Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].CN1CC[O:25][CH2:24][CH2:23]1.C(OC(Cl)=O)C(C)C.Cl.[OH:37][CH:38]([C:42]([F:45])([F:44])[F:43])[CH:39]([NH2:41])[CH3:40]>C(#N)C.C(Cl)(Cl)Cl>[F:43][C:42]([F:45])([F:44])[CH:38]([OH:37])[CH:39]([NH:41][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[C@@H:2]1[CH2:18][CH2:19][CH2:20][N:1]1[C:24](=[O:25])[CH3:23])[CH3:40]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(N)C(O)C(F)(F)F
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC(C)C(O)C(F)(F)F
Temperature: -15 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
Ac-L-prolyl-L-alanyl-L-proline (1.17 g, 3.61 mmol) was suspended in dry acetonitrile (55 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and internal thermometer. The suspension was cooled to -15° C. and N-methylmorpholine (0.40 ml, 3.61 mmol) was added followed by isobutylchloroformate (0.47 ml, 3.61 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Ten minutes after the addition was completed, a mixture of 3-hydroxy-4,4,4-trifluoro-2-butyl-amine hydrochloride (0.65 g, 3.61 mmol) and N-methylmorpholine (0.40 ml, 3.61 mmol) in chloroform (25 ml) was added at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was allowed to warm slowly to room temperature and then stirred at room temperature for 4 hours. The reaction mixture was evaporated on a rotary evaporator to an oily residue which was dissolved in water (65 ml) and treated with a mixed bed resin (J. T. Baker--ANGMI-615, 17 g). After 15 minutes the mixture was filtered and the filtrate evaporated on a rotary evaporator. Chromatography using methylene chloride - 10% methanol as the eluent gave the above-named product, (0.37 g) in 23% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1onc(-c2nonc2COc2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.0480 mmol), phenol (14 mg, 0.14 mmol) and triphenylphosphine (16 mg, 0.062 mmol) were dissolved in anhydrous THF (500 μL) then cooled to 0° C., followed by a dropwise addition of diethyl azodicarboxylate (9.8 μL, 0.062 mmol) in a solution of THF. Reaction was allowed to warm to rt then stirred 4 hrs. After concentration in vacuo, the sample was purified by reverse phase HPLC to yield a white powder (9 mg, 48%). MF=C17H10ClFN4O4; LCMS calculated for C17H11ClFN4O4(M+H)+: m/z=389.045
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+]>C(O)C.O>[C:22]([CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:23]
Reactant: [C-]#N
Reactant: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3c(CC#N)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 1.29 mmol) in ethanol (6 mL) was added a solution of potassium cyanide (0.1 g, 1.54 mmol) in water (0.5 mL). The mixture was refluxed for 1.5 h, then cooled to room temperature. Ethanol was evaporated and the mixture was extracted with ethylacetate. After chromatographic purification gave 4-cyanomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a yellow solid (0.29 g, 73% yield). Mass spec: MH+=311.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22](=[O:24])[CH3:23])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
4-(5-Isoquinolylsulfonyl)aniline 20 mg (0.1 mmol) was dissolved in a mixture solution of acetic anhydride 2 ml and pyridine 2 ml, the mixture was stirred overnight at room temperature, water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated potassium hydrogensulfate and with saturated sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N1-[4-(5-isoquinolylsulfonyl)phenyl]acetamide 10 mg (44.3%)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:35](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:35])[C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To ethyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, are added N,N-dimethylformamide and potassium carbonate, then, methyl iodide is added to the reaction solution, and the mixture is stirred at room temperature. Diluted hydrochloric acid is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water and then saturated saline, and dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain ethyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [compound 3-12 of the present invention].
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>C(#N)C>[CH:19]([N:6]1[CH2:7][CH2:8][C:3]([NH:2][CH3:1])([C:9]([NH2:11])=[O:10])[CH2:4][CH2:5]1)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: CNC1(C(N)=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC1(C(N)=O)CCN(C(C)C)CC1
Yield: 48.3 %

Procedure:
4-(methylamino)piperidine-4-carboxamide (250 mg, 1.59 mmol), potassium carbonate (264 mg, 1.91 mmol) and 2-bromopropane (0.179 ml, 1.91 mmol) in acetonitrile (10 ml) were heated at reflux for 1.5 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with ammonia in methanol/dichloromethane (90/10) to give 1-isopropyl-4-(methylamino)piperidine-4-carboxamide (153 mg, 48%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 0.92 (d, 6H); 1.45 (m, 2H); 1.77 (m, 2H); 1.86 (s, 1H); 2.06 (s, 3H); 2.38 (m, 4H); 2.59 (m, 1H); 6.82 (s, 1H); 7.15 (s, 1H).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(CCc3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Nc2ncnc(CCc3ccc4[nH]ncc4c3)n2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To a solution of 4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.03 g, 0.064 mmol) in DCM (2 mL) cooled to 0° C., TFA (0.025 mL, 0.320 mmol) was added and the reaction mixture was stirred at 23° C. overnight. The reaction mixture was concentrated, washed with diethyl ether, and purified by preparative HPLC on a SY C18 column (20×19 mm) using 0-100% mobile phase B (ACN) in mobile phase A (10 mM NH4OAc) over 17 min to give 4-(2-(1H-indazol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a white solid (4 mg, 16%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCO)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl (2-benzyloxy-4-nitrophenoxy)acetate (800 mg, 4.83 mmol) was dissolved in THF (50 ml); thereafter, sodium borohydride (457 mg, 12.1 mmol) was added and the mixture was heated to the reflux temperature. At the same temperature, methanol (5 ml) was slowly added dropwise over 30 min, followed by stirring at the reflux temperature for 30 min. The reaction solution was cooled to room temperature and water (10 ml) was added, followed by extraction with ethyl acetate (200 ml). The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 1:1 solvent system on n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 2-(2-benzyloxy-4-nitrophenoxy)ethanol (400 ml).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]([OH:17])=[O:16])=[CH:11][NH:12]2)=[CH:8][CH:7]=1>CO>[CH3:1][O:16][C:15]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([Br:5])=[CH:7][CH:8]=2)[NH:12][CH:11]=1)=[O:17]
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1c[nH]c2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Acetyl chloride (29.43 g, 374 mmol) is added slowly at room temperature to a solution of 6-bromo-indole-3-carboxylic acid (45 g, 187.46 mmol) in 500 mL of methanol and the resulting solution is stirred at 65° C. overnight. The reaction is cooled to room temperature. A white precipitates appears when cooling. After stirring 2 h at room temperature, the solid is filtered off and dried under vacuum. 34.4 g (72%) of the title compound is obtained as a light brown solid. MS (m/e): 254 (M+1)
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCl
Reaction time: 1 h

Procedure:
DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1 g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:14]#[N:15])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)[OH:17]>>[C:1]([NH:15][C:14](=[O:17])[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)C(=O)C#N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)C(=O)C(C)(C)C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
First 25.6 g (0.25 mol) of acetic anhydride and then 27.8 g (0.25 mol) of pivaloyl cyanide were introduced, in each case at room temperature, into 49.0 g (0.5 mol) of concentrated sulphuric acid, which had been initially introduced into the reaction vessel. After subsequently stirring the reaction mixture for 4 hours, 150 g of icewater were added and the mixture was stirred thoroughly. The reaction product which precipitated was filtered off, washed with 100 ml of water and dried. 37.0 g (86.5% of theory) of trimethylpyruvic acid N-acetylamide were obtained as colorless glistening flakes of melting point 82°-84° C.; content, according to determination by gas chromatography, >98%. No additional purification operations were required for further reactions.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH2:16]1[CH2:20]OC[CH2:17]1>C(Cl)Cl>[CH:16]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([Br:5])[C:7]=1[CH3:15])([CH3:20])[CH3:17]
Reactant: C1CCOC1
Reactant: Cc1c(Br)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cccc1C(=O)OC(C)C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (6 mL) was added over 1 min to a 0° C. suspension of 3-bromo-2-methyl benzoic acid (2.15 g, 10 mmol) in DCM (10 mL). After 30 min of stirring, THF (5 mL) was added to induce dissolution. The now homogeneous solution was stirred for 24 h at rt and the volatile component were removed in vacuo. A portion of the crude acid chloride was dissolved in dry isopropyl alcohol (10 mL) and pyridine (2 mL) was added. After stirring for 4 h at rt, the volatile components were removed in vacuo. The residue was partitioned between EtOAc (70 mL) and HCl (1M, 30 mL) and the layers were separated. The organic layer was washed with HCl (1M, 10 mL), NaHCO3 (3×20 mL), water (30 mL), brine (30 mL), and was dried over sodium sulfate. Removal of solvent in vacuo yielded the title compound as a light-yellow oil which was used without further purification. 1H-NMR (CDCl3): δ 7.69 (d, 2H, J=7.7 Hz), 7.11 (t, 1H, J=7.9 Hz), 5.26 (heptet, 1H, J=6.3 Hz), 2.63 (s, 3H), 1.39 (d, 6H, J=6.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]#[CH:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[O:23][CH3:24]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:20]#[C:19][CH2:18][C:16]2[CH:15]=[C:14]([O:21][CH3:22])[C:13]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:17]=2)=[CH:4][N:3]=1
Reactant: C#CCc1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(CC#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1,2,3-Trimethoxy-5-(prop-2-ynyl)benzene (412 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)pyrimidine as a white powder (251 mg, 80%): Rf=0.23 (9:1, CHCl3:MeOH); mp=decomposed above 190° C.; 1H NMR (DMSO-d6) δ 7.84 (s, 1H), 6.71 (s, 2H), 6.26 (s, 2H), 3.80 (s, 2H), 3.77 (s, 6H), 3.63 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.2, 158.7, 152.8, 136.0, 132.8, 105.2, 93.1, 90.1, 76.5, 60.1, 55.8, 25.6; Anal. (C16H18N4O3) C, H, N.
Reaction SMILES: [Li]CCCC.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:21][CH:22]=2)[N:17]=1.[C:30](=[O:32])=[O:31]>C1COCC1>[Cl:15][C:16]1[C:25]([C:30]([OH:32])=[O:31])=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:28])([F:27])[F:29])=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc2ccc(Cl)nc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
11 ml of BuLi (1M in hexane) were added dropwise at −78° C. to a solution of 1.9 ml (11 mmol) of DIPEA in THF (77 ml). After stirring for 30 min at −78° C., a solution of 2.31 g (10 mmol) of 2-chloro-7-(trifluoromethyl)quinoline in THF (30 ml) was added and stirring was carried out for a further 30 min at −78° C. The reaction solution was then poured onto finely divided, solid CO2. After heating to RT, most of the THF was removed in vacuo. A 1M aq. NaOH soln. was then added and the phases were separated. The aqueous phase was acidified with 10% hydrochloric acid and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 2.12 g (7.7 mmol, 71%) of 2-chloro-7-(trifluoromethyl)quinoline-3-carboxylic acid, which was reacted further without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[O:11][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Reaction time: 8 h
Yield: 66.81 %

Procedure:
To a flask containing 4-bromo-3-hydroxybenzoic acid (D.1) (available from Combi-Blocks Inc.) (2.40 g, 11.06 mmol) and cesium carbonate (8.287 g, 25.44 mmol) in DMF (40 mL), was added 1-bromobutane (2.494 mL, 23.22 mmol), and the mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by CombiFlash® chromatography (0 to 20% EtOAc/hexanes) to provide D.2 (2.4326 g, 66.81% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.16 ml of methanesulphonyl chloride followed by 3.86 ml of triethylamine are added to a solution of 5 g of (R)-3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester in 80 ml of DCM cooled to 0° C. The medium is stirred at 0° C. for 1 h 30 min and 0.7 ml of triethylamine and 0.54 ml of methanesulphonyl chloride are again added. After 30 min at 0° C., the medium is hydrolysed, and the organic phase is washed twice in water and then with a saturated NaCl solution, and then dried over MgSO4. The medium is evaporated, to give 6.8 g of a pale yellow oil.
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C:30]([NH2:32])=[S:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:32][C:30]1[S:31][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:29]=1
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Bromine (0.11 mL, 2.1 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.72 g, 2.1 mmol) in acetic acid (20 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (20 mL), to the solution were added thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 mL, 2.5 mmol) and the mixture was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was filtered and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=1/[CH:17]=[CH:18]/[CH:19]([OH:21])[CH3:20].N1C=CC=CC=1>ClCCl>[CH2:5]([O:4][C:2](=[O:14])[OH:3])[CH3:6].[OH:21][CH:19]([CH3:20])[CH:18]=[CH:17][C:9]1[C:10]([CH3:15])([CH3:16])[CH2:11][CH2:12][C:13](=[O:14])[C:8]=1[CH3:7]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CCC1=O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(C=CC(C)O)C(C)(C)CCC1=O
Product: CCOC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of ethyl chloroformate (1.74 g, 0.016 mol) in dichloromethane (10 mL) was added dropwise over a 1 hour period to a cold (5° C.) solution of 4-oxo-β-ionol (3.33 g, 0.016 mol, which may be prepared as described by R. Kaiser and D. Lamparsky, Helv. Chim. Acta, 1978, 61, 2328-2335), pyridine (1.28 g, 0.016 mol) and dichloromethane (30 mL). After stirring the mixure at 5°-10° C. for 2 hours it was added to ice water (20 mL) The organic layer was washed with 5% phosphoric acid solution until neutral and dried over sodium sulfate. The solvent was removed and the residue chromatographed. Kugelrohr distillation (bath temp. 150° C., 0.5 mm) gave 2.0 g (GLC purity; 85%) of 3-(3-hydroxy-1-butenyl)-2,4,4-trimethyl-2-cyclohexen--one ethyl carbonate. 1H-NMR (CDCl3) δ1.12 (6H,s), 1.35 (3H,d,J=7Hz), 1.40 (3H,t,J=7Hz), 1.77 (3H,s), 1.7-2.7 (4H,m), 4.20 (2H,q,J=7Hz), 4.8-5.4 (1H,m), 5.53 (1H,dd,J=16 and 6Hz), 6.31 (1H,d,J=16Hz); IR (film)vmax 2960, 1745, 1665, 1460, 1440, 1365, 1250 cm-1 ; MS m/e 280, 265, 236, 207, 191, 134.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:7]=12)=[O:5])[CH3:2].[Na].[CH3:18][O:19][C:20](=[O:28])[CH:21](Br)[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[CH:21]([N:9]1[C:10](=[O:11])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:8]12)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC(Br)C(=O)OC
Reactant: CCOC(=O)c1c2cccccc-2[nH]c1=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2cccccc-2n(C(CC(=O)OC)C(=O)OC)c1=O
Temperature: 100 °C

Procedure:
A mixture of 1,2-dihydro-2-oxocyclohepta[b]pyrrole-3-carboxylic acid ethyl ester, sodium salt (12.5 g, described in example 1) and 2-bromobutanedioic acid dimethyl ester (14.5 g) in DMF (14.5 g) was heated at 100° C. for 48 hr. The mixture was cooled, diluted with water and extracted with chloroform. The chloroform extract was passed through a column of silica gel. Subsequent elution of the column with chloroform-methanol (97:3) gave 2.0 g of 2-(3-ethoxycarbonyl-1,2-dihydro-2-oxocyclohepta[b]pyrrol-1-yl) butanedioic acid dimethyl ester, nmr (CDCl3) δ1.4 (t, 3H), 3.35 (m, 2H), 3.6 and 3.7 (2s, 6H), 4.4 (q, 2H), 5.6 (t, 1H), 7.45 (m, 4H), 9.05 (d, 1H).