Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[O:12][CH3:13].Cl.C(N=C=N[CH2:20][CH2:21][CH2:22][N:23](C)C)C.C(O[CH2:30][CH3:31])(=O)C>>[CH2:4]([C:5]1([CH2:8][CH2:30][CH3:31])[CH2:20][CH2:21][CH:22]([NH:23][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(C)=O
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: Cl
Product: CCCC1(CCC)CCC(NC(=O)Cc2ccc(O)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4,4-Dipropyl-2-cyclohexenone (2.0 g) was dissolved in ethanol (20 ml), 10% palladium/carbon (200 mg) was added to the solution, and the mixture was hydrogenated at 25° C. The catalyst was removed by filtration from the reaction mixture, and the solvent was removed in vacuo to give 4,4-dipropylcyclohexanone. The product was dissolved in methanol/water=1/1 (20 ml). Hydroxylamine hydrochloride (1.55 g) and sodium acetate (1.83 g) were added to the solution, and the mixture was stirred with heating at 50° C. for 12 hours. After removing the methanol in vacuo, the residue was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.4 g of 4,4-dipropylcyclohexanone oxime. A solution of the product in tetrahydrofuran (10 ml) was added dropwise to a solution of lithium aluminium hydride (420 mg) in tetrahydrofuran (10 ml) under ice-cooling, and the mixture was stirred. After 3 hours, the reaction was quenched by adding water (0.42 ml), 15% aqueous sodium hydroxide (0.42 ml), and then water (1.26 ml) dropwise to the reaction mixture. The precipitate was filtered off and then the solvent was removed in vacuo. The residue was dissolved in 2 mol/l aqueous hydrochloric acid, washed with diethyl ether, basified with 2 mol/l aqueous sodium hydroxide, and then extracted with chloroform. The organic layer was concentrated under reduced pressure to give 165 mg of 4,4-dipropylcyclohexylamine. The product (100 mg) was dissolved in ethyl acetate (5 ml), and 4-hydroxy-3-methoxyphenyacetic acid (100 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg) were added to the solution, and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was washed with water and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 120 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccsc1Br
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 230 mg (1 mmol) methyl (2-bromothiophene-3-yl)acetate and 310 mg (1 mmol) 4-iodo-3-nitrobenzoyl chloride in 15 mL of dry CH2Cl2 was added 432 mg of AlCl3 (4 mmol) in four portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography. (Hex/EtOAc=1:5) to give 310 mg of product as a light yellow solid (yield 60%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]=[C:20]=NC2CCCCC2)CCCCC1.O=C1C2C=CC=CC=2C(=O)N1CCCS(OCC(C)(C)[C@@H](OCC1C=CC=CC=1)C(O)=O)(=O)=O.CNC>ClCCl.O1CCCC1>[CH3:13][N:19]([CH3:20])[C:10](=[O:12])[CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)COCc1ccccc1
Agent: CC(C)(COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O)[C@@H](OCc1ccccc1)C(=O)O
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Adapting procedures or variations thereof according to Benington et al., J. Org. Chem. 1961, 26, 194-197; and Griffiths et al., Tetrahedron, 1997, 53(52), 17815-17822, a 250 mL round-bottomed flask equipped with a magnetic stirring bar and rubber septum was charged with 1.22 mL (1.41 g, 8.51 mmol) of 2-(phenylmethoxy)acetic acid. The acid was dissolved in 30 mL of anhydrous dichloromethane (DCM). To the solution was added 1.86 g (9.0 mmol) of dicyclohexylcarbodiimide (DCC) and the reaction mixture was stirred for two hours at room temperature. Twenty (20) mL (40 mmol) of a two molar (2 M) solution of dimethyl amine (Me2NH) in tetrahydrofuran was added and the mixture stirred overnight at room temperature. The precipitated dicyclohexyl urea (DCU) was filtered off and the solvents removed under reduced pressure using a rotary evaporator. The residue was diluted with ethyl acetate (EtOAc) and the solution filtered again to remove residual DCU. The solution was washed successively with one molar (1.0 M) hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvent removed under reduced pressure using a rotary evaporator to yield a brown solid. Final purification by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:9) provided 1.08 g (65% yield) of the title compound (36a). Rf=0.30 (EtOAc/Hxn=1:9). 1H NMR (400 MHz, CDCl3): δ=2.97 (s, 3H), 2.99 (s, 3H), 4.18 (s, 2H), 4.62 (s, 2H), 7.28-7.37 (m, 5H) ppm. MS (ESI) m/z: 194.1 (M+H)+, 216.1 (M+Na)+. The analytical data was consistent with the proposed structure and the data in the literature.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=[O:14].CN1CCC[C:17]1=[O:21].[CH:22]1(C=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1CCC[C@H]1C(O)=O>O>[CH:22]1([C@H:13]([OH:14])[C@H:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:17]=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CN1CCCC1=O
Reactant: O=CC1CCCCC1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O
Product: O=C[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (2.04 g, 10.7 mmol) was dissolved into a minimal amount of anhydrous N-methylpyrrolidinone (5.0 mL). Heating was required for full dissolution. The solution was cooled to rt and cyclohexanecarboxaldehyde (5.60 g, 50 mmol) was added. The solution was cooled to 0° C. and solid L-proline (0.40 g, 3.4 mmol) was added in one portion. The reaction was stirred for 1 h at 0° C. and the orange mixture was stored in the refrigerator (6° C.) for 36 h. The crude reaction was taken up in 5:1 Et2O/Hexanes (100 mL) and water (20 mL). The layers were separated and the aqueous phase mixture was extracted with 5:1 Et2O/Hexanes (3×10 mL). The combined organic layers were washed with water (5×10 mL) and brine (3×10 mL), dried over Na2SO4, decanted and stripped to give crude (2S,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropanal (4.55 g), which was used in the next step without purification.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([NH:6][NH:7][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (1 g, 0.008M) in toluene (30 ml) at room temperature was added dropwise a 50% aqueous solution of sodium hydroxide (0.64 g, 0.008M). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (1.12 g, 0.008 M) in toluene (5 ml) and a solution of aqueous 50% sodium hydroxide (0.64 g, 0.008 M) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction was diluted with hexane and the solid N'-t-butyl-N-benzoylhydrazine was isolated by filtration.
Reaction SMILES: [C:1]([C:3]1([OH:16])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[CH:2].[C:17]1(O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:16]1[C:3]2([C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:1]=[CH:2][C:24]2[CH:23]=[CH:22][C:21]3[C:26]([C:25]1=2)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: Oc1cccc2ccccc12
Reactant: C#CC1(O)c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1=CC2(Oc3c1ccc1ccccc31)c1ccccc1-c1ccccc12

Procedure:
3.09 g of 9-ethynyl-9-fluorenol (15 mmoles) and 2.49 g of 1-naphthol (17.25 mmoles) were dissolved under reflux in 30 ml of anhydrous toluene in an inert atmosphere. 0.03 g of PTSA was then added. The reaction mixture was refluxed in an inert atmosphere for 2 hours 30 minutes. On returning to room temperature, the mixture was poured onto an aqueous 10% caustic soda solution. After decanting, the aqueous phase was continuously extracted with dichloromethane. The organic phases were combined and dried over magnesium sulphate. The solvent was removed under reduced pressure. The compound was precipitated out with hexane then recrystallised from toluene.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[CH2:11]([O:14][CH2:15]CCO)[CH:12]=[CH2:13].C([N:21]([CH2:24][CH3:25])CC)C>ClCCl>[CH2:11]([O:14][CH2:15][CH2:25][CH:24]=[N:21][OH:3])[CH:12]=[CH2:13]
Reactant: C=CCOCCCO
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOCCC=NO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution containing oxalyl chloride (5.45 mL) in dichloromethane (130 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution containing dimethyl sulfoxide (4.85 mL) in dichloromethane (5 mL) was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for 10 minutes, a solution containing 3-allyloxy-propan-1-ol (4.99 g) in dichloromethane (5 mL) was added dropwise to the reaction solution. After stirring at the same temperature for one hour, triethylamine (20.4 mL) was added to the reaction solution. The cooling bath was removed. The reaction solution was warmed to room temperature and stirred at room temperature for one hour. Saturated aqueous ammonium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (100 mL) and water (10 mL). Sodium acetate (12 g) and hydroxylamine sulfate (8.02 g) were added to the reaction solution at room temperature. The reaction solution was stirred at room temperature for 15 hours. Then, a saturated sodium chloride solution and ethyl acetate were added and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride again. The organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (5.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:54])[CH2:21][N:22]([C@@H:43]([CH3:53])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)C([C@@H]2CCCN2S(C2C=CC3C(=CC=CC=3)C=2)(=O)=O)=O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO.O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:54])[CH2:21][NH:22][C@@H:43]([CH3:53])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@H](C)N(C[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)C(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Yield: 68.6 %

Procedure:
2.61 g of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)-N-((2S)-1-(2-naphthylsulfonyl)-pyrrolidine-2-carbonyl)amino]ethyl}carbostyril are dissolved in 100 ml of methanol, and 35 ml of 1N potassium hydroxide-methanol and 10 ml of water are added thereto. The mixture is refluxed for 3 hours with stirring. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized twice from ethyl acetate. 1.1 g of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril are obtained as colorless needles. Yield: 68.8%.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[C:22]1([C:28]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:32][CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([C:28]2[C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:32][C:31]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(-c2nccnc2-c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCOCCCC
Solvent: O
Product: c1ccc(-c2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
First, 5.5 mL of a dibutyl ether solution of phenyl lithium (manufactured by Wako Pure Chemical Industries, Ltd., 2.1 mol/L) and 50 mL of diethyl ether were mixed under a nitrogen atmosphere. Then, 2.43 g of 2,3-diphenylpyrazine was dropped into this solution while the solution was being cooled, with ice, and the mixture was stirred at room temperature for 24 hours. Water was added to the mixture, and the organic layer was extracted with diethyl ether. The extracted organic layer was washed with water and dried with magnesium sulfate. After the drying, an excess amount of activated manganese dioxide was added to the organic layer, and the mixture was filtered. After the solvent of the solution was distilled off, the obtained residue was recrystallized with ethanol to give a pyrazine derivative, Htppr (a yellow powder, 56% yield). The synthetic scheme of Step 1 is represented by (a-1) below.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[O:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[N:17]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[O:10][C:9]=1[C:7]1[S:8][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2nc3ccncc3o2)s1
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 2-(5-nitrothiophen-2-yl)oxazolo[5,4-c]pyridine (170 mg, 0.69 mmol), NH4Cl (199 mg, 3.73 mmol), iron powder (328 mg, 5.87 mmol), H2O (10 mL) and methanol (40 mL) was heated to reflux for 6 hrs under N2. The mixture was concentrated in vacuo followed by addition of 100 mL of water and left overnight at 4° C. The precipitate was collected by filtration and dried to give 5-(oxazolo[5,4-c]pyridin-2-yl)thiophen-2-amine as a brown solid (52 mg, yield 35%). 1HNMR (400 MHz, DMSO-d6) δ: 8.84 (1H, s); 8.40 (1H, d, J=5.2); 7.64 (1H, d, J=4); 7.57 (1H, d, J=5.2), 7.06 (2H, s), 1.09 (1H, d, J=4.4).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[N:14]1([C:20]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a stirred solution of tert-butyl 1-piperazinecarboxylate (2.50 g, 13.42 mmol) in CH2Cl2 (75 mL) cooled in an ice-water bath was added 4-morpholinecarbonyl chloride (1.57 mL, 13.42 mmol) followed by Et3N (3.74 mL, 26.84 mmol), and the reaction mixture was allowed to warm to room temperature. After 15 h, the reaction mixture was washed with 1.0 N HCl (50 mL), saturated NaHCO3 (75 mL), and brie (50 mL), dried, and concentrated to give the title compound (3.80 g, 95%) as a white solid. Mp: 171-173° C. 1H NMR: δ3.69 (t, J=4.9 Hz, 4H, CH2OCH2), 3.46-3.40 (m, 4H, CH2NCH2), 3.28 (t, J=4.9 Hz, 4H, CH2NCH2), 3.25-3.20 (m, 4H, CH2CH2), 1.47 (s, 9H, t-Bu). MS (DCI/CH4): m/z (rel itensity) 300 (MH+, 73), 272 (28), 244 (100), 200 (73). Anal. (C14H25N3O4): C, H, N.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[CH2:3]1>C(OCC)(=O)C.CO.[Pt]=O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[CH2:3][C:4]2=[O:14])=[CH:9][CH:8]=1
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(=O)c2cc(N)ccc21
Yield: 194.1 %

Procedure:
3,3-Dimethyl-6-nitro-indan-1-one (22.2 g, 54.1 mmol) and platinum oxide (0.44 g, 1.94 mmol) in 30 mL of ethyl acetate and 60 mL of methanol was hydrogenated on a Parr Shaker for 40 min. The mixture was filtered through a pad of celite. The filtrate was evaporated and the residue was triturated with hexane to give 18.4 g (97% yield) of the title product as yellow solids; 1H-NMR (CDCl3) δ 1.38 (s, 6H), 2.56 (s, 2H), 6.98 (d, J=2.3 Hz, 1H), 7.02 (dd, J=2.3, 8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H); MS m/e 176 (MH+).
Reaction SMILES: [NH2:1][C:2](=[N:45][C:46]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:47])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH2:41][CH2:42][OH:43])[C:33]=2[F:44])[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:76](O)(=[O:78])[CH3:77]>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[C:76]([O:43][CH2:42][CH2:41][O:40][C:34]1[C:33]([F:44])=[C:32]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:45][C:46]([O:48][CH2:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:47])=[CH:8][CH:7]=2)[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)(=[O:78])[CH3:77]
Reactant: CC(=O)O
Reactant: CCC(CC)C(=O)OCOc1nc([C@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)OCOc1nc([C@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-ethylbutanoic acid 5-{(R)-(4-{amino[2,2-dimethylpropoxycarbonylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester (37 mg), DMAP (0.6 mg), and triethylamine (0.056 mL) were dissolved in DMF (2.5 mL) and dichloromethane (2.5 mL). To the solution, a mixture of TFFH (26.5 mg), acetic acid (0.00576 mL), and dichloromethane (3 mL) was slowly added, and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, ice, THF, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous ammonium chloride solution were added to the residue obtained, and the resulting mixture was extracted with the mixture of THF and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product of the captioned compound.
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=O)(C)(C)C.Cl[C:16]1[C:20]([S:21]([CH2:24][CH3:25])(=O)=O)=[N:19][S:18][N:17]=1.I[CH2:27][CH2:28]CC>C1COCC1.O.CN(C=O)C>[CH2:24]([S:21][C:20]1[C:16]([O:14][CH:12]2[CH2:11][NH:10][CH2:13]2)=[N:17][S:18][N:19]=1)[CH2:25][CH2:27][CH3:28]
Reactant: CC(C)(C)NC(=O)N1CC(O)C1
Reactant: CCS(=O)(=O)c1nsnc1Cl
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1nsnc1OC1CNC1
Temperature: 8 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (0.24 g, 0.006 mol) in THF (30 mL) was treated with 1-t-butylcarbamoyl-3-hydroxyazetidine (1.6 g, 0.0092 mol), and the reaction stirred 1 h. After cooling to 8° C., 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1.96 g, 0.0092 mol) in THF (5 mL) was added, the reaction stirred 30 min, cooling removed for 30 min, and the reaction heated to 35° C. for 45 min. Heating was removed, the reaction stirred overnight, and the solvent evaporated. The residue was suspended in cold water, the mixture extracted with EtOAc, the extracts washed with brine, dried, and the solvent evaporated to give a tan liquid, (2.98 g). A DMF (30 mL) solution of the liquid was treated with freshly ground flaked Na2S-9H2O (3.3 g, 0.0138 mol). After 1 h, 1-iodobutane (2.1 mL) was added, the reaction stirred 2 h, diluted with cold water, and extracted with ether. The ether was dried, the solvent evaporated, the residue dissolved in EtOAc, and the solution treated with a stream of dry HCl for 5 min. After 1 h, the reaction was treated with icewater and the organic solvent evaporated. The aqueous solution was extracted with ether, made basic, and extracted with EtOAc. The EtOAc extracts were dried and the solvent evaporated to give a tan liquid that was purified by radial chromatography (10% EtOH-1% NH4OH-CHCl3). The HCl salt (0.41 g) crystallized from EtOAc, m.p. 138-139° C. (Compound 51).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 124.8 %

Procedure:
A solution of 3-(Trifluoromethyl)phenol (2.0 g, 12.34 mmol), 4-Fluorobenzaldehyde (2.0 g, 16.11 mmol), and Cs2CO3 (5.0 g, 15.35 mmol) in N,N-Dimethylformamide (DMF) (20 mL) was heated at 100° C. for 2 h, then cooled to rt. The solid suspension was removed by filtration over silica pad, and concentrated to afford crude title product (4.1 g) as a yellow liquid. LC-MS (ESI): m/z 267 [M+H]+; 3.60 min (ret time).