Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C:11]([CH2:28]C)([CH3:27])[CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:16]=2[N:17]=1)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1>O1CCCC1>[CH3:9][C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([CH:22]([F:40])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:16]=2[N:17]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(C)(CC)Cc1nc2cc(CC(=O)OC)ccc2o1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 3.85 ml, 0.0077 mol) was added dropwise to a solution of methyl [2-(2,2-diethylpropyl)benzoxazol-5-yl]acetate (2.0 g, 0.0077 mol) in tetrahydrofuran (40 ml) at −78° C. under a nitrogen atmosphere and the mixture was stirred at −78° C. for 1 hour. A solution of N-fluorobenzenesulfonimide (2.42 g, 0.0077 mol) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture allowed to warm to room temperature over a period of 20 hours. The reaction mixture was diluted with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 5:95, and was further purified by column chromatography on silica gel, eluting with ethyl acetate:hexane 1:3, to give methyl [2-(2,2-dimethylpropyl)benzoxazol-5-yl]fluoroacetate (1.4 g).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)[CH2:3][C:4](OCC)=[O:5].[Cl-].[OH:32][NH3+:33].[OH-].[Na+].Cl>O1CCOCC1>[OH:32][NH:33][C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:11]=1
Reactant: [NH3+]O
Reactant: CCOC(=O)CC(=O)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(CC(=O)NO)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-oxo-4-(4-((2-phenoxybenzyl)oxy)phenyl)butanoate (40 mg) in 1,4-dioxan (0.12 ml), 9 mg of hydroxylammonium chloride and 0.1 ml of 2.5N sodium hydroxide were added under ice-cooling, and the reaction solution was stirred at 0° C. for 1.5 hours. Concentrated hydrochloric acid (0.07 ml) was further added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was extracted with chloroform, the combined organic layers were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., hexane/ethyl acetate (1:1) to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].CC(CCC[C@H](CCC[C@H](CCC/C(=C/CO)/C)C)C)C>>[CH3:1][C:2]([C:9]#[C:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: CC(=O)CCC=C(C)C#CCC(C)=CCCC(C)C

Procedure:
A mixture of 155 mg (0.965 mmole) of 2-chloromethyl-6-methyl-1-heptene and 1-chloro-2,6-dimethyl-2-heptene (produced in accordance with Example XVII), 137 mg (1.01 mmoles) of 6-methyl-5-octen-7-yn-2-one (produced in accordance with Example II), 223 mg (1.61 mmoles) of anhydrous potassium carbonate, 20 mg (0.20 mmole) of cuprous chloride, and 23 mg (0.10 mmole) of benzyltriethylammonium chloride in 1.00 mL of acetonitrile (HPLC-grade) was stirred vigorously at room temperature for 20 hours, during which time the mixture was maintained under a nitrogen atmosphere. Isolation of the product in the manner described in the procedure of Example III afforded, after fractional evaporative distillation, 184 mg (73% yield) of the two named unsaturated ketones: boiling point 122°-138° C. (bath temperature, 0.25 mm). The proton NMR spectrum of 6-methyl-10-[4-methylpentyl]-5,10-undecadien-7-yn-2-one exhibited a doublet (J=6.6Hz) at δ0.88 [6H's, (CH3)2C], a singlet at δ1.79 (vinyl CH3 bonded to C-6), a singlet at δ2.13 (CH3C=O), a singlet at δ2.97 (two hydrogens bonded to C-9), two singlets at δ4.78 and 5.00 (two vinyl H's, C=CH2), and a triplet at δ5.65 (vinyl H bonded to C-5). The presence of 6,10,14-trimethyl-5,10-pentadecadien-7-yn-2-one as the other compound in the product mixture was indicated by two triplets at δ5.35 and 5.15 (vinyl H bonded to C-11, Z and E stereoisomers) on the proton NMR spectrum. There is no need to separate these two C-18 unsaturated ketones, since catalytic hydrogenation (H2 /Pd-C in ethanol) will yield the same product in both cases: 6,10,14-trimethyl-2-pentadecanone. The latter ketone has previously been converted to phytol by F. G. Fischer and K. Lowenberg [Ann., 475, 183 (1929)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2O.C(NC(C)C)(C)C.[Cl:23]CCCl>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: ClCCCl
Reactant: COc1cc2ncnc(O)c2cc1OC
Solvent: CC(C)NC(C)C
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 6,7-Dimethoxy-quinazolin-4-ol (1.65 g, 8.0 mmol) and phosporousoxychloride (1.52 ml, 16.4 mmol) in 1,2-dichloroethane (16 ml) was added diisopropylamine (3.48 ml, 20 mmol) in a dropwise fashion. The mixture was then heated to 80° C. under an inert atmosphere for 16 hours. After this time the reaction was cooled to room temperature and concentrated in vacuo to dryness, dissolved in CH2Cl2 (50 ml) and washed with sodium bicarbonate solution (5% aqueous, 2*25 ml). The organic layer was separated, dried using MgSO4, filtered and concentrated in vacuo to give a brown residue that was purified by flash chromatography (SiO2) eluted with CH2Cl2:EtOAc—2:98 then 5:95 to give the title compound (1.6 g, 88.9%) as a yellow solid. m/z (LC-MS, ESP): 207 [M+H]+, R/T=3.51 mins
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]2[CH2:28][CH2:27][CH2:26][CH:25]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:24]1([C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C1=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
The mixture of 2-(2-cyclopent-1-enyl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (131) (560 mg, 1.43 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (132) as a pale yellow solid (518 mg, 100%).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12](#[N:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:12]([CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])#[N:21]
Reactant: N#CCCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
920 mg sodium (40 mmole) is dissolved in 45 ml ethanol and to the ice-bath cooled solution is added 4.66 g diethyl oxalate (31.9 mmole) and 4.17 g hydrocinnamonitrile (31.9 mmole). The mixture is stirred at room temperature for 1 hour, under reflux for 3 hours, and then allowed to stand at room temperature overnight. Evaporation, acidification of the residue, and extraction with methylene chloride affords ethyl 3-cyano-2-oxo-4-phenylbutanoate in 38% yield. The compound crystallizes from petroleum ether in colorless needles; m.p. 80°-83° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1cn(N)c2cnccc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2ccncc21
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 3-methyl-pyrrolo[2,3-c]pyridin-1-yl amine (467 mg, 3.18 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (683 g, 3.18 mmol), HATU (1.45 g, 3.81 mmol), DIPEA (1.23 g 9.54 mmol) in DMF (10 mL) is stirred at 1500 C. for 1 h. The reaction is quenched with water, and NaHCO3 (320 mg, 3.81 mmol) and EtOAC are added. The resulting solid is collected by filtration and then triturated with hot water. The mixture is filtered again and the solid is dried under vacuum to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (484 mg). MS: 345 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.24 (s, 1H), 8.79 (d, 2H), 8.65 (d, 1H), 8.21 (d, 1H), 8.05 (t, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 2.88 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 4-bromophenol (2.2 g, 12.7 mmol) and 4-bromo-1,1,1-trifluorobutane (2.4 g, 12.7 mmol) in anhydrous DMF (15 mL) was added K2CO3 (3.5 g, 25.4 mmol). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc (120 mL) and the solids were removed by filtration. The filtrate was washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 11A (3.05 g, 85%) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:26])([F:25])[C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:20](OCC)=[O:21])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:26][C:8]([F:7])([F:25])[C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][OH:21])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nc(-c2cccc(C(F)(F)F)c2)cs1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (50 mL) of lithium aluminum hydride (710 mg, 19 mmol) in tetrahydrofuran was added dropwise a solution (40 mL) of the compound (5.6 g, 19 mmol) obtained in Example 190a in tetrahydrofuran, and the mixture was stirred at 0° C. for 3 hr. After confirmation of the termination of the reaction by TLC, sodium sulfate 10 hydrate was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The resulting salt was removed and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (1.2 g, 25%) as an orange oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC#N>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:31][CH2:32]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)Cn1ccc2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Yield: 59.4 %

Procedure:
To a solution of methyl 2-(5-(methylsulfonamido)-1H-indol-1-yl)acetate (1.8 g, 6.38 mmol) (prepared in an analogous manner as described in, Example 14, Scheme 14, Steps 1, 2, 3) in CH3CN (30 ml), K2CO3 (1.762 g, 12.75 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.186 g, 6.38 mmol) were added, and the mixture heated to reflux for 3 hours. The solvent was removed and the residue was purified by flash chromatography on silica gel (DCM/MeOH 99:1 to 97:3) recovering methyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetate (1.5 g, 3.79 mmol, 59.5% yield, UPLC-MS purity: 96%, MS/ESI+ 396.2 [MH]+).
Reaction SMILES: Br[CH2:2][C:3]1([NH:6][C:7]([NH:9][C@@:10]([C:25]2[CH:30]=[C:29]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:28]=[C:27]([F:38])[CH:26]=2)([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4]1.[C-:39]#[N:40].[Na+]>CS(C)=O>[C:39]([CH2:2][C:3]1([NH:6][C:7]([NH:9][C@@:10]([C:25]2[CH:30]=[C:29]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:28]=[C:27]([F:38])[CH:26]=2)([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4]1)#[N:40]
Reactant: O=C(NC1(CBr)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.3 %

Procedure:
To a solution of (R)-1-(1-(bromomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (8 mg, 0.013 mmol) in DMSO (0.3 mL) was added NaCN (18 mg, 0.37 mmol) and KI (20 mg, 0.12 mmol). The reaction mixture was stirred at rt for 3 days. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Phenomenex AXIA Luna column, 30×100 mm, flow rate 40 mL/min, 30-100% ACN/H2O/0.1% TFA over 12 min) to yield (R)-1-(1-(cyanomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (Example 242, 5 mg, 63% yield). LCMS: RT=3.88 min [M+H]548.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.76-0.91 (m, 4H), 2.58 (qt, J=17 Hz, 2H), 3.78 (qt, J=12 Hz, 2H), 5.49 (s, 1H), 5.52 (s, 1H), 5.87 (t, J=53 Hz, 1H), 6.66 (d, J=6.6 Hz, 2H), 6.84-6.95 (m, 3H), 6.96-7.07 (m, 2H), 7.07-7.26 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (1.5 g), 4-chlorothiophenol (1.63 g) and potassium carbonate (1.56 g) in toluene (15 ml) was stirred at 70° C. for 5 hours. Ethyl acetate and water were added, and the organic layer was separated, washed with water, dried and evaporated to dryness. The residue was washed with toluene to give yellow crystals of 3'-(4-chlorophenylthio)-4'-nitroacetophenone (1.9 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:52])([CH3:51])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:39]([F:50])[CH:38]=1)[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12]>ClCCl>[CH3:51][C:9]([CH3:8])([CH3:52])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:39]([F:50])[CH:38]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:12]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)O)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (2 mL) was added dropwise over 5 min to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hexanoate (876 mg, 1.41 mmol) in anhydrous dichloromethane (6 mL) under nitrogen at 20° C. The solution was stirred for 16 h and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure (twice). Purification by flash chromatography (eluting with hexane:ethyl acetate:acetic acid=75:25:1) gave the title compound as a yellow gum (784 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCCCCc1ccccc1
Yield: 28 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 5-phenyl-1-pentanol (56 mg, 0.34 mmol) as the coupling partner. Chromatography (gradient 5–95% ethyl acetate/hexane) through SiO2 yielded 6 mg (28%) of the titled compound. ESI-MS m/z 438 (MH+), 436 (M−H−).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:38])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)[C@H](C)O)c(F)cc43)c(C)c2C1=O
Yield: 40.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b as starting materials to obtain (S,Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 8 (28 mg, yield 40.8%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([NH:19][CH2:30][CH3:31])[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CCI
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1cc(C#N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 140 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl) -1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μL, 1.2 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3:1:4 afforded 6 mg (38%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 7.80 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.12 (br, s, 1H), 3.26 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([F:16])[CH:9]=1.[BH4-].[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5])=[C:10]([F:16])[CH:9]=1
Reactant: CC(N)CCO
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(CCO)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 3-aminobutan-1-ol (1.8 g, 20.2 mmol), 4-bromo-2-fluorobenzaldehyde (4.1 g, 20.2 mmol), and ZnCl2 (28 mg, 0.202 mmol) in MeOH (20 mL) was stirred at ambient temperature for 1 hour. To the mixture at 0° C. was added NaBH4 (3.84 g, 101 mmol) and stirred at ambient temperature for 22 hours. The reaction mixture was quenched with H2O and extracted with EtOAc (30 mL×4). The extracts were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleumn ether/EtOAc (5/1) and EtOAc/NEt3 (500/1) as eluting solvents to afford 3-(4-bromo-2-fluorobenzylamino)butan-1-ol as corlorless oil (3.2 g, 57%). 1H-NMR (500 MHz, CDCl3) δ 7.25-7.20 (m, 3H), 3.90 (d, 1H), 3.87-3.83 (m, 1H), 3.77-3.173 (m, 2H), 3.00-2.93 (m, 2H), 1.77-1.71 (m, 1H), 1.59-1.52 (m, 1H), 1.20 (d, 3H); LCMS (ESI): m/z=276.1 [M+H]+.