Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[F:34][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCNS(C)(=O)=O)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCC1(F)c1ccc(OCCNS(C)(=O)=O)cc1
Temperature: -78 °C

Procedure:
Into a 50 mL 3 neck flask fitted with a stirrer and thermometer, [2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine (150 mg, 0.36 mmol) in CH2Cl2 (5 mL) is added dropwise to 0.01 mL DAST in CH2CL2 (15 mL) while stirring at −78° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and diluted with CH2Cl2 (20 mL). This organic layer is washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield the product. This material is purified via silica gel chromatography employing the Chromatotron® and using 2000 micron rotor while eluting with a suitable eluent, such as hexanes/ethyl acetate to provide the final title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]=S.C(N(CC)CC)C.[NH:27]1[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[N:28]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:35]([O:34][C:32]([C:30]1[CH:31]=[N:27][N:28]([C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:12][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:29]=1)=[O:33])[CH3:36]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N=C(Nc1ccc(OC)c(OC)c1)n1cc(C(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A solution of 3,4-dimethoxyaniline (0.15 g, 1.0 mmol), ethyl isothiocyanatoformate (0.14 mL, 1.2 mmol) and DCM (10 mL) was stirred at room temperature for 1 h. Triethylamine (0.42 mL, 3.0 mmol), ethyl pyrazole-4-carboxylate (0.17 g, 1.2 mmol), and EDCl (0.19 g, 1.2 mmol) were added and the solution was stirred at room temperature for 5 h. The mixture was concentrated, diluted with water, and extracted with DCM. The organic layer was dried and concentrated to provide the crude titled compound (390 mg, 100%). This material was used without purification: MS (ESI): mass calcd. for C18H22N4O6, 390.4; m/z found, 391.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1Cl.[CH2:24]1[CH:31]2[C:27]3([NH2:33])[CH2:28][CH:29]([CH2:32][CH:25]1[CH2:26]3)[CH2:30]2.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1[NH:33][C:27]12[CH2:28][CH:29]3[CH2:32][CH:25]([CH2:24][CH:31]1[CH2:30]3)[CH2:26]2
Reactant: CCN(CC)c1ccc(C(=O)Cn2ncc(Cl)c(Cl)c2=O)cc1
Reactant: NC12CC3CC(CC1C3)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)Cn2ncc(NC34CC5CC(CC3C5)C4)c(Cl)c2=O)cc1
Yield: 18.2 %

Procedure:
4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one (30 mg, 0.0846 mmol), hexahydro-2,5-methanopentalen-3a(1H)-amine (22 mg, 0.126 mmol) and triethylamine (59 μL, 0.423 mmol) were stirred in N,N-dimethylacetamide (1 mL) at 90° C. for 3 days. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the desired product (7 mg, 17% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C=O)C.O.C(OCC)(=O)C>[CH2:16]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a stirred solution of 4-cyanophenol (50 g, 0.42 mol) and potassium carbonate (150 g, 1.1 mol) in DMF (800 ml) was added benzyl bromide (75 ml, 0.63 mol). The reaction mixture was stirred for 2 h at room temperature before filtering off solid and reducing the filtrate in vacuo to give an oil. The solid precipitate was dissolved in water and the pH adjusted to 0.5 using 6.0M hydrochloric acid and extacted into ethyl acetate. The solvent was dried over magnesium sulphate and removed by evaporation in vacuo to give an oil. The two oil products were combined and triturated with diethyl ether/hexane to give a white solid, which was washed with hexane and dried to give the title compound (81 g, 93%). 1H NMR (CDCl3) δ 7.5 (2H, d, 1 8.6 Hz), 7.45-7.30 (5H, br m), 7.0 (2H, d, J 8.6 Hz) and 5.14 (2H, s). MS (ES) m/e 210 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]([CH3:13])=[C:7]([C:10](=[O:12])[CH3:11])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(Cl)([Cl:23])(=O)=O>ClCCl>[Cl:23][CH2:13][C:6]1[NH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:8]([CH3:9])[C:7]=1[C:10](=[O:12])[CH3:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1[nH]c(C)c(C(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1[nH]c(CCl)c(C(C)=O)c1C
Temperature: 0.5 °C

Procedure:
To a stirred mixture of 2,4-diacetyl-3,5-dimethylpyrrole (1.0 g), dichloromethane (35 cm3) and potassium carbonate (7.73 g) at 0°-5° C. was added a solution of sulphuryl chloride (0.79 g) in dichloromethane (15 cm3). The temperature of the mixture was maintained at 0.5° C. during the addition by external cooling and then the mixture was stirred at this temperature until adjudged complete by t.l.c. (ca 2 h). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl-4-methylpyrrole. This material was dissolved in acetic acid (10 cm3), sodium acetate (1.83 g) added, and then more acetic acid (10 cm3) added. The mixture was stirred overnight at room temperature, evaporated in vacuo, and the residue stirred with ice-cold water for 2 h. A solid was collected by filtration and the filtrate extracted twice with ethyl acetate. The extracts were dried (MgSO4), evaporated and the residue combined with the solid above, to give the crude product. Chromatography on silica eluting with ethyl acetate-hexane (1:1) gave 0.075 g. of pure product as an off-white solid m.p. 112.5°-114.5° C.; m/z 238 (M+ +1, FAB), δH, CDCl3) 2.16 (3H, s, OCOCH3), 2.50 (3H, s, CH3), 2.53 (3H, s, CH3), 2.62 (3H, s, CH3), 5.38 (2H, s, OCH2).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:23][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:24])([CH3:25])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0, 2.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(3-chloro-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (840 mg, 90%) as a white foam: LC/MS m/e calcd for C18H17ClFNO2 (M+H)+: 334.79, observed: 334.1.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(CCC(Cl)=S)(=O)C.SCC(SC)C([N:25]1[CH2:32][C:31](=[O:33])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=O>>[C:1]([S:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([N:25]1[CH2:32][C:31](=[O:33])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: CSC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CC(=O)SCC(C)(C)C(=O)Cl
Agent: CC(=O)CCC(=S)Cl
Product: CC(=O)SCC(C)(C)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
Following the procedure of Example 1 but substituting 3-acetylthio-2,2-dimethylpropionyl chloride for the 3-acetylthiopropionyl chloride in part (d), one obtains 1-[3-(acetylthio)-2,2-dimethyl-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:10]2[CH2:9][CH2:8][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)([OH:13])[CH2:12][CH2:11]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a 20 mL vial equipped with a magnetic stirring bar was added 78 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.37 mmol, 1.0 equiv.), 100 mg of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.41 mmol, 1.1 equiv), and 207 mg of (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.40 mmol, 1.1 equiv.). The reagents were dissolved in 3 mL of DMA and to the resultant solution was added 0.26 mL of DIPEA (1.5 mmol, 4.1 equiv). The reaction solution was stirred for 5 h and then poured into 50 mL of EtOAc. The organic phase was washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic phase was then dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 129 mg of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (80% yield): MS (ES) M+H expected=414.2, found 414.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.10-7.14 (m, 2H), 6.99-7.03 (m, 2H), 5.00 (d, J=15.6 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.32-4.35 (m, 1H), 3.64-6.68 (m, 1H), 3.42-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.26 (s, 3H), 1.55-1.61 (m, 4H), 1.23 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH3:26])([CH2:23][CH2:24]C)[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH2:20].[K+].[Br-]>>[CH3:26][C:12]([CH3:11])([CH2:23][CH3:24])[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCC(C)(C)CNc1c(N)c(C)nn1C
Agent: [Br-]
Agent: [K+]
Product: CCC(C)(C)CNc1c(NCc2ccc(C#N)cc2)c(C)nn1C
Yield: 19 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 5 except that 4-cyanobenzaldehyde was used in place of 4-pyridinecarboxaldehyde and N(3)-(2,2-dimethyl-pentyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine was used in place of N(3)-(2,2-dimethyl-propyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine. Yellow oil, yield: 19%, 1H NMR (300 MHz, CDCl3): δ 0.83 (t, 3H), 0.89 (s, 6H), 1.28 (q, 2H), 2.10 (s, 3H), 2.61 (s, 2H), 3.59 (s, 3H), 4.04 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), IR (KBr, cm−1): 3340m, 2961s, 2877m, 2226s, 1588m, 1565m, 1537m, 1462m, 1378m, 1365m, 1296w, 821w, MS (ES) nm/z (relative intensity): 326 (M+H+, 100).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]1[O:20][C@@H:19]1[CH2:21][OH:22]>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:18][CH:19]([OH:20])[CH2:21][OH:22])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1CO1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Solvent: CO
Product: OCC(O)CNc1ccc(OCc2ccccc2)cc1

Procedure:
The product is obtained with a 90% yield; m.p.: 102° C.; [α]D20 =+12,7° (c=1, CH3OH). This same product can be obtained by heating 4-benzyloxyaniline in ethanol in the presence of (R)-glycidol.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[C:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.[CH3:24][Li].[Cl-].[NH4+]>C1C=CC=CC=1.C(OCC)C>[CH3:1][CH:2]1[C:11]([CH3:24])([OH:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: [Li]C
Reactant: CC1C(=O)c2sccc2C(=C2CCN(C)CC2)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1c2ccccc2C(=C2CCN(C)CC2)c2ccsc2C1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 11.0 g of 9-methyl-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen10(9H)-one in 150 ml of benzene was added dropwise in a nitrogen atmosphere at 25°-30° to a solution of 150 ml of diethylether and 43 ml of 2 molar methyllithium in diethylether. The reaction mixture was stirred for 3 hours at room temperature and then treated with 500 ml of 20% w/v aqueous ammonium chloride. The organic phase was separated off and worked up to give solid 9,10-dihydro9,10-dimethyl-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-ol which was further reacted in crude form.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[C:10]([OH:13])(=[S:12])[CH3:11]>C(OC(C)C)(C)C>[C:10]([S:12][CH2:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8])(=[O:13])[CH3:11]
Reactant: CC(O)=S
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CC(C)OC(C)C
Product: CC(=O)SCC(CC(=O)O)C(=O)O
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
400 g (3.07 mol) of itaconic acid (VIII) are added in portions within a period of approximately 30 minutes to 280 g (3.68 mol) of thioacetic acid, with simultaneous heating of the heating bath to 95° C. After 2.5 hours' stirring at 90°-100° C., the reaction mixture is cooled to room temperature and diluted with 300 ml of diisopropyl ether (DIPE), whereupon the product crystallises out within a period of approximately 12 hours. There are obtained 582 g of crystals having a melting point of 89°-91° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1.[N:31]1[CH:36]=C[CH:34]=[CH:33][CH:32]=1.ClC(OC1C=CC=CC=1)=[O:39].C1(N)CC1>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH:27][C:36]([NH:31][CH:32]4[CH2:34][CH2:33]4)=[O:39])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1)NC1CC1
Temperature: 60 °C
Yield: 35.9 %

Procedure:
To a stirred solution of compound 280 (6.32 g, 14.92 mmol) and pyridine (2.41 mL, 17.91 mmol) in DMF (70 mL) at 0° C. was added phenyl chloroformate (2.25 mL, 17.91 mmol). After 30 min cyclopropylamine (2.63 mL, 37.3 mmol) was added at RT and the reaction mixture was heated at 60° C. for 45 min. After cooling to RT the reaction mixture was diluted with water to form a precipitate that was collected by filtration, dried and purified by Biotage (SNAP 100 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 10/90 over 20 CV), to produce a material that upon trituration with EtOAc afforded the title compound 281 (2.71 g, 5.35 mmol, 36% yield) as a beige solid. MS (m/z): 507.2 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[NH4+].[Cl-]>C1COCC1.O>[CH3:16][C@H:8]([C@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@@H](O)[C@@H](C)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of diisopropyl-(R)-(+)-malate (9.4 mL; 45.8 mmol; 1.0 eq.) in anhydrous THF (17 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (96.2 mL; 1.00 M; 96.2 mmol; 2.1 eq.) in THF. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Iodomethane (3.4 mL; 55.0 mmol; 1.2 eq.) was added and the mixture stirred at RT for 16 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product (mixture of diastereoisomers) as a colourless oil (9.80 g, 92%).
Reaction SMILES: I.CSC1NCCCN=1.I.CS[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.NC1[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:21]2[N:22]([C:27](=[O:31])C=1N=O)[CH2:23][CH2:24][CH2:25][N:26]=2>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:20]2[C:15]3[NH:14][CH:13]=[N:17][C:16]=3[C:27](=[O:31])[N:22]3[CH2:23][CH2:24][CH2:25][N:26]=[C:21]23)=[CH:34][CH:35]=1
Reactant: CSC1=NCCN1
Reactant: NC1=C(N=O)C(=O)N2CCCN=C2N1Cc1ccc(Cl)cc1
Agent: CSC1=NCCCN1
Agent: I
Product: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCCN12

Procedure:
--Procedure 1 is repeated with substitution of 2-(methylthio)-3,4,5,6-tetrahydropyrimidine hydroiodide for the 2-(methylthio)-2-imidazoline hydroiodide specified. The resulting 8-amino-3,4-dihydro-9-[(4-chlorophenyl)methyl]-7-nitroso-2H,5H-pyrimido(1,2-a)pyrimidin-6(9H)-one is converted to the corresponding 7-formylamino compound according to the method of Procedure 2, and the latter is then cyclized to the desired product by the method of Procedure 4.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C3C(F)=C(F)C(F)=C(F)C=3F)=O)=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>N1C=CC=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([N:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[CH:45][CH:44]=3)=[O:20])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one (0.100g, 0.029 mmol) was agitated with 4-morpholinoaniline (0.155 mg, 0.87 mmol) in 10% pyridine in dimethylformamide (2 ml) for 24 h. The resin was filtered and washed liberally with dimethylformamide, MeOH, DCM, and dried under vacuum. The dry resin was cleaved in 60% trifluoroacetic acid in dichloromethane (2 ml) for 2 h at room temperature. The supernatant was evaporated under vacuum, and the crude product was purified by preparative TLC (eluent: 10% methanol in dichloromethane to give product as a white solid. Yield 6.6 mg (50%). MS (m/z): 457.2 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH3:7].[C:9](OCC)(=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:19][NH:20][NH2:21]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:20]([CH3:19])[N:21]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1
Reactant: CC(=O)CCCCCl
Reactant: CNN
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(CCCCCl)n(C)n1

Procedure:
Ethyl 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylate was prepared from 6-chloro-2-hexanone (50.0 g, 357 mmol) and diethyl oxalate (48.4 mL, 357 mmol) according to the procedure described in Part A of Example 19 using methyl hydrazine (19.0 mL, 357 mmol) in place of ethylhydrazine oxalate. Ethyl 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylate was isolated as a dark oil that was used without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](O)[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].COS([O:27][CH3:28])(=O)=O>CC(C)=O>[CH3:16][O:14][C:12]([C:8]1[C:7]([O:27][CH3:28])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc2cc(Br)ccc2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2cc(Br)ccc2cc1OC
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
A mixture of 7-bromo-3-hydroxy-naphthalene-2-carboxylic acid (J. Med. Chem. 1990, 33(1), 171) (5.3 g, 19.85 mmol), potassium carbonate (13.7 g, 99.25 mmol) and dimethylsulfate (3.8 mL, 45.66 mmol) in acetone (50 mL) was heated at reflux for 3.5 hours. The reaction mixture was then filtered; the filtrate was treated with water (5 mL) and the resulting mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure; the residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 5.946 g of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid methyl ester without further purifications.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[CH:9]=[CH:8]2.Cl>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 60 °C

Procedure:
To a mixture of 20 g. of sodium hydroxide and 400 ml. of methanol are added 24.5 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate. The resulting reaction mixture is heated to 60° C. for five hours. The cooled mixture is neutralized by the addition of aqueous 1 N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-methoxy-2-naphthyl-α-methylacetic acid.