CH2:11]3)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=CC(=O)O)cc1OC1CCCC1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2CC(=O)NN2)cc1OC1CCCC1
Yield: 60.1 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxycinnamic acid (7.9 g, mmol) in toluene (25 ml) is added hydrazine hydrate (2.91 n-A, 60 mmol). The reaction mixture is heated to 100° (bath temperature) for 24 hours. Toluene is partially removed and ether carefully added, and the product allowed to crystallize. The solid is filtered to give crude product (6 g). A crystallization from chlorofom-hexane gives the pure product (5 g) m.p. 185°-186°. 1H NMR (CDCl3) δ 7.02 (1H, s, NH--CO), 6.88 (3H, m, arom), 4.79 (2H, m, carbinolic and benzylic), 4.28 (1H, m, NH), 3.84 (3H, s, CH3O--), 2.79 (2H, d, --CH2CO), 1.9 (5H, m, cyclopentyl C-H), 1.61 (3H, m, cyclopentyl C-H); IR(KBr),3420,3220,3160,2960,1700,1660 cm-1 ; MS m/z 276 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=2[F:16])[C:6](=[O:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].NC1N(C2C(F)=CC(OCCCCCI)=CC=2F)C(=O)C=CC=1C(=O)C1C=CC(F)=CC=1F>CC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:16])=[CH:10][C:11]([O:15][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:12][C:13]=2[F:14])[C:6](=[O:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(O)cc1F
Reactant: ClCCCCCBr
Agent: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCI)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Temperature: 70 °C

Procedure:
To a solution of 6-amino-5-(2,4-difluorobenzoyl)-1-(2,6-difluoro-4-hydroxyphenyl)-pyridin-2(1H)-one (300 mg, 0.79 mmol) in acetone (6 ml) under an atmosphere of nitrogen was added 1-bromo-5-chloropentane (0.115 ml, 0.87 mmol, 1.1 eq), sodium iodide (238 mg, 1.59 mmol, 2 eq) and potassium carbonate (438 mg, 3.17 mmol, 4 eq). The mixture was heated at 70° C. for 16 hours, before being allowed to cool to room temperature and partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (30% EtOAc in heptane) afforded a 3:2 mixture of the title compound and 6-amino-1-{4-[(5-iodopentyl)oxy]-2,6-difluorophenyl}-5-(2,4-difluorobenzoyl)pyridin-2(1H)-one (142 mg) which was used without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-(5-indanoxy)benzaldehyde (6.2 g) in ethanol (100 mL) was added a solution of semicarbazide hydrochloride (3.2 g) and sodium acetate (2.3 g) in water (50 mL) at room temperature. The mixture was stirred for 1 h, and the resulting solid was collected by filtration, washed with water (3×100 mL) and dried in vacuo to yield the title compound as a pale yellow solid (7.5 g, 97%), mp: 218-220° C. 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 7.24 (d, J=8.1, 1H), 6.94 (d, J=8.7, 2H), 6.92 (s, 1H), 6.82 (d, J=8.1, 1H), 6.45 (s, 2H), 2.84 (t, J=7.5, 4H), 2.05 (m, 2H).