Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][C:2]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(Cl)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)nc1Cl
Temperature: 50 °C

Procedure:
2,6-Dichloropyridine, 25.0 gm (0.168 mole) was added slowly under constant stirring to concentrated sulfuric acid at 20°–25° C. To this solution, 75.0 gm of concentrated nitric acid (98.0%) was added slowly, keeping the reaction temperature below 50° C. After the addition, the resulting mixture was heated to 100°–105° C. for 5.0 hrs. The progress of the reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 50° C. and poured in ice water. The resulting precipitate was filtered and washed with water. The wet cake thus obtained was dried to give 24.5 gm of 2,6-dichloro-3-nitropyridine. The yield of 2,6-dichloro-3-nitropyridine was 75.38% and the GC purity was 99.5%.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[N:27](C(OC(C)(C)C)=O)/[N:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)=[O:16])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:5]1[N:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[S:7]/[C:6]/1=[N:14]\[C:15](=[O:16])[C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[CH:19][C:18]=1[NH:27]/[N:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1N(/N=C/c1cccc(C)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1nc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1N/N=C/c1cccc(C)n1
Yield: 60.9 %

Procedure:
A solution of Example 205B (120 mg, 0.19 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (0.15 mL, 1.9 mmol) at room temperature for 3 hours. The mixture was then concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The ethyl acetate layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with 1:1 hexanes-Et2O to afford 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.5 Hz, 3H), 1.29-1.48 (m, 11H), 1.77-1.96 (m, 2H), 2.43-2.56 (m, 3H), 4.46 (t, J=7.3 Hz, 2H), 7.23 (d, J=6.8 Hz, 1H), 7.65-8.00 (m, 4H), 8.15 (s, 1H), 8.59 (d, J=1.7 Hz, 1H), 12.29 (s, 1H); MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:11]1=[S:12])[CH3:14]
Reactant: Cc1cc(C)c(N=C=S)cc1C
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(C)c(C)cc2C)C1=S
Yield: 58.4 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (15.3 g) as an off-white solid, m.p. 162°-164° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.21; H, 6.93; N, 10.80. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1CBr
Yield: 69.3 %

Procedure:
A mixture of 1-benzyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.64 g, 10.3 mmol), N-bromosuccinimide (2.01 g, 11.3 mmol), and benzoyl peroxide (250 mg, 1.03 mmol) in CCl4 (100 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-40% EtOAc/hexanes) to give 2.4 g of the title compound as a viscous oil. MS: (+) m/z 335.92, 337.89 (M+1, 79/81Br)
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([F:25])[C:13]=1[CH3:26].CO>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[C:14]([F:25])[C:13]=2[CH3:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Yield: 103.8 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-3-fluoro-5-(3-fluorophenyl)-2-methyl-benzamide (0.9 g, 2.4 mmol, 1.0 eq) in THF (20 mL) under N2 was added a solution of BH3 (1 M in THF, 11.9 mL, 11.9 mmol, 5.0 eq). The reaction mixture was heated at reflux overnight. Methanol was added to quench the reaction and the solution was then concentrated in vacuo to give the title compound (900 mg, 100%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:33][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:32])([CH3:31])[CH3:30])(=[O:43])[CH3:42]
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](CCc1ccccc1C(C)(C)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100 gm) in dichloromethane (500 ml) at 25-30° C. 4-di(methyl amino)pyridine (5.32 gm) was added and cooled to 0° C. To the reaction mixture Triethylamine (26.4 gm) was added at 0° C. Acetic anhydride (26.7 gm) was added slowly at temp. 0-5° C. over 30-60 min and maintained the reaction at temp. 0-5° C. over 30 min. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3(500 ml) and stirred for 15 min. Temperature was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and separated the organic layer. Aq.layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 25% NH4Cl solution (500 ml). Organic layer was distilled below 40° C. to get the desired product as residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)[CH3:12]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C/C=C/c1cccc(F)c1)N(C)C(=O)OC(C)(C)C
Temperature: 112 °C
Yield: 108.4 %

Procedure:
A 180 mL thick-walled glass pressure tube was charged with 3-bromofluorobenzene (0.95 g, 5.41 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.08 g, 5.41 mmol), prepared as previously described, palladium(II) acetate (12.2 mg, 0.05 mmol), tri-o-tolylphosphine (65.92 mg, 0.22 mmol), triethylamine (3 mL, 21.52 mmol) and anhydrous acetonitrile (6 mL). The tube was flushed with nitrogen, sealed and the mixture was stirred and heated at 112° C. (oil bath temperature) for 66 h. The resulting mixture containing oily, brown solids, was cooled to ambient temperature and concentrated on a rotary evaporator. The resulting orange-yellow solids were diluted with water (20 mL) and extracted with CH2Cl2 (4×20 mL). The combined CH2Cl2 extracts were washed with saturated NaCl solution (30 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was dried under high vacuum to produce a light-brown oil (1.72 g). The crude product was purified by column chromatography on silica gel (90 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.29) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.36 g (85.8%) of a light-yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:5][CH:4]=1)(=[O:30])=[O:29]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2)cc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-[4-(hydroxymethyl)phenoxy]phthalonitrile (1.0 g, 3.9 mmol) prepared according to procedures described in literature, and triethylamine (0.80 ml, 5.8 mmol) in anhydrous CH2Cl2 (50 ml), kept at 0° C. under stirring and in an inert atmosphere, methylsulfonylchloride was added (0.33 ml, 4.3 mmol). The mixture was stirred at 0° C. for 1 hour, then ft was diluted with CH2Cl2 (50 ml) and washed with 1% HCl solution (60 ml), then with brine (50 ml), the organic layer was dried on Na2SO4 and the solvent was evaporated. 1.2 g (92%) of the title compound were obtained as a viscous fluid that crystallised on standing.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C(O)CCC>CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 140 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (1.0 g, 5.0 mmol) and (R)-2-(2,5-difluorophenyl)pyrrolidine (Prepared as described in Preparation A; 1.9 g, 11 mmol) in n-butanol (4.6 mL, 50 mmol) was sealed in a pressure reaction tube and stirred in a 140° C. oil bath overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (250 mL), then washed with water (2×150 mL) and brine (150 mL), filtered through a Biotage Phase Separator filter paper and concentrated. The crude material was purified by silica gel chromatography, eluting with 2:1 EtOAc/hexanes to yield the product as a foamy yellow powder (1.3 g, 75% yield).
Reaction SMILES: Br.[NH:2]=[C:3]1[N:7]([CH2:8][C:9](O)=O)[CH:6]=[CH:5][S:4]1.P(Br)(Br)([Br:14])=O.[OH-].[Na+]>>[Br:14][C:9]1[N:2]=[C:3]2[N:7]([CH:8]=1)[CH:6]=[CH:5][S:4]2
Reactant: O=P(Br)(Br)Br
Reactant: N=c1sccn1CC(=O)O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Brc1cn2ccsc2n1
Temperature: 140 °C

Procedure:
A mixture of 10.0 g of 2-imino-4-thiazolin-3-yl-acetic acid hydrobromide and 30.0 g of phosphorus oxybromide is heated for 2 hours at 140° C. After cooling, the reaction mixture is poured into ice water, neutralized with 10% sodium hydroxide solution and filtered to collect the precipitated crystals. The crystals are recrystallized from toluene to afford the title compound of mp. 96°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Cl:18])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1c(Br)ccc2oc(CCl)c(C)c12
Yield: 92 %

Procedure:
To a solution of (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl)-methanol in 7 mL of dichloromethane was added 0.5 mL of thionyl chloride at room temperature. After 2 h the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give 216 mg (92%) of 5-bromo-2-chloromethyl-4-methoxy-3-methyl-benzofuran. 1H NMR (400 MHz, CDC3) δ ppm 2.4 (s, 3 H) 3.9 (s, 3 H) 4.7 (s, 2 H) 7.1 (d, J=8.8 Hz, 1 H) 7.4 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CC(C)(C)[Si](C)(C)OCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 52 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) was reacted with (2-bromoethoxy)(tert-butyl)dimethylsilane (60 mg, 0.254 mmol), following the procedure of Example 136. The product was triturated with ether-hexanes to yield 36 mg (52%) of pure product. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1 H), 7.87 (s, 1 H), 7.79 (d 1 H), 7.56 (m, 2 H), 7.33 (m, 4 H) 7.15 (d, 1 H), 6.67 (s, 1 H), 5.63 (s, 2 H) 4.10-3.2 (m, 7 H), 3.00-1.75 (m, 4 H), 0.85 (m, 9 H), 0.05 (s, 6 H); ES-MS m/z 568.3 [M+H]+, HPLC RT (min) 3.11.
Reaction SMILES: C[Li].[CH2:3](OCC)C.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>O>[OH:10][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)(=[O:27])=[O:26])[CH:20]=2)=[CH:13][CH:12]=1)([CH3:3])[CH3:9]
Reactant: CC(=O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: O
Product: CC(C)(O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
With cooling with ice, methyllithium (0.66 mL, 0.98 M diethyl ether solution) was dropwise added to a diethyl ether (1.0 mL) solution of the compound (50.0 mg) obtained in Example 92, and stirred for 1 hour with cooling with ice. After heated up to room temperature, water was added to the reaction liquid, and then extracted three times with ethyl acetate. This was dried with sodium sulfate, then the drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (51.1 mg, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]([NH:25][C:26](=NC(=O)OC)SC)=[O:24].C(O)(=O)C>ClC(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C:26]1[NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][CH2:10][CH2:11][O:12]3)=[CH:14][C:15]=2[N:20]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(C2(c3ccc(F)cc3)OCCO2)cc1N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C3(c4ccc(F)cc4)OCCO3)ccc2[nH]1
Yield: 42 %

Procedure:
A mixture of 5.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan2-yl]-1,2-benzenediamine, 6.2 parts of methyl [(methoxycarbonylamino)(methylthio)methylene]carbamate, 4.8 parts of acetic acid and 225 parts of trichloromethane is stirred and refluxed for 17 hours. The reaction mixture is evaporated in vacuo. The residue is triturated in methanol. The product is filtered off, washed with 2,2' -oxybispropane and dried, yielding 3 parts (42%) of methyl{ 5-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1H-benzimidazol-2-yl}carbamate; mp. 227.7° C.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[F:5][C:6]([F:24])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO.CCOC(C)=O.[Pd]>[F:24][C:6]([F:5])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH:1]=[O:3])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=CNc1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Yield: 77.8 %

Procedure:
Ammonium formate (1.38 g, 22 mmol) and 10% Pd/C (230 mg, 0.2 mmol) are added to a solution of 1-(2,2,2-trifluoroethyl)-4-(4-nitrophenyl)piperidine (1.26 g, 4.4 mmol) in EtOH (10 mL) and EtOAc (10 mL). The suspension is heated at reflux for 24 hours, adding further portions of ammonium formate (2 g) after 4 h and 8 h. The mixture is filtered through celite and evaporated to afford an orange solid. This is partitioned between DCM (40 mL) and water (20 mL) and the layers separated. The aqueous phase is extracted with DCM (2×20 mL) and the combined organic layers are dried over MgSO4 and evaporated under reduced pressure to afford N-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}formamide as a pale orange solid (980 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][OH:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
3,4-Methylenedioxyphenylacetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (4.0 g) in ether (400 ml) and the mixture was stirred at room temperature for two hours, quenched by the cautious addition of saturated aqueous ammonium chloride solution and filtered. The filtrate was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil (15.0 g), which was characterised by its 1H-NMR spectrum.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:28]5[CH2:30][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11.5 mg, 51%), MS (ISP) m/z=414.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-cyclopropylacetic acid.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[C:26]([F:33])[CH:25]=1>CN(C)C=O.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[CH3:31])=[C:26]([F:33])[CH:25]=1
Reactant: CC(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.9 %

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (2.483 mmol) in N,N-dimethylformamide (10 mL) was treated with potassium carbonate (7.45 mmol) and 4-bromo-1-(1-bromoethyl)-2-fluorobenzene (2.483 mmol). The reaction was stirred at room temperature for three days. The solution was diluted with water (200 mL) and was extracted three times with ethyl acetate. The organic layers were combined, washed with brine (five times), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.01 g, 89%). MS(ES)+ m/e 411.0/412.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[S:10][C:9](N)=[N:8][N:7]=1.[BrH:12].N([O-])=O.[Na+]>O>[Br:12][C:9]1[S:10][C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[N:7][N:8]=1
Reactant: Nc1nnc(C2CCCO2)s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1nnc(C2CCCO2)s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 5-(Tetrahydro-furan-2-yl)-[1,3,4]thiadiazol-2-ylamine (0.5 g, 2.9 mmol) was added 48% HBr (7 ml) and H2O (7 ml). The reaction mixture was cooled to 0° C. using an icebath. Cu(I)Br (0.42 g, 2.9 mmol) was added, followed by a the dropwise addition of solution of NaNO2 (0.48 g, 10 mmol) in H2O (18 ml). The reaction mixture was stirred for a further 10 mins at 0° C. then allowed to warm up to room temperature over a 35 min period. A solution of saturated bicarbonated was added to the reaction mixture until the pH=6, then extracted with EtOAc, dried (MgSO4), filtered and the solvent removed in vacuo to afford the product (0.5 g, 2.1 mmol). MS: [M+H]+235, 237.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccc(Br)cc1

Procedure:
Into a 250-mL round-bottom flask were placed a solution of 4-bromoaniline (17.1 g, 99.42 mmol) and triethylamine (30 g, 297 mmol) in dichloromethane (100 mL). Then, 2-phenylacetyl chloride (18.6 g, 120 mmol) was added dropwise with stirring, and the resulting solution was stirred at room temperature for 6 hours. The solids were filtered out, and the filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ethyl acetate to provide the title compound as a white solid.