Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13](NCC)C1C=CC=CC=1.CC#N.O.CC#N>O>[CH2:1]([N:8]([CH2:12][CH3:13])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCc1ccccc1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Solvent: CC#N
Solvent: O
Product: CCN(Cc1ccccc1)C(=O)Cl

Procedure:
The title compound is prepared analogously as described for benzyl-methyl-carbamoyl chloride from benzyl ethylamine. MS (LC-MS): [M+H]+=198.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.12 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CCCN)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-(3-tert-butoxycarbonylamino-propyl)-thiophene-2-carboxylic acid methyl ester prepared of Preparation 5, Step B (0.118 g, 0.5 mmol) in 50 mL MeOH was cooled to 0° C. and was saturated with HCl (g). The reaction was stirred at room temperature for 90 minutes. The solution was concentrated to a solid which was partitioned between EtOAc and saturated NaHCO3. The layers were separated, and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil (399 mg). MS 200 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:2].I.CS[C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[NH:36]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[NH:36])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:2]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Compound 9 (75 mg, 0.172 mmol) was dissolved in anhydrous ethanol (5 mL) in a dry argon purged flask. Palladium, 10wt % on activated carbon (18.3 mg, 0.0172 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) shows complete conversion to 10, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (5 mL) and the ethanolic solution of the amine 10 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (63.8 mg, 0.224 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 45 hours. The solution was diluted with diethyl ether (100 ml) and cooled in an ice bath. No precipitate formed thus the solvent was evaporated. The residue was purified using silica gel column chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5 to 5:95) to afford a pale yellow residue 11 (47 mg, 53.0%). 1H NMR (MeOD) δ 0.98 (t, 6H, J=7.1 Hz), 2.47-2.56 (2×m, 6H), 4.13 (t, 2H, J=7.1 Hz), 4.24 (s, 2H), 6.24 (s, 1H), 6.84 (dd, 1H, J=8.4, 1.6 Hz), 7.09-7.13 (m, 2H), 7.17-7.24 (m, 2H), 7.33-7.39 (m, 3H), 7.56 (d, 1H, J=5.2 Hz), 7.64 (d, 1H, J=3.7 Hz); ESI-MS (m/z, %): 515 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:10][C:11](=[O:12])[C:5]2=[C:4]([CH3:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25]1([C:28]([NH2:30])=O)[CH2:27]C1.O.C[C:33]([N:35](C)C)=O>>[CH3:18][C:4]1[CH:3]=[C:2]([O:1][C:28]2[CH:25]=[CH:27][N:35]=[CH:33][N:30]=2)[C:7](=[O:8])[N:6]2[C:9]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:10][C:11](=[O:12])[C:5]=12
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(O)c(=O)n2c1C(=O)NC21CCCCC1
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Oc2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a solution of 6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 1 g, 4.03 mmol) in dimethylacetamide (20 mL) is added potassium carbonate (1.67 g, 12.09 mmol) and 4-bromopyrimidine (4, 0.77 g, 4.84 mmol). The reaction is stirred at 130° C. overnight. The resulting mixture is cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 8′-methyl-6′-(pyrimidin-4-yloxy)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 209).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Ethyl 6-[(4-fluorophenyl)oxy]-3-pyridinecarboxylate (D13) (0.275 g, 1.054 mmol) was taken up in 1,4-dioxane (5 mL) and lithium hydroxide (0.050 g, 2.109 mmol) was dissolved in water. The two solutions were combined and stirred at room temperature for 2 h. The mixture was acidified to pH 5 with 2M HCl and concentrated. The residue was taken up in ethyl acetate, dried and concentrated to yield the title compound as a cream/white solid (0.233 g). δH (DMSO-d6, 400 MHz) 13.20 (1H, bs), 8.65 (1H, dd), 8.28 (1H, dd), 7.26 (4H, m), 7.12 (1H, d). MS (ES): MH+ 234.2, (M-H+) 232.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[CH3:23][C:24](=[CH2:28])[C:25](O)=[O:26].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[F:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[C:24]([CH3:28])=[CH2:23])=[CH:7][C:6]=1[C:8]1[C:9]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cc(N)ccc3F)c12
Reactant: C=C(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(F)c(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude ethyl 4-(5-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (133 mg, 0.443 mmol) was added THF (4.43 mL), TEA (93 μL, 0.66 mmol), methylacrylic acid (57 mg, 0.66 mmol) and 1-propanephosphonic acid cyclic anhydride (3.26 mL, 0.443 mmol). The reaction was stirred at 25° C. overnight. The reaction was quenched by pouring into a separatory funnel containing aqueous sodium hydrogen carbonate (5%) and was extracted with ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and evaporated in vacuo. The crude reaction was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The products were collected and lyophilized to afford a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH:36]([O:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)([CH3:38])[CH3:37]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CC(C)Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), 2-chloro-5-isopropoxy-pyrimidine (25 mg), potassium carbonate (45 mg), and N-methyl-pyrrolidinone (2 ml) is stirred in a microwave oven at 150° C. for 20 min. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:5:0→5:5:1) to give the title compound. LC (method 3): tR=0.93 min; Mass spectrum (ESI+): m/z=526 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:25]1([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:28][C:27](=[O:30])[O:26]1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][N:14]([C:25]2([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:28][C:27](=[O:30])[O:26]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cl)CCC(=O)O1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
In 3 ml of N,N-dimethylformamide was dissolved 236 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution was added 326 mg of cesium carbonate. The mixture was stirred at room temperature for 20 minutes, to which was added 179 mg of the Compound (13) obtained in Example 13, followed by stirring for two hours. To the reaction solution was added a dilute saline solution. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, which was dried (Na2SO4), then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 101 mg of the subject Compound (12). The IR and NMR spectra of this product were in complete agreement with those of the Compound (12) obtained in Example 12.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([OH:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)O
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 18 h

Procedure:
4-Methyl-3-nitroaniline (5.0 g, 32.86 mmol) was dissolved in anhydrous THF (25 mL). t-Butyl bicarbonate (7.5 mL, 32.86 mmol) dissolved in anhydrous THF (25 mL) was added slowly to the reaction mixture, which was stirred at 65° C. for 18 hours. After the reaction was completed the remaining organic solvent was distilled under reduced pressure, and water was added thereto. The resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]2[C@@H:11]([C:19]([OH:21])=O)[O:10]1.[CH2:22]([NH2:24])[CH3:23].C(OCC)C>ClCCl.CN(C)C=O>[CH2:22]([NH:24][C:19]([C@@H:11]1[C@@H:12]2[C@@H:13]([O:14][C:15]([CH3:17])([CH3:18])[O:16]2)[C@H:9]([O:8][CH3:7])[O:10]1)=[O:21])[CH3:23]
Reactant: CO[C@@H]1O[C@H](C(=O)O)[C@@H]2OC(C)(C)O[C@@H]12
Reactant: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Oxalyl chloride (14.0 ml, 160 mmol) was added dropwise to a stirred solution of (3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (J. Amer. Chem. Soc., 80, 5168–5173 (1958)) (23.30 g, 107 mmol) in anhydrous dichloromethane (120 ml) and N,N-dimethylformamide (2 drops) and the mixture stirred at room temperature for 3 hours until gas evolution had ceased. TLC analysis showed that some starting material still remained and therefore further N,N-dimethylformamide (2 drops) was added and stirring continued for 1 hour. The solvent was removed under reduced pressure and the residue azeotroped with anhydrous dichloromethane (×2). The residue was dissolved in anhydrous dichloromethane (200 ml) and the solution treated dropwise with ethylamine (2 M solution in tetrahydrofuran, 140 ml, 280 mmol). This solution was allowed to stand at room temperature for 48 hours. Diethyl ether (250 ml) was added and the mixture stirred for 15 minutes. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:ethyl acetate (44:66, by volume) to afford the title compound as a yellow solid (24.70 g).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:17]Cl)[C:6]=1[CH2:19]Cl)(C)(C)C.[C:21]([O:26]C)(=O)[CH:22]([CH3:24])[CH3:23].O>BrCCBr.C1COCC1>[C:6]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][CH:5]=[C:6]3[C:7]=2[CH2:17][C:21]([CH:22]([CH3:24])[CH3:23])([OH:26])[CH2:19]3)=[CH:12][CH:13]=1)([CH3:19])([CH3:7])[CH3:5]
Reactant: COC(=O)C(C)C
Reactant: CC(C)(C)c1ccc(-c2ccccc2)c(CCl)c1CCl
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1(O)Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
633 mg (26 mmol, 4 eq.) of Mg powder (50 mesh/Aldrich) were dried under reduced pressure with the aid of a hair dryer. 10 ml of THF and 10 drops of 1,2-dibromoethane were added. The mixture was heated to reflux until gas evolution took place and the activation was complete. The solvent was removed under reduced pressure and 10 ml of fresh THF were added. A solution of 2.0 g (6.5 mmol) of tert-butyl-2,3-bis(chloromethyl)biphenyl in 120 ml of THF was added and the suspension was stirred vigorously at room temperature for 3 hours. Stirring was continued overnight and the slightly greenish turbid solution obtained was filtered to remove excess magnesium. The filtrate was cooled to −78° C. and a solution of 665 mg (6.51 mol) of methyl isobutyrate in 60 ml of THF was added dropwise over a period of 1 hour. The reaction solution was warmed to 0° C. over a period of 2 hours. 80 ml of water were subsequently added and the solution was concentrated under reduced pressure. To dissolve the magnesium salts, 3 ml of concentrated hydrochloric acid were added and the aqueous phase was extracted with methylene chloride (3×50 ml). The combined organic phases were dried over magnesium sulfate, and the solvent was subsequently removed under reduced pressure. The product was purified by column chromatography, with the nonpolar by-products being separated off using a heptane/dichloromethane mixture and the product being eluted with pure dichloromethane, giving a yellow product. Yield: 0.66 g (2.14 mmol/33% 96% by GC). 1H NMR (400 MHz, CDCl3): δ=7.41–7.21 (m, 7H, aromat.), 3.18–2.91 (m, 4H, CH2), 1.92 (m, 1H, CH), 1.36 (s, 9H, tert-butyl), 1.02 (t, 6H, CH3) ppm.
Reaction SMILES: C[Mg]Br.[C:4]1([CH3:10])[CH:9]=C[CH:7]=[CH:6][CH:5]=1.C1C[O:14]CC1.[O:16]=[C:17]1[NH:21][C@@H](CC(OCC2C=CC=CC=2)=O)C[O:18]1>C(O)(=O)C.O>[OH:14][C:4]([CH3:10])([CH3:9])[CH2:5][C@H:6]1[CH2:7][O:18][C:17](=[O:16])[NH:21]1
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Reactant: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Agent: C[Mg]Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(O)C[C@H]1COC(=O)N1
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (227 mL of 3M solution in diethyl ether) was added to a mixture of toluene (340 mL) and THF (340 mL) at −20° C. A warm THF solution (170 mL) of the ester from Step 2 (40 g) was then added dropwise maintaining the temperature below −10° C. The mixture was aged for 2 hours and was then slowly added to a mixture of water (1000 mL) and acetic acid (200 mL) and the resultant mixture was stirred for 2 hours at room temperature. The aqueous layer was separated and the organic layer was extracted with water (2×200 mL). The product was extracted from the combined aqueous layers using dichloromethane and a continuous extractor. The dichloromethane extract was evaporated to dryness using heptane as a co-solvent to azeotrope off the acetic acid. The residue was purified by chromatography on SiO2 using ethanol and dichloromethane (1:30) to yield (4S)-4-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1
Reactant: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)C(C)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2CCC3(CCNCC3)C2=O)C(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.535 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (2.06 mL, 26.8 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles the residue was dissolved in methylene chloride (1 mL) and treated with hydrogen chloride (4 mL, 1N in diethyl ether) and concentrated to give 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 265.19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[CH2:28][CH2:27][N:26]3[CH2:29][CH2:30][CH2:31][C@H:25]3[CH2:24]2)=[C:18]([F:32])[CH:17]=1.BrC1C=C2C(=CC=1)[C:40](=[O:44])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:44][CH3:40].[F:32][C:18]1[CH:17]=[C:16]([NH2:15])[CH:21]=[C:20]([F:22])[C:19]=1[N:23]1[CH2:28][CH2:27][N:26]2[CH2:29][CH2:30][CH2:31][C@H:25]2[CH2:24]1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1cc(F)c(N2CCN3CCC[C@H]3C2)c(F)c1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Product: Nc1cc(F)c(N2CCN3CCC[C@H]3C2)c(F)c1

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 1.87 g (72.2% yield) of light brown solid is obtained from 1.45 g (5.14 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 1.3 g (5.14 mmol) of {3,5-difluoro-4-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]phenyl}amine: mp 190-191° C.; MS (ESI) m/z 503.1 (M+H)+1
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[CH3:12][C:6]1([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)[S:9][CH2:8][CH2:7]1
Reactant: CC1(C)CCSc2cc(Br)ccc21
Reactant: CCCCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc2c(c1)SCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 7-bromo-4,4-dimethyl-thiochroman (2.0 g, 7.78 mmole) in 45 mL of THF at −78° C. was, treated with 3.9 mL of 2.5M butyllithium. After 30 minutes at −78° C. a solution of hexanoic acid methoxy-methyl-amide (1.486 g, 9.33 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −78° C. for 30 minutes, warmed to room temperature, quenched by the addition of 50 mL of saturated aqueous ammonium chloride solution and extracted with three 50 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 3% ethyl acetate in hexanes) to yield 1.183 g of 1-(4,4-dimethyl-thiochroman-7-yl)-hexan-1-one as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]#N.Cl.[NH2:21][OH:22].C(N(CC)CC)C.[OH2:30]>CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]([NH:21][OH:22])=[O:30]
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Reactant: NO
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)NO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-Amino-4′-trifluoromethyl-biphenyl-3-carbonitrile (10 g) was dissolved in 250 ml of methanol and added 5.6 g of hydroxylamine hydrochloride and 8.1 g of triethylamine. The reaction mixture was stirred at 50° C. overnight, added 100 ml of water and 100 ml of ethyl acetate. The water phase was extracted with 100 ml of ethyl acetate. The organic phases was washed with 100 ml water and after that with 100 ml saturated sodium chloride. The organic phase was dried with magnesium sulfate and evaporated to an oil. Yield 10.8 g (96%).