Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Br)c1
Temperature: 80 °C

Procedure:
A mixture of 2.13 g (10 mmol) of N-(4-acetylphenyl)methanesulfonamide, 1.78 g (10 mmol) of N-bromosuccinimide and 0.28 g of dibenzoyl peroxide in 100 ml of carbon tetrachloride is heated for 16 hrs at 80° C. (oil bath). The resulting product is concentrated and extracted with methylene chloride. The extract is deposited on silica gel and chromatographed with 1% methanol-methylene chloride to give a product which is recrystallized from methylene chloride-pet. ether; m.p. 124°-126° C. MW 292.17.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([OH:23])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 2-iodopropane (0.826 mL, 8.26 mmol), 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (2.00 g, 7.51 mmol), and K2CO3 (1.56 g, 11.3 mmol) in DMF (20 mL) was heated to 60° C. overnight. Additional 2-iodopropane (0.9 mL) and K2CO3 (0.9 g) were added. The resulting mixture was heated to 50° C. for 4 days, then cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography with 50-70% EtOAc in hexanes to give a yellow syrup (2.0 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1 H) 7.03 (d, J=1.01 Hz, 1H) 4.90-5.05 (m, 1 H) 4.58-4.66 (m, 1 H) 3.81-3.88 (m, 1 H) 3.67-3.77 (m 1 H) 3.21 (dd, J=16.42, 9.60 Hz, 1 H) 2.94 (dd, J=16.42, 7.07 Hz, 1 H) 1.60 (s, 9 H) 1.32-1.34 (m, 6 H); LCMS for C17H24O5 m/z 253.00 (M-tBu+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9]([Cl:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
470 mg (1.71 mmol) of (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid were dissolved in 8 ml of dichloromethane, and a drop of DMF was added. At 0° C., 1.7 ml (3.42 mmol) of oxalyl chloride were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was evaporated under reduced pressure and the residue obtained was taken up in 50 ml of dichloromethane and then once more evaporated to dryness. This gave 500 mg (99% of theory) of the title compound as a colourlees oil. The product obtained in this manner was used without further purification and without further spectroscopic characterization in subsequent reactions.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Br)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+].[CH:27]1([SH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([S:32][C:5]2[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([CH:2]([F:24])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Reactant: SC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1SC1CCCC1
Yield: 100.2 %

Procedure:
This compound was prepared as described in Example 108: 8.4 g (0.02 mol) of product of Example 106, 0.88 g (0.022 mol) of 60% NaH, and 2.45 g (0.024 mol) of cyclopentylmercaptan in 100 ml of dry THF were reacted affording 8.85 g of a light brown oil. The crude product mixture was kugelrohr distilled at 110°-130° C./67 Pa affording 8.44 g (96%) of product as a light yellow oil, nD25 1.4808.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])OCC.[NH3:15].[ClH:16]>C(O)C.C(OCC)C>[ClH:16].[CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH2:9])=[NH:15]
Reactant: N
Reactant: CCOC(=N)c1cccc(C)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1c(C)cccc1C(=N)N
Reaction time: 72 h

Procedure:
Ethyl 2-methoxy-3-methylbenzimidate borofluoride (28 g.) was mixed with a saturated anhydrous solution of ammonia in ethanol (46 ml.), the mixture was kept at room temperature in a stoppered vessel for 3 days and then evaporated to dryness in vacuo. The residue was dissolved in water (25 ml.) and treated with 5N sodium hydroxide solution (50 ml.). The solution was saturated with sodium chloride and extracted with diethyl ether. The extract was dried over potassium hydroxide and evaporated to give crude 2-methoxy-3-methylbenzamidine, m.p. 72°-74° C. This was dissolved in anhydrous ethanol (40 ml.) and the solution treated with a saturated anhydrous solution of hydrogen chloride in diethyl ether (100 ml.), and diluted with anhydrous diethyl ether (100 ml.). The solid which separated was filtered off and washed with anhydrous diethyl ether to give 2-methoxy-3-methylbenzamidine hydrochloride (17.8 g.), m.p. 208°-209° C. (with decomposition).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:18][C:17]([F:19])([F:20])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:12]=1)([OH:25])[C:21]([F:22])([F:24])[F:23]
Reactant: C[C@H]1CNCCN1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 45.6 %

Procedure:
(S)-2-Methylpiperazine (28 mmol, 2.8 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (28 mmol, 9.42 g) and potassium carbonate (55.9 mmol, 9.42 g) were stirred at room temperature in acetonitrile (50 mL) overnight The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 85/15/1.5 dichloromethane/methanol/ammonia) to afford the title compound (4.55 g). MS (ESI) m/z 357.0 [M+H]+
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]#N)[CH2:6][CH2:5]1)[CH2:2][CH3:3].S(=O)(=O)(O)[OH:13].[OH2:17]>>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:13])=[O:17])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: CCC[C@H]1CC[C@@H](C#N)CC1
Product: CCC[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5.17 g of Compound J was added 30 ml of a mixture of water and conc. sulfuric acid (1:1) and the mixture was stirred for three hours at 110° C. to 130° C. After cooling to room temperature, the reaction mixture was poured into 60 ml of water and extracted with ethyl acetate, and then the extract was concentrated under reduced pressure. To the residue was added 30 ml of 1N aqueous solution of sodium hydroxide and the mixture was stirred for five minutes at room temperature. The alkaline aqueous solution was extracted with diethyl ether to remove the neutral substance, and the remaining aqueous solution was adjusted again to pH 3 with 3N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of cis-4-propylcyclohexanecarboxylic acid (Compound K) as crude product having the following physical data:
Reaction SMILES: [CH2:1]([CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH:9]([NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][CH:9]([CH3:10])[CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)C(Cc4ccccc4)OC(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using acetic acid 1-benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-propyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[C:39]([OH:42])([CH3:41])[CH3:40])[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-]>C(OCC)(=O)C>[OH:42][C:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH3:41])[CH3:40]
Reactant: C=CCC1C(C(C)(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Temperature: -78 °C

Procedure:
The cis-isomer of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(2-hydroxy-2-propyl)azetidin-2-one (10 ) (0.188 g) was dissolved in ethyl acetate (14 ml). An excess of trifluoroacetic acid (0.37 g) was added and the mixture cooled to -78° C. Ozone was passed into the reaction mixture until it was pale blue in colour. Argon was then bubbled through the solution until all the excess ozone had been removed. A solution of triphenylphosphine (0.085 g) in ethyl acetate was added and argon bubbled through the mixture for a further ten minutes. The reaction flask was then transferred to an ice bath and a saturated aqueous solution of sodium bicarbonate (20 ml) was added and the mixture stirred vigourously under argon for thirty minutes. The ethyl acetate layer was separated, washed with brine and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: Fc1ccccc1Br
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of 2-bromofluorobenzene (49 g), 1-dodecyne (210 ml) triethylamine (210 ml), and tetrahydrofuran (50 ml) was added (bis)triphenylphosphine palladium(II)chloride (532 mg) and copper(l)iodide (532 mg). The reaction mixture was warmed to 55° C. and stirred for 24 hr. The mixture was allowed to cool to room temperature and filtered. The precipitate was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 11 g (15%) of product, bp 175°-180° C. at 1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.F[B-](F)(F)F.F[B-](F)(F)F.CN([CH:31]=[C:32]([CH2:37][NH+](C)C)[CH2:33][NH+](C)C)C.Cl.C([O-])(O)=[O:43].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl.C1COCC1>[CH3:17][N:11]1[C@@:6]2([CH2:7][C:8]3[CH:9]=[C:10]4[C:2](=[CH:3][C:4]=3[CH2:5]2)[N:1]=[CH:33][C:32]([CH:37]=[O:43])=[CH:31]4)[C:14](=[O:15])[NH:13][C:12]1=[O:16]
Reactant: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)cc1C2
Reactant: O=C([O-])O
Reactant: CN(C)C=C(C[NH+](C)C)C[NH+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)NC(=O)[C@]12Cc1cc3cc(C=O)cnc3cc1C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (0.500 g, 2.16 mmol, described in Intermediate 8) and 2-dimethylaminomethylene-1,3-bis(dimethylammonio)propane bis(tetrafluoroborate) (1.77 g, 4.97 mmol) were suspended in glacial acetic acid and the mixture was heated to reflux for 20 h. The mixture was allowed to cool to ambient temperature before the bulk of the acetic acid was removed in vacuo. THF (10 mL) and 1 N aqueous HCl (10 mL, 10 mmol) were added and the mixture was stirred at ambient temperature for 2.5 h. The mixture was then poured into a separatory funnel containing CHCl3 (150 mL) and saturated aqueous NaHCO3 (30 mL). The aqueous layer was extracted once with CHCl3 (100 mL) and the combined organics were dried over Na2SO4. Filtration to remove drying agent gave a solution which was concentrated in vacuo to give a yellow residue. The impure product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:1 to 94:6, to give the title compound. MS: m/z=296 (M+1).
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.[ClH:30].[CH3:31]O>>[N:1]#[N:2].[ClH:30].[CH3:31][O:28][C:27](=[O:29])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])[NH:18][S:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1)(=[O:16])=[O:17]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Reactant: CO
Agent: Cl
Agent: N#N
Product: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccc(OC)cc2c1
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine in 15 ml of anhydrous methanol was saturated with dry hydrogen chloride for one hour. The reaction mixture was refluxed for an additonal one hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a crystalline product. After crystallization from methanolethyl ether, N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine methyl ester hydrochloride was obtained in 95% yield; mp. 115 - 118° C.
Reaction SMILES: [CH:1]([S:4]([N:7]1[CH2:10][C:9]2([CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11]2)[CH2:8]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]>CC(O)=O.C(Cl)Cl.[Pd]>[CH:1]([S:4]([N:7]1[CH2:8][C:9]2([CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:10]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)N1CC2(CCN(C(=O)OCc3ccccc3)C2)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)N1CC2(CCNC2)C1
Reaction time: 1.5 h

Procedure:
A solution of benzyl 2-isopropylsulfonyl-2,6-diazaspiro[3.4]octane-6-carboxylate (230 mg, 0.65 mmol) in AcOH (2 mL) was treated with Pd (7.0 mg, 0.06 mmol) (10% on activated carbon) and stirred under an atmosphere of hydrogen for 1.5 h. The reaction mixture was diluted with DCM, filtered and washed with 1N HCl and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain 2-isopropylsulfonyl-2,6-diazaspiro[3.4]octane in quantitative yield. LC/MS m/z 219.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](NC)[C:31]([O:34][CH3:35])=[N:32][CH:33]=1.[CH:38]([N:41](C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:41][CH2:38][C:30]3[C:31]([O:34][CH3:35])=[N:32][CH:33]=[C:28]([F:27])[CH:29]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc(F)cnc1OC
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(F)cc1CNc1ncc([N+](=O)[O-])c(NCC2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (200 mg, 0.52 mmol) in DMF (2 mL) were added a solution of (5-fluoro-2-methoxy-pyridin-3-yl)-methylamine (120 mg, 0.78 mmol) in DMF (1 mL) followed by diisopropylethylamine (181 μL, 1.04 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and water (×4). The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford [4-({2-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester which was then dissolved in CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was then treated with 1M Na2CO3 and extracted with CH2Cl2. MeOH was added to the mixture during the extraction to solublize the product into the organic phase. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.2 CH2Cl2:MeOH:NH4OH as an eluent to afford 156 mg of the title compound as a pale yellow solid (74%), m/z 406.4 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(O)c(N)c1
Product: Cc1ccc(O)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-hydroxy-5-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a brown solid (10 mg, 15%). 1H NMR (Acetone-d6): 9.58 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.72–8.68 (m, 2H), 7.89 (s, 1H), 7.58–7.53 (m, 1H), 7.24 (s, 1H), 6.92 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=[CH:11][C:10]1=2.[BH3-]C#N.[Na+].CC(O)=O.[O:29]=[C:30]1[C:34]2[CH:35]=[CH:36][C:37]([CH2:39][CH:40]=O)=[CH:38][C:33]=2[CH2:32][O:31]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:40][CH2:39][C:37]2[CH:36]=[CH:35][C:34]3[C:30](=[O:29])[O:31][CH2:32][C:33]=3[CH:38]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=[CH:11][C:10]1=2
Reactant: N#Cc1ccc2c(c1)CCCC2CN1CCNCC1=O
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2c(c1)CCCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(2-Oxopiperazin-1-yl)methyl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.15 mmol), NaBH3CN (19 mg, 0.30 mmol) and HOAc (18 mg, 0.298 mmol) in 20 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (52 mg, 0.30 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the desired product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.39˜7.51 (m, 4H), 7.31 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.74˜3.80 (m, 1H), 3.32˜3.43 (m, 3H), 3.25˜3.28 (m, 1H), 3.21 (s, 2H), 2.97˜3.01 (m, 2H), 2.74˜2.84 (m, 6H), 1.89˜1.96 (m, 1H), 1.71˜1.79 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[C:8]([F:10])[CH:9]=1)[CH3:2].[I-:14].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C1COCC1.O>[F:10][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([I:14])[CH:7]=1
Reactant: [I-]
Reactant: CCOc1cc(F)cc(B(O)O)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(F)cc(I)c1
Reaction time: 20 h

Procedure:
(3-Ethoxy-5-fluorophenyl)boronic acid (2.5 g, 0.014 mol) was dissolved in THF (30 mL) and a solution of sodium iodide (4.1 g, 0.028 mol) in H2O (15 mL) was added followed by a solution of chloramine T (7.8 g, 0.1 mol) in H2O (15 mL). After 20 h stirring, the reaction mixture was extracted with diethylether (3×50 mL). The organic layers were combined and the solvent was evaporated. The resulting residue was triturated with hexanes (3×) and the hexanes layers were combined. The solvent was evaporated to yield 1-fluoro-3-iodo-5-ethoxybenzene as an orange oil. The product was used in the next reaction step without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]2>CN(C)C=O>[Br:1][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[NH:15][C:14]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.5 %

Procedure:
N-Bromosuccinimide (440 mg) was added to a solution of ethyl 5-chloroindole-2-carboxylate (500 mg) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 18 hours, and the solvent was distilled off under reduced pressure. The residue was partitioned in ethyl acetate and water, and a water layer was extracted with ethyl acetate. The resultant organic layers were combined, washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9), and white powder thus obtained was washed with hexane to obtain the title compound (680 mg).