Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[OH:15][N:14]=[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1cccc(C(=O)O)c1
Yield: 94.8 %

Procedure:
3-Acetylbenzoic acid (10.0 g, 60.9 mmol), hydroxylamine hydrochloride (33.9 g, 487.4 mmol) and sodium acetate (45.0 g, 548.3 mmol) were suspended in ethanol (115 mL) and water (115 mL) and the mixture heated at reflux for 30 minutes. The solvents were removed under reduced pressure, and the residue was triturated with water. The resulting precipitate was isolated by filtration and dried in vacuo to give the sub-title compound as a white solid (10.34 g, 95% yield). 1H NMR (400 MHz, DMSO) δ 2.18 (s, 3H), 7.52 (t, 1H), 7.88 (dd, 1H), 7.91-7.95 (m, 1H), 8.22 (s, 1H), 11.36 (s, 1H) and 12.86 (s, 1H); MS (ES+) 180.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([OH:9])=O)([O-])=O.C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[CH:26][CH:27]=1)=[O:9]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Nc1cc(C(=O)Nc2ccc(F)cc2)ccc1OC(F)(F)F
Yield: 88.5 %

Procedure:
Prepared according to the procedure described for Example 1 using 3-nitro-4-trifluoromethoxybenzoic acid from Step A (5.1 g, 20.5 mmol), oxalyl chloride (2.1 mL, 20.5 mmol), and 4-fluoroaniline (Aldrich. Milwaukee, Wis.) (4.6 g, 41.1 mmol) to afford the product (5.7 g); m.p. 139-140° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:15]1([CH2:14][C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml ; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm)(CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:33].[OH-].Cl>C1COCC1.O>[C:29]([O:28][C:26]([N:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:18]([CH2:19][C:20]([O-:22])=[O:21])[C:17](=[O:25])[C:12]21[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:27])([CH3:32])([CH3:30])[CH3:31].[Li+:33]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate from Step C (50 mg, 0.11 mmol) in THF (0.75 mL) and H2O (0.25 mL) was added 1 N aqueous LiOH (0.12 mL, 0.12 mmol) and the resulting mixture was stirred at ambient temperature for 6 h. The mixture was adjusted to pH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=369 (M-C4H7).
Reaction SMILES: [CH3:1][N:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[CH3:1][N:2]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCCC12CCN(c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCCCC12CCN(c1ccc(N)cc1)CC2
Reaction time: 5 h
Yield: 98.4 %

Procedure:
To a mixture of 1-methyl-9-(4-nitrophenyl)-1,9-diazaspiro[5.5]undecane (680 mg), ethanol (10 mL), and tetrahydrofuran (10 mL) was added 10% palladium-supported carbon (50% wet product) (150 mg), followed by stirring for 5 hours under a hydrogen gas atmosphere (1 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 4-(1-methyl-1,9-diazaspiro[5.5]undec-9-yl)aniline (0.6 g) as a pale purple solid.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Br:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[C:8]([Br:15])[N:7]=1>>[Br:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[CH:9]=[C:8]([Br:15])[N:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
Methanol (1.48 g, 46.1 mmol) is slowly added to a cooled suspension (0° C.) of NaH (2.12 g, 53.2 mmol, 60% dispersion in mineral oil, washed with hexane prior to use) in THF (20 mL). Upon completion of the addition the mixture is stirred at 0° C. for 150 min before 2,6-dibromo-4-nitropyridine (10.0 g, 35.4 mmol) is added. The temperature rises to 14° C. The mixture is stirred at rt for 3 h before the reaction is quenched with sat. aq. NH4Cl solution. The mixture is diluted with water and extracted twice with EA (250 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM to give 2,6-dibromo-4-methoxy-pyridine (6.43 g) as an off-white solid; LC-MS: tR=0.90 min, [M+1]+=267.75.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:21][CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Product: COc1cccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)c1

Procedure:
The subtitle compound was prepared from the product of example 15 step (iii) (20 g) and 3-methoxybenzyl chloride (17.4 ml) by the method of example 15 step (iv). Purification was by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 20.53 g. MS: APCI(+ve): 324 (M+1).
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[C:9]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1csc(Br)n1
Yield: 5 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (15.6 g) and acryloylchloride (7 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml), maintaining reaction temperature at 0° C. with an ice bath. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate and stirred for 30 minutes. The mixture was filtered and separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was recrystallised from carbon tetrachloride to give the title compound (0.7 g) m.p. 152°-4° C. (Found: C, 30.5; H, 2.2; N, 11.8. C6H5BrN2OS requires C, 30.9; H, 2.2; N, 12.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:19]1([CH3:22])[CH2:21][CH2:20]1.O>CN(C=O)C>[CH:19]1([CH2:22][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC1CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
4-Amino-3-nitrophenol (26.00 g, 165.5 mMol) was dissolved in 200 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was then cooled to 0° C. and to this mixture was added Cs2CO3 (64.7 g, 199 mMol), and cyclopropyl methane bromide (17.7 mL, 182 mMol). After stirring for 15 minutes, the reaction mixture was then warmed up to ambient temperature and then stirred overnight. The reaction mixture is then poured into 800 mL of water. The precipitate was collected via suction filtration and partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was saved and washed again aqueous 0.1 N NaOH, then with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 31.52 g of 4-cyclopropylmethoxy-2-nitro-phenylamine 133A as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].[CH3:14]N(C=O)C>>[CH3:14][NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (1.73 g, 10.0 mmol) in DMF (40 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) at 0° C. followed by excess amount of Mel (3.0 mL). The mixture was stirred at 0° C. for 1 hr then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (1.86 g, quant): 1H NMR (DMSO-d6) δ 2.95 (d, 3H), 6.69 (dd, 1H), 7.03 (d, 1H), 8.08 (d, 1H), 8.28 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=O.CCO>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15](/[CH:16]=[N:9]/[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: NNc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(N/N=C/c2cc(Br)ccc2F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A 1000 mL round bottom flask was charged with 20.0 g (123 mmol) of 4-fluorophenylhydrazine and 28.4 g (140 mmol) of 5-bromo-2-fluorobenzaldehyde and 400 mL of EtOH and warmed at 90° C. After 2 hours, the mixture was cooled to room temperature and then diluted with 200 mL of water and filtered. The solid were then dissolved in EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a pad of silica gel to afford 37 g (97%) of N-[1-(5-bromo-2-fluorophenyl)meth-(E)-ylidene]-N′-(4-fluorophenyl)hydrazine. MS m/z 312.11 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[CH:11]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12]2>>[F:10][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=1)[CH2:2][C@@H:14]1[CH2:13][CH2:12][CH2:11][C@H:15]1[OH:16]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: C1CC2OC2C1
Product: O[C@@H]1CCC[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Reaction of the Grignard reagent prepared from 1-(bromomethyl)-3,5-difluorobenzene with 6-oxabicyclo[3.1.0]hexane gave trans-2-(3,5-difluorobenzyl)cyclopentanol. Conversion to the mesylate, followed by displacement with sodium azide and reduction with triphenylphosphine afforded cis-2-(3,5-difluorobenzyl)cyclopentanamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[O:11][CH2:12][C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)cc1
Yield: 93.9 %

Procedure:
Under nitrogen, 4.10 g (11.7 mmol) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone (prepared in Step 4), 6.52 mL (46.8 mmol) of triethylamine, 4.89 g (25.7 mmol) of p-toluenesulfonic acid, and 12 g of 4Å molecular sieves were added to 117 mL of acetonitrile and stirred at reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The dichloromethane layer was dried (MgSO4) and reconcentrated in vacuo. Recrystallization from hexane/ethyl acetate (2:1) gave 3.65 g (94%) of 3-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one as a solid: mp 166°-167° C.; NMR (CDCl3) δ3.08 (s, 3H), 5.19 (s, 2H), 7.10 (t, J=9 Hz, 2H), 7.42 (dd, J=6 and 9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.97 (d, J=9 Hz, 2H); HRMS. Calc'd for C17H13FO45 : 332.0519. Found: 332.0501. Anal. Calc'd for C17H13FO45 : C, 61.44; H, 3.94; O, 19.26. Found: C, 61.11; H, 4.06; 0, 19.32.
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[C:3]=1[F:23]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (360 mg, 1.12 mmol), N-2-pyridinyl-1,2-ethanediamine (230 mg, 1.68 mmol) and triethylamine (0.234 mL, 1.68 mmol) in DMSO (5 mL) was stirred for 3 hours at 100° C. The reaction mixture was poured into ice-water and stirred for 30 minutes. The resulting precipitate was collected by filtration, washed with water, suspended in EtOH (10 mL) and stirred at reflux for 1 hour. The suspension was cooled to room temperature, and the resulting precipitate was collected by filtration and dried to yield the title compound (459 mg, 93%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.91-2.03 (2H, m), 2.08-2.17 (2H, m), 2.61-2.69 (2H, m), 3.44-3.48 (2H, m), 3.58-3.66 (2H, m), 6.35-6.40 (1H, m), 6.45-6.49 (2H, m), 6.71 (1H, t, J=5.5 Hz), 6.88 (2H, brs), 7.35 (1H, td, J=6.7, 1.8 Hz), 7.97 (1H, dd, J=4.9, 1.2 Hz), 8.71 (1H, s), 15.30 (1H, s). HRESIMS (+): 440.17267 (−0.74 mmu).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1.[ClH:35].Cl.C(OCC)C>C(Cl)(Cl)Cl>[ClH:35].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:30]5[N:29]=[CH:28][C:27]6[O:26][CH2:25][S:24][C:32]=6[CH:31]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=Cc1cc2c(cn1)OCS2
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(F)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCS3)[C@H](O)C1

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 24(b). The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of 1M HCl/diethyl ether, then evaporating to dryness. MS as that of free base.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(Cl)c2)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 9.99 mmol) in DMF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (10.69 mL, 10.69 mmol) was added and stirred at the temperature for 30 min. The resultant clear red brown solution was treated with 3-chloro-4-fluorobenzyl bromide (2.34 mL, 10.49 mmol), and stirred at 0° C. for 2 hours. The product mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was washed successively with 5% aq KHSO4, sat. NaHCO3, and brine. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-100% gradient of ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the benzylated product.
Reaction SMILES: C([C@H]1COC(=O)N1C([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17]1)=O)C1C=CC=CC=1.[C:35](=O)([O:38]C)[O:36][CH3:37].C[O-].[Na+]>ClCCl>[CH2:28]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C@H:16]([C:35]([O:36][CH3:37])=[O:38])[CH2:17]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)OC
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of (4S)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one, from preparation 24 (2.51 g, 5.28 mmol) and dimethyl carbonate (2.22 mL, 26.4 mmol) in dichloromethane (40 mL) was added sodium methoxide (1.42 g, 26.4 mmol) at room temperature. The reaction mixture was stirred for 24 hours and diluted with dichloromethane (50 mL). The phases were separated and the organic phase was washed with water (2×40 mL), dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using ethyl acetate:pentane (5:95-20:80) as eluent to afford the desired product as a colourless oil, 1.61 g (79%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:17]([OH:41])=[C:18]([C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].O[CH2:43][CH:44]1[CH:48]=[CH:47][CH2:46][N:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[C:17]([O:41][CH2:43][CH:44]2[CH:48]=[CH:47][CH2:46][N:45]2[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Reactant: CC(C)(C)OC(=O)N1CC=CC1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OCC1C=CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.8 %

Procedure:
Diisopropylazodicarboxylate (1.4 g) was added to a suspension of methyl 3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxybenzoate (Intermediate 13, 2.58 g), tert-butyl 2-hydroxymethyl-2,5-dihydropyrrole-1-carboxylate (Prepared according to Morriello et al, Bioorg. Med. Chem, 2008, 16(5), 2156; 1.27 g) and triphenylphosphine (1.82 g) in anhydrous THF (20 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (4.13 g) as a light brown oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[N:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27])=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([N:26]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:27])=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Hydrogen chloride is bubbled into a solution of 81 (110 mg, 0.25 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT for 6 h. The solvent is removed by rotary evaporation, and the residue triturated with Et2O. The insoluble material is dissolved in dichloromethane and Et2O is added, and the precipitate is filtered to give 43 mg of the product 82. 1H NMR (DMSO-d6) δ 9.28 (s, 2 H), 7.60-7.30 (m, 5 H), 7.25-6.95 (m, 10 H), 5.58 (s, 2 H), 4.78 (s, 2 H), 3.15 (s, 3 H); MS: m/z 342 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:14]=[C:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:12]=1
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Nc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a mixture of (4-chloro-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)amine (3.97 g, 14.4 mmol), potassium carbonate (2.20 g, 15.9 mmol) and 18-crown-6 (46 mg, 0.17 mmol) in toluene (25 ml), cooled in an ice bath, was added a solution of aniline (1.4 ml, 15.4 mmol) in toluene (10 ml) over 15 minutes. After stirring at room temperature for 24 hours, the mixture was treated with ethyl acetate (35 ml) and filtered through a pad of celite under suction. The filtrate was concentrated under vacuum and the residue was recrystallized (chloroform) to give 6-Chloro-N-(4-chlorophenyl)-N′-phenyl[1,3,5]triazine-2,4-diamine (2.20 g, 46% yield) as a white solid. 1H NMR (d6-DMSO) δ 10.1–10.4 (2 H, br s), 7.5–7.8 (4 H, br s), 7.3–7.5 (4 H, m), 7.15–7.05 (1 H, m), ESMS m/z 330 (M−H)−.