Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]([F:31])([O:9][C:10]([F:30])([O:15][C:16]([F:29])([F:28])[CH2:17][O:18][C:19](CCCCC(O)C)=[CH2:20])[C:11]([F:14])([F:13])[F:12])[C:5]([F:8])([F:7])[F:6].[F:34]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.N12CCCN=[C:57]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2>C1(C)C=CC=CC=1>[F:1][C:2]([F:33])([F:32])[O:3][C:4]([F:31])([O:9][C:10]([F:30])([O:15][C:16]([F:29])([F:28])[CH2:17][O:18][C:19]([CH2:52][CH2:53][CH2:54][CH2:55][CH:56]([F:34])[CH3:57])=[CH2:20])[C:11]([F:14])([F:13])[F:12])[C:5]([F:8])([F:7])[F:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=C(CCCCC(C)O)OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C(CCCCC(C)F)OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: -15 °C

Procedure:
Under a nitrogen atmosphere, (R)-8-(2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-7-hydroxyoct-1-ene (60 g, 0.103 mol) and dry toluene (120 mL) were added to an oven-dried flask with stirring. The resulting solution was cooled to -15° C., perfluorobutanesulfonyl fluoride (58.9 g, 0.185 mol) was added, and the resulting reaction mixture was stirred for 5 minutes. 1,8-Diazabicyclo[5.4.0]undec-7-ene (28.7 g, 0.189 mol) was then added at a rate so as not to exceed a temperature of 5° C. for the reaction mixture. The reaction mixture was stirred for 1 hour at ambient temperature and was quenched by the addition of toluene (120 mL) and water (60 mL). The resulting organic phase was separated from the resulting aqueous phase, and the aqueous phase was washed with toluene. The combined organic extracts were washed with 120 mL of 7 volume % HCl. The combined extracts were concentrated under reduced pressure (25 torr), and the resulting crude product was distilled (b.p. 58-° C. at 0.01 torr) to give 33.8 g of (S)-8-(2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-7-fluorooct-1-ene.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>C(OCC)(=O)C>[Cl-:1].[CH2:2]([C:12]1[S:11][CH:15]=[CH:14][NH+:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: c1cscn1
Solvent: CCOC(C)=O
Product: O=C(Cc1[nH+]ccs1)c1ccccc1
Product: [Cl-]
Temperature: 75 °C
Reaction time: 24 h

Procedure:
15.46 g (0.10 mol) of 2-chloroacetophenone was weighed out and dissolved in 60 ml ethyl acetate. The clear solution was heated to 75° C. and 4.4 ml (0.0624 mmol) thiazole was added drop wise with stirring. The resulting clear solution was then stirred under reflux for 3.5 hours and then allowed to stand under a nitrogen atmosphere for one day; the resulting suspension was filtered off under suction and dried in a high vacuum. Yield: 1.94 g (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2.[CH:24]([N-]C(C)C)(C)[CH3:25].[Li+].C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]([CH2:24][CH3:25])[C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(CC)C2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mmol of ethyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in tetrahydrofuran, and 50 mmol of lithium diisopropylamide followed by 50 mmol of ethyl iodide are added at -78° C. The mixture is heated to room temperature and stirred for 1 hour, and is worked up analogously to Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:18]([CH3:17])[CH2:19][CH2:20][OH:21])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: CNCCO
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(N(C)CCO)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of 2-(methylamino)ethanol and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. 2-((6-(4-Methoxyphenylamino)pyrimidin-4-yl)(methyl)amino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([CH2:21][CH3:22])[CH2:19][OH:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[O:20]=[CH:19][C@@H:18]([NH:17][C:16](=[O:23])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:21][CH3:22]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 32.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 126 mg, 0.283 mmol), (1S,2R)-2-phenylcyclohexanol (50.0 mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0 mL), to yield the title compound (55.7 mg, 33%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21])=[O:15])=[CH:8][CH:7]=[CH:6]2.[CH3:29][I:30]>CC(C)=O>[I-:30].[CH3:29][N+:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20](=[O:21])[NH:19][CH2:18][CH2:17][O:16][C:14](=[O:15])[CH:13]([CH3:28])[C:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:23]=1
Reactant: CI
Reactant: COc1ccc2c(C(C)C(=O)OCCNC(=O)c3cccnc3)cccc2c1
Solvent: CC(C)=O
Product: COc1ccc2c(C(C)C(=O)OCCNC(=O)c3ccc[n+](C)c3)cccc2c1
Product: [I-]

Procedure:
The quaternization of the naproxen ester prepared in Example 92 (1.0 g, 2.6 mmol) was carried out using methyl iodide (2.3 g, 16 mmol) in acetone (45 mL). The solution was heated to reflux for 20 hours. Methyl iodide (1.1 9, 8.0 mmol) was again added to the reaction flask. The precipitated product was filtered after an additional 4 hours of reaction time. The offwhite powder was dried. The material weighed 2.2 9 and was found to be analytically pure without recrystallization. The solvent was removed from the acetone filtrate and the residue was solidified with anhydrous ether. The resulting dark yellow powder was dissolved in water and washed with ether (4×30 mL). The water was then removed under vacuum giving 0.2 g of a lighter yellow powder. The overall yield of the reaction was 93%; mp 169°-170° C. The product had the structural formula ##STR125## as further confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([NH:23][C:24]2[N:29]=[C:28](SC#N)[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][N:25]=2)[CH:10]=1.C(N(CC)C(C)C)(C)C>C1COCC1.CCOC(C)=O>[C:18]([O:17][C:16](=[O:22])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][C:11]=1[NH:23][C:24]1[N:25]=[C:26]([NH:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[C:27]([N+:33]([O-:35])=[O:34])=[CH:28][N:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To the solution of 96 mg (0.95 mmol) of 4-amino-tetrahydropyran in 35 mL anhydrous THF was added 0.35 g (0.86 mmol) tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate, then 0.3 mL N,N-diisopropylethyl amine (1.7 mmol). The slightly cloudy mixture was stirred at room temperature for 3 hrs till HPLC showed the completion of reaction. The mixture became clear then. The reaction mixture was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 0.28 g (˜70% yield) orange-yellow solid as the crude product.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:6]2[CH2:5][NH:4][CH2:3]1)=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.O>ClCCl>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH2:9][C:10]4[C:15]([CH:6]3[CH2:5]2)=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=4)=[O:33])=[CH:30][CH:29]=1
Reactant: COc1cc2c(cc1OC)C1CNCC(=O)N1CC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)C1CN(C(=O)c3ccc(Cl)cc3)CC(=O)N1CC2
Yield: 99.9 %

Procedure:
To a solution of 2.62 g of (±)-4-oxo-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (I; R1 =H, R2 =R2 =OCH3) in 10 ml of dichloromethane was added 2 ml of triethylamine, and then 1.9 g of p-chlorobenzoyl chloride was slowly added 0°~5° C. The resultant mixture was stirred at 10° C. for 1.5 hours. To the reaction mixture was added water, and the organic layer was seperated. The organic extract was concentrated, and then the residue was triturated with ethyl acetate-ether to obtain 4.0 g (~100%) of the product, m.p. 139°~140° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(N(CC)CC)C>[C:1]([O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)CCl
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(=O)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a flask equipped with a stirrer was added 172.8 parts methacrylic acid and 202 parts triethylamine. This mixture was allowed to stir for 5 min. To this was added 245 parts ethyl chloroacetate. The reactants were heated to 60° C. and the exotherm carried the temperature up to 100° C. The temperature was kept between 90°-97° C. by cooling for 1/2 hour after which heat was supplied to hold the temperature at 90° for 1 hour. The mixture was cooled and filtered. This crude product was distilled at 65.5°-66° C. at 0.1 cm to yield 318 g of pure EMA as confirmed by chemical analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.C([Li])CCC.[CH:20]1[N:24]=[CH:23][N:22]2[CH2:25][CH2:26][C:27](=[O:28])[C:21]=12.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[OH:28][C:27]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]3)[C:21]2[N:22]([CH:23]=[N:24][CH:20]=2)[CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=C1CCn2cncc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 12.2 %

Procedure:
6-Bromo-2-naphthoic acid (1.51 g) was dissolved in dry THF (50 ml), and cooled to −100° C. in a liquid nitrogen/diethyl ether bath. Under stirring a solution (1.6M; 7.88 ml) of n-butyllithium in hexane was added dropwise at −95° C. or below over 5 min. After stirring at −100° C. for 30 min and at −80° C. for 10 min, the mixture was cooled to −100° C. again. A solution of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.61 g) in dry THF (11 ml) was added dropwise at −90° C. or below over 5 min. After stirring at the same temperature for 30 min, the temperature was raised to −70° C. over 30 min, and saturated aqueous ammonium chloride solution (25 ml) was added to quench the reaction. After stirring for 10 min, ethyl acetate (50 ml) was added to partition the solution. The organic layer was removed and the aqueous layer was concentrated to dryness. The obtained residue was purified by flash column chromatography, and the object fraction was dissolved in methanol. This solution was concentrated, ether was added to the precipitated powder and the powder was collected by filtration and dried. The title compound (180 mg) was obtained as a colorless powder. The mother liquor was concentrated to give a residue (449 mg) containing the title compound.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([Cl:48])[CH:43]=1>C1COCC1.O>[Cl:48][C:44]1[CH:43]=[C:42]([NH:41][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:32])[CH:47]=[CH:46][N:45]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(Cl)c1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.36 mmol) and triethylamine (55 μL, 0.8 mmol) were dissolved in THF (5 mL). At 0° C. triphosgene (48.5 mg, 0.16 mmol) was added and the reaction mixture stirred for 5 h at reflux. Then at ambient temperature 4-amino-2-chloropyridine (63 mg, 0.36 mmol) and triethylamine (55 μL, 0.8 mmol) were added. After stirring the reaction mixture at 50° C. over night water was added (20 mL) and the mixture extracted with ethyl acetate (3×15 mL). The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel; methylene chloride, methanol 100:0=>90:10) to yield the title compound (68 mg, 44%) as a yellow solid; MS: (ISP) 431.0 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:22]2[O:23][C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:26](=[O:28])[CH:27]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:22]2[O:23][C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:26](=[O:28])[CH:27]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of [4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-1-yl]-carbamic acid tert-butyl ester (3.25 g) in CH2Cl2 (25 ml) was added trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 18 hrs whereupon it was cooled (0° C.) and quenched by dropwise addition of saturated NaHCO3 until the pH 9 was attained. The mixture was then extracted using CH2Cl2 (3×20 mL), the combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a semi-crystalline solid that was applied onto a thin silica pad and eluted with EtOAc (100%) going to EtOAc:MeOH (9:1). The eluent was concentrated in vacuo to give the title compound as a mild amber oil (1.46 g, 56.4% over three steps) m/z (LC-MS, ESP): 393 [M+H]+, R/T=3.79 mins
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14](O)=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
To a solution of ethyl {3-chloro-4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]phenyl}acetate (0.60 g, 1.32 mmol) in DMF (6 ml), was added sodium carbonate (0.280 g, 2.65 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.460 g, 1.98 mmol). This was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the resulting brown solid was collected by filtration. This was purified by chromatography on silica gel eluting with 5-60% ethylacetate in hexane to give the title compound (0.258 g, 0.48 mmol). LC/MS: Rt=3.85, [MH]+ 536.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:26][OH:27].Cl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:26][OH:27])=[NH:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C#N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=N)NO)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile (0.2413 g, 0.72 mmol) in DMF (7 mL) was added NH2OH.HCl (0.1127 g, 1.44 mmol) and DIPEA (0.25 mL, 1.44 mmol), and stirred at 60° C. for 16 hours. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 66.1 mg (58%) of COMPOUND 286 as a yellow solid. 1H NMR (CD3OD) 1.70-1.87 (m, 4H), 2.15 (s, 6H), 2.36-2.58 (m, 3H), 3.71 (d, 2H), 3.82 (s, 4H), 7.19-7.24 (m, 2H), 7.53 (d, 2H, J=7.5 Hz), 8.25 (d, 2H, J=4.8 Hz). 13C NMR (CD3OD) δ 18.70, 28.15, 48.19, 55.78, 59.90, 124.62, 136.04, 140.60, 146.72, 158.48, 160.89. ES-MS m/z 369.3 (M+H). Anal. Calcd. for C20H28N6O.0.9H2O: C, 62.44; H, 7.81; N, 21.85. Found: C, 62.60; H, 7.82; N, 21.74.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[N:33](CC2C=CC=CC=2)[N:32]=[N:31][N:30]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C(OC(=O)[C@H](C)C[C@H](NC(C1N=NN(CC2C=CC=CC=2)N=1)=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:28])[CH2:11][C@@H:10]([CH3:41])[C:9]([OH:42])=[O:8])=[CH:15][CH:16]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnnn1Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn[nH]1)C(=O)O

Procedure:
A mixture of (2R,4S)-4-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester and (2R,4S)-4-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester (126 mg, 0.225 mmol) in MeOH is hydrogenated with 10% Pd/C for 6 h. The reaction mixture is concentrated and purified by reverse phase HPLC to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(1H-tetrazole-5-carbonyl)-amino]-pentanoic acid. HPLC Retention time 1.16 minutes (condition D); MS 380.0 (M+1);
Reaction SMILES: C(OC1C=CC([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=CC=1)C1C=CC=CC=1>CO>[CH3:20][C:18]1([CH3:21])[C:17](=[O:22])[C:16]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:15][O:19]1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(c2ccncc2)C1=O
Solvent: CO
Product: CC1(C)OC=C(c2ccncc2)C1=O
Reaction time: 1 h
Yield: 147983.3 %

Procedure:
To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 544-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 60%) as a solid.