Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.CCOCC>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)cc1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 1-(4-methoxyphenyl)piperidin-4-one (5.65 g, 27.6 mmol) and (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.65 g, 30.3 mmol) in MeOH (200 mL) was added STAB (10.49 g, 49.5 mmol) in small portions. The reaction mixture was stirred overnight, then was concentrated to 1/10 of the original volume. NaOH (100 mL, 1N aqueous) and CH2Cl2 (100 mL) were added and the organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated. Upon the addition of ether, tert-butyl {(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}carbamate (6.98 g, yield 67.5%) precipitated as a white solid. The resulting solid was dissolved in CH2Cl2 (50 mL) to which was added 4N HCl/dioxane (50 mL). After 2 h at room temperature, ether was added until (3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-amine precipitated (as the HCl salt) from the solution, and was collected by filtration as a white solid (6.40 g, 52% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43]
Reactant: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCNCC3)c2)ccc1OCC(=O)O

Procedure:
Cyclopropyl adduct 300a was deprotected with TFA/CH2Cl2 in the usual way to provide a pale grey solid. IR(KBr): cm-1 3200-2500(br), 1738, 1680. HR-MS: Calc'd 411.1920, Found 411.1925.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH2:24][NH2:25]>>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:25][CH2:24][C:20]3[S:21][CH:22]=[CH:23][C:19]=3[CH3:18])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccsc1CN
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(NCc3sccc3C)cc2n1

Procedure:
In analogy to example 1, on reaction of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline with 3-metylthiophene-2-metylamine there was obtained (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-(3-methyl-thiophen-2-ylmethyl)-amine as yellow foam. ISP mass spectrum, m/e: 338.3 (M+1 calculated for C20H23N3S: 338).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14](Cl)=[O:15])[CH2:10][CH2:11][CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(CCC)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 5.16 g. 3-ethylthio-1,2,4-triazole, 7.8 g. N-n-butyl-N-propylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1 to give a residual oil. This oil was distilled under reduced pressure to give 1-(N-n-butyl-N-propylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 127° C./0.2 mm. (91.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:9]([NH2:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1.[NH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>O1CCOCC1.CN(C=O)C>[NH2:24][C:9]1[C:8]([C:31]2[CH:32]=[CH:33][C:28]([C:26]([NH2:25])=[O:27])=[CH:29][CH:30]=2)=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc(C(N)=O)cc3)c2)cc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 56 %

Procedure:
Aqueous K2CO3 solution (1 M, 0.4 mL) was added to a suspension of 3-bromo-5-[4-(methylsulfonyl)phenyl]pyridin-2-amine obtained as described above (0.15 g, 0.46 mmol), 4-aminocarbonylphenylboronic acid (0.120 g, 0.51 mmol) and Pd[(PPh)3]4 (0.016 g, 0.02 mmol) in dioxane (5 mL) and DMF (2 mL) under N2. The reaction mixture was stirred at 120 ° C. for 14 h, poured onto H2O (10 mL) and extracted with MeOH/CHCl3 (1:4) (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5% MeOH/EtOAc) to yield the desired product (0.26 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H, J=2.4 Hz), 8.07 (s, 1H), 8.02-7.92 (m, 6H), 7.78 (d, 1H, J=2.4 Hz), 7.64 (d, 2H, J=8.4 Hz), 7.44 (bs, 1H), 6.11 (bs, 2H) and 3.24 (s, 3H). LC-MS APCI: Calculated for C19H17N3O3S, 367; Observed m/z 368 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:28]1([CH3:33])[CH2:27][N:26]([C:15]2[CH:14]=[CH:13][C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:42]5[C:37]([F:36])=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:8][CH:9]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:31][CH2:30][O:29]1
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)CCO1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A 25 mL RB flask was charged with (R)-2-amino-2′-(2,2-dimethylmorpholino)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (270 mg, 0.526 mmol), tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.053 mmol), 2-fluoropyridin-3-ylboronic acid (119 mg, 0.841 mmol), DMF (2629 μL) and sodium carbonate (2M solution) (789 μL, 1.577 mmol). The mixture was stirred under argon for 2 hrs at 85° C. The mixture was diluted with water (2 ml) and extracted with 10 ml of EtOAc. The organic layer was washed with water, brine, passed through plug of Celite and concentrated. Dark residue was purified by silica gel chromatography on a 12 g RediSep column using 5-70% DCM/MeOH/NH4OH in DCM to afford (S)-2′-(2,2-dimethylmorpholino)-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=461.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>C(#N)C.O>[N+:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:15])([F:14])[F:5])[C:8]=1[OH:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Acetyl nitrate obtained mixing acetyl anhydride (3.30 g, 33 mmol) with fuming nitric acid (2.05 g, 33 mmol) at 0° C. was dropped into a solution of 2-trifluoromethylphenol (4.86 mg, 30 mmol) in acetonitrile (60 ml) at 0° C. followed by stirring for 10 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (60 g of silica gel; developing solvent, hexane:methylene chloride=5:1) to provide 2.1 g (yield 33%) of 2-nitro-6-trifluoromethylphenol as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].[OH-:18].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:6]=1[C:7]([NH2:8])=[O:18]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Temperature: 80 °C

Procedure:
A suspension of 0.26 g (1.139 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carbonitrile in 5 cm3 of concentrated sulphuric acid is heated at a temperature in the region of 80° C. for 1 hour. After having cooled the reaction mixture to a temperature in the region of 20° C., it is poured over crushed ice and then a 5N aqueous sodium hydroxide solution is slowly added to a basic pH in the region of 10. The reaction mixture is extracted with 7 times 10 cm3 of a dichloromethane/MeOH mixture (98/2 by volume). All the organic phases are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.19 g of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide, in the form of a red-brown solid; EI: m/z=246 (M+) base peak, m/z=229 (M−NH3+).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]2[O:15][N:14]=[CH:13][C:12]=2[C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=2)[CH2:10][CH2:9]1.Cl>ClCCl>[C:13]([CH:12]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:15])[C:16]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=1)=[O:26])#[N:14]
Reactant: CSc1cc(C(=O)c2cnoc2C2CC2)ccc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cc(C(=O)C(C#N)C(=O)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Triethylamine (0.5 g) was added to a solution of 5-cyclopropyl-4-(4-methyl-3-methylsulphenylbenzoyl)isoxazole (0.66 g) in dichloromethane. The mixture was stirred at room temperature overnight. Further triethylamine (0.2 g) was added and the mixture was stirred for a further 24 hours. Hydrochloric acid (2M) was added and the layers were separated. The organic layer was washed with aqueous sodium chloride solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-cyano-3-cyclopropyl-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (COMPOUND 665, 0.12 g) as an orange gum which solidified, m.p. 64.7°-67.9° C.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24]Br)=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC.O1CCCC1>[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24][CH2:7][C:6]#[N:8])=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(CBr)c(Br)cc1OCc1ccccc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CCC#N)c(Br)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of n-butyllithium (1.8 mL of a 2.5 M solution in hexane, 4.5 mmol) in 5 mL of tetrahydrofuran is added a solution of acetonitrile (1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 15 min. A solution of 5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene (0.7 g, 1.8 mmol) in 3 mL of tetrahydrofuran is added and stirring is continued for 1 hour at −78° C. The reaction is quenched by the addition of 15 mL of water and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate and the organic layers combined, then dried with sodium sulfate. After reducing in vacuo, the crude product is purified by flash chromatography using a gradient of 95:5 to 4:1 hexanes/ethyl acetate as an eluent. The clean fractions are combined, reduced in vacuo and dried to yield 0.343 g of 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white solid, mp 52-53° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[N:30]1([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:39][C:38]3[CH:37]=[N:36][C:35]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:42][CH:41]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCN(Cc2ccc(N3CCCC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a mixture of 11.9 mg of 7-methyl-8-(piperazin-1-ylcarbonyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, 15.9 mg of 6-(1-pyrrolidinyl)nicotinaldehyde, 0.3 mL of 1,2-dichloroethane, and 30 μL of acetic acid was added 19.1 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 9.7 mg of 7-methyl-8-[(4-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}piperazin-1-yl)carbonyl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:15][NH:16][CH3:17]>CO.CN(C=O)C>[OH:1][CH:2]([CH2:14][N:16]([CH3:17])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-(2,3-Epoxypropoxy)nitrobenzene (obtained as described in Synthetic Communications, 1994, 24, 833; 4.3 g,) was dissolved in methanol (30 ml) and DMF (10 ml). A solution of dimethylamine in methanol (2M, 17 ml) was added and the mixture was stirred overnight. Volatile material was removed by evaporation and the residue was partitioned between saturated sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The organic layer was separated and washed with saturated sodium chloride (2×100 ml) and dried (MgSO4). Concentration gave the product as an oil that slowly crystallised under high vacuum (4.79 g, 89.9%). NMR (CDCl3): 2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m, 3H), 7.00 (d, 2H), 8.20 (d, 2H); MS (M+H)+: 241.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH3:14][CH:15]([CH3:19])[CH:16]=[C:17]=[O:18].O1CCCC1>CN(C)C=O>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:17]([OH:18])[CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: FC(F)(F)C(Cl)Br
Reactant: CC(C)C=C=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Sodium t-butoxide (1.39 g of a 42% solution in dry dimethyl formamide was added dropwise over a period of 5 minutes to a stirred mixture of 1-bromo-1-chloro-2,2,2-trifluoroethane (0.535 ml), 3-methylbut-1-en-1-al (0.538 ml) and dry tetrahydrofuran (10 ml) maintained at a temperature of -78° C. by external cooling under a nitrogen atmosphere. The mixture was then stirred for a further 40 minutes at the temperature after which the external cooling was removed and the reaction quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The mixture was then partitioned between water and diisopropyl ether and the aqueous phase separated, washed with diisopropyl ether (3×25ml), and the washings combined with the organic phase. The organic phase was washed with brine and dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. After purification by a procedure similar to that set out in the previous Example there was obtained 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (1.39 g), identified by nuclear magnetic resonance and infra-red spectroscopy.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])([O-:9])=[O:8].[CH2:20](I)[CH3:21].Cl>CN(C=O)C>[Cl:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[CH:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: CCI
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To potassium carbonate (103 g) was added DMF (1 L), and a solution of 3-nitro-4-chlorobenzoic acid (125 g) in DMF (500 ml) was added thereto under ice-cooling. Ethyl iodide (116 g) was added thereto and the resulting mixture was stirred at 60° C. for 3 hours. The reaction solution was added to a 1N aqueous hydrochloric acid solution and the crystals precipitated were collected by filtration, washed with a 1N aqueous hydrochloric acid solution and water and then dried under reduced pressure to obtain ethyl 4-chloro-3-nitrobenzoate quantitatively.
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:35][CH2:36][S:37][CH2:38][CH2:39]4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCSCC4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Ethyl 3-(methyl{[4-({2-methyl-1-[3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl]propyl}amino)phenyl]carbonyl}amino)propanoate (485 mg) synthesized in Example A203 was dissolved in ethanol (2.0 mL) and tetrahydrofuran (2.0 mL), and 1N aqueous sodium hydroxide solution (1.96 mL) was added to the solution, and the mixture was stirred at room temperature for 0.5 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.96 mL) under ice-cooling, and stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (421 mg, 91%) as a colorless amorphous form.
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][CH:2]1[CH:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C(F)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 0.287 mol) in anhydrous methylene chloride (630 mL) was treated with triethylamine (60 mL, 0.43 μmol) followed by methane sulfonyl chloride (26.7 mL, 0.345 mol) at 0° C. under N2 atmosphere. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride (2×500 mL). The combined organic phases were washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 20-30% EtOAc/Hexane to provide the tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g, 91%). 1HNMR (CDCl3, 400 MHz): δ 4.98-4.86 (m, 1H), 4.80-4.74 (m, 0.5H), 4.67-4.63 (m, 0.5H), 3.92-3.45 (m, 3H), 3.44-3.25 (m, 1H), 3.08 (s, 3H), 2.20-2.07 (m, 1H), 1.93-1.80 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[I:9][C:10]1[N:11]=[C:12]([CH:23]=O)[N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1.O.[OH-].[Na+]>CS(O)(=O)=O.C(Cl)(Cl)Cl>[I:9][C:10]1[N:11]=[C:12]2[N:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]2[O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[CH:14]=1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (223 mg, 2.02 mmoles) in methanesulfonic acid (3.4 mL) is added a solution of 4-Iodo-1-phenethyl-imidazole-2-carbaldehyde (example 2B) (220 mg, 0.675 mmoles) in chloroform (1 mL). The reaction mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the pH is adjusted to 9-10 by adding 12N NaOH dropwise. The aqueous phase is extracted three times with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5) to give 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 126° C.