Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=4)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[C:42](O)(=O)C.C=O.C([BH3-])#N.[Na+]>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([N:28]([C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=4)[CH3:42])[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl 4-[N-[-2-acetoxymethyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]amino]benzoate (0.060 g, 0.106 mmol) in THF (6 ml) was added glacial acetic acid (2 ml) followed by 37% aqueous formaldehyde (0.090 ml). The solution was stirred for 2.5 hours at room temperature and then sodium cyanoborohydride (0.017 g, 0.27 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with more ethyl acetate (2×25 ml). The combined organics were washed with saturated aqueous sodium bicarbonate (30 ml), brine (30 ml), dried (Na2SO4) and concentrated in vacuo to leave an oil (0.060 g, 98%); 1H-NMR (CDCl3) 1.20 (s, 9H, POM C(CH3)3), 1.58 (s, 9H, CO2C(CH3)3), 2.15 (s, 3H, CH3CO), 2.02, 2.52 (2×m, 2H, 7-CH2), 2.74 (s, 3H, N10-Me), 3.13 (m, 2H, 8-CH2) 5.21 (s, 2H, 2-CH2), 5.66 (t, 1H, J=8.1 Hz, 6-H), 6.12 (AB system, J=10.8 Hz, 2H, POM CH2), 6.85 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.58 (s, 1H, 9-H), 7.90 (d, J=8.9 Hz, 2H, 2,6′-ArH), 8.08 (s, 1H, 5-H); MS (ESI, m/z) 578 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[OH:41][C:37]1[CH:36]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 65, 100 mg, 0.225 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (27 mg, 0.25 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 31% (42 mg, 0.0954 mmol) of the title compound.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[C:22]([N+:23]([O-])=O)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)=O)(C)(C)C>C(O)(=O)C.[Fe]>[O:5]=[C:6]1[N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[N:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[NH:23]1
Reactant: COC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cnc2c(c1)[nH]c(=O)n1cccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
To a suspension of methyl 6-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5-nitronicotinate (0.0672 g, 0.193 mmol) in Acetic Acid (Volume: 1.5 mL) was added IRON (0.054 g, 0.967 mmol) at 23° C. The reaction was stirred at 80° C. for 6 hr. The reaction mixture was then cooled to room temperature and concentrated to dryness via rotary evaporation. The resulting residue was diluted with 1:1 DCM:MeOH (4 mL), filtered, rinsed with 1:1 DCM:MeOH (3×2 mL), and the filtrate was then concentrated to dryness via rotary evaporation. The residue was re-suspended in H2O (4 mL), filtered, rinsed with H2O (3×2 mL), and the resulting solid was dried in vacuo. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation to provide methyl 6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine-3-carboxylate (0.0294 g, 0.121 mmol, 62.5% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H) 6.82 (dd, J=3.54, 3.03 Hz, 1 H) 7.26 (dd, J=3.54, 1.52 Hz, 1 H) 7.80 (dd, J=3.03, 1.52 Hz, 1 H) 8.07 (d, J=2.02 Hz, 1 H) 8.88 (d, J=1.77 Hz, 1 H) 11.84 (s, 1 H). ESI-MS: m/z 244.1 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24]>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]([OH:24])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of diisopropyl amine (12.4 mL, 88.2 mmol) in THF (50 mL) at −78° C. was added n-butyllithium (35.3 mL, 88.2 mmol). The reaction mixture was stirred at −78° C. for 30 min, at which time ethyl acetate was added (16.1 mL, 163.2 mmol). After 1 h, 3-chloro benzaldehyde was added and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was quenched with aqueous saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was rinsed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford yellow oil. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:4) to afford ethyl 3-(3-chloro-phenyl)-3-hydroxy-propionate as a yellow oil (10.0 g, 99.0%). 1H NMR (400 MHz, d-DMSO): δ 7.43-7.30 (m, 4H), 5.66 (d, 1H), 5.01-4.95 (q, 1H), 4.14-4.04 (m, 2H), 2.71-2.58 (m, 2H), 1.24-1.17 (t, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:3); Rf=0.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12](OCC)=[O:13])=[N:7]1.O.[NH2:21][NH2:22].CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:21][NH2:22])=[O:13])=[N:7]1
Reactant: NN
Reactant: CCOC(=O)c1nc(C)n(Cc2cccc(Br)c2)n1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (1.28 g, 3.92 mmol) in MeOH (19 mL) was added hydrazine hydrate (784 μL, 7.84 mmol) and NEt3 (2.47 mL, 17.6 mmol). The reaction was allowed to stir overnight at RT. The solvent was then removed under reduced pressure and the crude material was spun down from toluene (3×) to give a white solid, which was used directly for the next step without further purification. MS (ES+) C11H12BrN5O requires: 309, 311 found: 310, 312 [M+H]+(1:1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3N=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[C:36](O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:34])([F:33])[F:35])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[CH:36]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Product: NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.088 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.03 g, 14%). MS (ISN) 485.2 [(M−H)−]; mp 263° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 2) was dissolved in 1.4 ml of N,N-dimethylformamide, and to this was added 0.10 g of anhydrous potassium carbonate, and 0.11 g of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 3 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residues was subjected to silica gel column chromatography to obtain 0.28 g of methyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 2-1 of the present invention].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]3[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:24]=1.C(=O)([O-])[OH:26].[Na+]>O1CCOCC1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:24]=[C:3]([CH2:2][OH:26])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=C([O-])O
Reactant: Fc1ccccc1C1=NCc2nc(CCl)cn2-c2ccc(I)cc21
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 1.2 g of 2-chloromethyl-6-(2-fluorophenyl)-8-iodo-4H-imidazo [1,2-a][1,4]benzodiazepine in 20 ml of dioxan was treated with a solution of 0.4 g of sodium hydrogen carbonate in 10 ml of water and the mixture was stirred at 80° C. for 2 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethanol. There was obtained 0.6 g of amorphous 6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol which was converted into the crystalline hydrochloride (m.p. 274-276° C.),
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(O[CH2:20][C:21]#[N:22])=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[CH2:20][C:21]#[N:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
4-Nitrobenzotrifluoride (5 g, 0.026 mole) and 4-chlorophenoxyacetonitrile (4.86 g, 0.029 mole) in dry DMF (50 ml) were added dropwise to a solution of potassium-t-butoxide (6.4 g, 0.057 mole) in dry DMF (30 ml) under argon at −10° C. over 1 hour. The mixture was stirred at −10° C. for a further 3 hours, after which it was poured into 5N HCl/ice water (1:1) (300 ml) and extracted into DCM (3×200 ml). The DCM extract was washed with 10% aqueous sodium hydroxide solution, 5N hydrochloric acid and brine, dried (Na2SO4) and evaporated in vacuo. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/60-80° petroleum ether to afford the title compound (1.9 g, 32%) as an orange oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH3:11]>>[CH2:9]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:10][CH3:11]
Reactant: CCCCl
Reactant: O=C1CCNCC1
Product: CCCN1CCC(=O)CC1

Procedure:
1-Propyl-4-piperidone is prepared from 4-piperidone and 1-chloropropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:29])[N:7]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Cl[C:54]1[C:59]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:57]=[CH:56][N:55]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-3](Cl)(Cl)(P(C2C=CC=CC=2)C2C=CC=CC=2)[C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[F:28][C:25]([F:27])([F:26])[C:22]1[CH:23]=[CH:24][C:19]([N:7]2[C:6](=[O:29])[C:5]3[C:9](=[CH:10][C:2]([C:54]4[C:59]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:57]=[CH:56][N:55]=4)=[CH:3][CH:4]=3)[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C[Si](C)(C)CCOCn1c2cc(Br)ccc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd-3](Cl)([c-]1cccc1)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c2cc(-c3ncccc3C(F)(F)F)ccc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
The product of Step 5 (1.3 g, 2.6 mmol), was dissolved in dioxane (10 mL) and flushed with N2. Bis(pinacolato)diboron (680 mg, 2.6 mmol), bis(diphenylphosphino)ferrocenyl palladium(II) dichloride (60 mg) and KOAc (380 mg, 3.9 mmol) were added. The mixture was stirred at 100° C. overnight. 2-Chloro-3-trifluoromethylpyridine (470 mg, 2.6 mmol), bis(diphenylphosphino)ferrocenyl palladium(II) dichloride (20 mg) and saturated Na2CO3 solution (1 mL) were added, and the mixture heated at reflux for a further 18 h. Purification by column chromatography gave 0.2 g of product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a stirred solution of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.555 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (381.8 mg, 1.555 mmol) in anhydrous dichloromethane (3 mL) was added diisopropylethylamine (1.35 mL, 7.775 mmol). The mixture was stirred at room temperature for 30 minutes. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with saturated Na2CO3 (aq.), water then brine. Organic layer was dried over MgSO4. The reaction mixture was purified via flash column chromatography to yield 1-[(3,4-dichlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine in 75.7% yield (538 mg) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:15]1[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]1=[O:22])[CH2:7][CH2:6]2
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 2.3 %

Procedure:
A mixture of 0.5 g 5-methoxy-1-indanone, 1.23 g oxindole and 2.7 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a greenish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Chromatography afforded 20 mg of 3-(5-methoxyindan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=1)[CH3:2].C(OC(=O)C1C=CN=CC=1CC)C.C(C1C=[N+]([O-])C=CC=1C1OC(=O)N(C)N=1)C.OO.C(=O)([O-])[O-].[K+].[K+].C(Cl)[Cl:54]>C(O)(=O)C>[Cl:54][C:6]1[CH:7]=[C:8]([C:9]2[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=2)[C:3]([CH2:1][CH3:2])=[CH:4][N:5]=1
Reactant: ClCCl
Reactant: CCc1cnccc1-c1nn(C)c(=O)o1
Agent: CCOC(=O)c1ccncc1CC
Agent: CCc1c[n+]([O-])ccc1-c1nn(C)c(=O)o1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: CCc1cnc(Cl)cc1-c1nn(C)c(=O)o1
Temperature: 80 °C
Yield: 70 %

Procedure:
Step-2: 5-(3-Ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one: The title compound was prepared from ethyl-3-ethylisonicotinate by following the similar procedure sequentially as described instep-2, step-3 and step-4 of Intermediate-1a. 1HNMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 3.56 (s, 3H), 3.03 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H); GC-MS (m/z) 205 (M)+ Step-3: 3-Ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-1-oxide: To a stirred solution of step-2 intermediate (3.50 g, 17.1 mmol) in acetic acid (30 mL) was added hydrogen peroxide (0.62 mL, 20.4 mmol) drop-wise at RT and the resulting mixture was heated to 80° C. and maintained for 12 h. The reaction was cooled to RT and basified with solid potassium carbonate. The resulting slurry was diluted with DCM (50 mL) and filtered. The filtrate was concentrated under vacuum to afford 2.70 g (70%) of the title compound as white solid. GC-MS (m/z) 221 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>ClCCl.CO>[ClH:23].[N:17]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[O:16])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane (140.0 g, 0.44 mol) in dichloromethane:methanol (1:1, v/v, 600 ml) at 0° C. was saturated with hydrogen chloride gas and the reaction mixture was stirred at room temperature under nitrogen for 18 hours after which time the reaction mixture was evaporated under reduced pressure and slurried in ethyl acetate to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with diethyl ether and drying in vacuo at 60° C. to give the title compound as a colourless solid (99.0 g, 90%). Rf 0.41 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 214 (MH)+. Found: C,47.50; H,8.10; N,16.55; C10H19N3O2HCl 0.2H2O requires C, 47.41; H, 8.12; N,16.59%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Al+3].[Li+].[Cl-].[Cl-].[Cl-].[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.[OH-].[Na+]>CCOCC.O>[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH2:18][CH2:19][NH2:20])=[CH:14][CH:13]=1
Reactant: N#CCCOc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCOc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 183.4 %

Procedure:
A suspension of aluminium chloride (7.95 g) in ether (25 ml) was added to a stirred suspension of lithium aluminium chloride (2.02 g) in ether (45 ml). A solution of 3-(4-chlorophenoxy)propionitrile (10. 4 g) in ether (75 ml) was then added to the stirred suspension in a dropwise fashion over a period of 0.5 hours. The reaction mixture was allowed to reflux during the addition and was stirred for a further 0.75 hours after the addition was complete. Water (20 ml) was slowly added to the cooled reaction mixture, followed by sodium hydroxide solution (0.001M, 10 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and the filtrate dried using phase separating paper and evaporated to give 3-(4-chlorophenoxy)propylamine as an oil (7.5 g). Treatment of this oil with ethereal hydrogen chloride solution gave a solid which was recrystallised from ethanol to yield the hydrogen chloride salt of 3-(4-chlorophenoxy)propylamine as a solid (1.6 g), m.p. 182° C.; microanalysis, found: C, 48.5; H, 5.9; N, 6.3, Cl 31.6%; C9H12ONCl.HCl requires: C, 48.6; H, 5.9; N, 6.3; Cl, 32.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(=O)oc2ccc(Cl)cc21

Procedure:
Under an argon atmosphere, to a mixture of 5-chloro-1,3-benzoxazol-2(3H)-one (50.0 g) and acetone (750 mL) were added K2CO3 (61.1 g) and tert-butyl bromoacetate (52.3 mL) at room temperature, followed by heating to reflux for 1.5 hours. The reaction mixture was filtered while hot, and washed with acetone. The filtrate and the washed solution were combined and concentrated under reduced pressure. The obtained solid was stirred with a mixed solvent of Hex/EtOAc (6/1) and collected by filtration, and further stirred with water and collected by filtration to obtain tert-butyl (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (81.1 g).