Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:43]=[CH2:44])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[O:40])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:41][CH3:42])=[CH:27][C:26]=1[CH2:25][CH2:24]3)(C(C)(C)C)([CH3:11])[CH3:10]>>[C:18]([C@H:19]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:43]=[CH2:44])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:40])[C:2]([F:1])([F:3])[F:4])[CH2:34][C@:18]12[CH2:17][O:16][SiH:9]([CH3:10])[CH3:11])[C:31]1[CH:30]=[CH:29][C:28]([O:41][CH3:42])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC=O)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Reactant: C[Si](C)(C)C(F)(F)F
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(O)C(F)(F)F)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 900 mg of aldehyde 9a yields 804 mg of alcohol 14a as a colorless foam (GC-MS: m/z theor.: 580, pract.: 580) and a mixture of its diastereomers.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].I.II>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: I
Agent: II
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 167.1 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose, 90 mg of hydriodic acid (57%) and 50.8 mg of iodine and the mixture was refluxed with stirring in a water bath at 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 12.07 g (83.6%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥98%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[CH2:48][CH2:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1.CO.O>CS(C)=O.O>[NH:51]1[C:50]([CH2:49][CH2:48][N:34]2[CH2:33][CH2:32][N:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([C:22]4[S:23][C:16]5[C:17](=[N:18][CH:19]=[CH:20][C:15]=5[O:14][C:11]5[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]6[CH2:3][CH2:2]6)=[O:6])=[CH:9][C:10]=5[F:37])[CH:21]=4)=[N:25][CH:26]=3)[CH2:36][CH2:35]2)=[N:54][N:53]=[N:52]1
Reactant: ClCCc1nnn[nH]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCc6nnn[nH]6)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a stirred suspension of 49 (300 mg, 0.578 mmol, scheme 15) and DIPEA (303 μl, 1.74 mmol) in DMSO (5 ml) under nitrogen at rt was added 5-(2-chloroethyl)-1H-tetrazole (137 mg, 1.03 mmol), and the reaction mixture was stirred at rt for 1 h, heated at 60° C. overnight, then at rt. More 5-(2-chloroethyl)-1H-tetrazole (300 mg, 2.27 mmol) was added and the reaction mixture was heated at 60-65° C. for 24 h, then rt. The reaction mixture was diluted with water, and sonicated. The solid was collected by filtration, rinsed with water and air-dried. The crude material was purified three times by Biotage (Snap 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 25/75 over 20 CV, then 25/75 to 50/50 over 20 CV; Silia Sep HP 12 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 10/90 to 30/70 over 20 CV, then 30/70 to 40/60 over 20 CV; Snap 30 g KP-C18-HS (reverse phase): MeOH/water (millipore): 20/80 to 95/05 over 40 CV), to afford the desired product 512 (14 mg, 0.02 mmol, 3.9% yield) as a beige sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): one NH is missing, 8.74 (s, 1H), 8.54 (bd, J=1.6 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (dd, J=9.0, 1.4 Hz, 1H), 6.64 (dd, J=5.4, 0.7 Hz, 1H), 6.60 (bd, J=2.5 Hz, 1H), 3.55 (s, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.59-2.32 (m, 9H), 0.72-0.58 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 615.7 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[Br-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>C1COCC1.O.CCOC(C)=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>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccn2nc(Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (100 mg, 0.34 mmol) and Tetrakis (392 mg, 0.034 mmol) in THF was heated to 80° C. for 0.5 hrs before 2,4 difluoro benzyl zinc bromide was added. The reaction was complete after 0.5 hrs, cooled to ambient temperature, and diluted with H2O and EtOAc. The organic layer was extracted with EtOAc, H2O, brine, dried over MgSO4, and concentrated to a solid. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[Mg+2].[Br-].[Br-].CCOCC.C(OO[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=O)C1C=CC=CC=1>C1COCC1>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: CC(C)(C)OOOC(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)cccc1OC(C)(C)C
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of the compound of Example f (3.7 g, 20 mmol) and TMEDA (6.0 mL, 40 mmol) in anhydrous THF (100 mL) at -78° C. under nitrogen was added dropwise 1.3M s-BuLi (34 mL, 44 mmol). After 30 min MgBr2.Et2O (15.5 g, 60 mmol) was added, and the solution was warmed to ambient temperature, then cooled to -78° C. and stirred for 1 h. t-Butylperoxy benzoate (4.3 g, 22 mmol) was added, and the solution was warmed to -30° C. and worked up in the usual manner. Purification by HPLC with 3:17 ethyl acetate/hexanes gave 1.7 g of the desired compound as a white solid, a yield of 33%. m.p. 126-127° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(CNCc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophene-2-carboxaldehyde (22.4g, 200 mmol) was dissolved in anhydrous ethanol (200 mL) and treated with 2,2-dimethoxyethanamine (26.6 g, 200 mmol) and para-toluenesulfonic acid hydrate (0.1 g, catalytic) and the mixture heated to reflux for 4 h. The reaction was allowed to cool down to room temperature and sodium borohydride (7.6 g, 200 mmol) was added in small portions to the reaction. Following complete addition, the reaction was stirred at room temperature for 15 min, then at reflux for 2 h. The reaction was allowed to cool down to room temperature and all the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, passed through a pad of silica gel, concentrated and placed on a vacuum line to afford an off-white solid. Yield=40.1 g. MS (M+H)+ 202.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])C.[ClH:24]>ClCCl>[ClH:24].[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1

Procedure:
A solution of 90 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 2 ml of dichloromethane is stirred at 20° C. for 18 hours with 1 ml of 2N hydrochloric acid. The solid is filtered off, washed with dichloromethane and then with diisopropyl ether, and dried to give 67 mg of 6-acetyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=4)[N:28]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[H-].[Na+].I[CH3:40]>CN(C=O)C>[CH3:40][N:9]([CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=4)[N:28]=3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: O=C(NCCN1CCCC1=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN1CCCC1=O)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
A solution of N-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (obtained as described in Example 639) (150 mg, 0.30 mmol) in DMF (2 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil) (13.16 mg, 0.33 mmol) in DMF (1 mL) under nitrogen. The resulting suspension was stirred at ambient temperature for 5 minutes, then iodomethane (0.028 mL, 0.45 mmol) was added and the mixture was stirred at ambient temperature for a further 10 minutes. The reaction was quenched with MeOH (0.5 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-methyl-N-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (84 mg, 55%) as a solid.
Reaction SMILES: C(OC([NH:8][CH:9]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O.Cl>C(OCC)(=O)C.CCOCC>[NH2:8][CH:9]([C:18]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25]1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 18 h
Yield: 114.3 %

Procedure:
To a solution of 1-(1-(t-butoxycarbonyl)amino-2-(4-chlorophenyl)ethyl)carbonyl-4-(benzyl)piperazine (0.20 g, 0.44 mmol) in a solution of CH2Cl2 (3 mL) was added trifluoroacetic acid (3 mL). The resultant mixture was stirred at ambient temperature. After 18 hours, the mixture was concentrated in vacuo to afford a yellow oil. This was dissolved in ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 0.17 g of a clear, colorless film. This was dissolved in ether and treated with an ethereal solution of HCl, resulting in formation of a white precipitate. Concentration afforded 0.18 g of 1-(1-amino-2-(4-chlorophenyl)ethyl)carbonyl-4-(benzyl)piperazine as a white solid; NMR (CDCl3) 7.4 (m, 7), 7.1 (m, 2), 4.0 (t, 1), 3.7-3.1 (m, 4), 2.8 (m, 2), 2.4-2.2 (m, 5), 1.8 (m, 1) ppm.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=[C:15]([F:18])[C:16]=1F.[CH:22]12[CH2:27][CH:26]1[CH2:25][NH:24][CH2:23]2.Cl>CN(C=O)C.C(OCC)(=O)C>[F:18][C:15]1[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=[C:11]([F:10])[C:16]=1[N:24]1[CH2:25][CH:26]2[CH:22]([CH2:27]2)[CH2:23]1
Reactant: C1NCC2CC12
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N2CC3CC3C2)c(F)c1
Temperature: 45 °C

Procedure:
Diisopropylethylamine (0.39 mL, 2.25 mmol) and 3,4,5-trifluoronitrobenzene (0.143 g, 0.81 mmol) were added to a solution 3-aza-bicyclo[3.1.0]hexane (prepared by the general procedure of Brighty, K. E., Castaldi, M. J. Synlett, 1996, 1097-1099; 0.106 g of the HCl salt, 0.9 mmol) in DMF (2 mL). The mixture was heated for three days at 45° C. and then cooled to room temperature. The solution was diluted with ethyl acetate and washed with 0.5 M HCl, saturated NaHCO3, brine, and dried (MgSO4). The mixture was filtered and concentrated to give 3-(2,6-difluoro-4-nitro-phenyl)-3-aza-bicyclo[3.1.0]hexane as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NCc1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in intermediate-1, using (1H-indol-5-yl)methanamine and isobutyryl chloride (169 mg, 99%); MS: 217.0 (M+1).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]3[CH2:16][C:15](=[O:17])[C:14]([C:18](=O)[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]3)=[CH:4][C:3]=2[O:2]1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>>[CH2:24]([O:26][N:27]=[C:18]([C:14]1[C:15](=[O:17])[CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:12][C:13]=1[OH:22])[CH2:19][CH3:20])[CH3:25]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCCO3)CC1=O
Reactant: CCON
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)OCCO3)CC1=O

Procedure:
2-[1-(Ethoxyimino)propyl]-5-(3,4-ethylenedioxyphenyl)-3-hydroxycyclohex-2-en-1-one was prepared from 5-(3,4-ethylenedioxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1 part (iv). The product was obtained as an oil and was characterized by proton nuclear magnetic resonance spectroscopy. Pmr spectrum (CDCl3 ; δ in ppm): 1.08-1.40 (6H, 2xt); 2.27-3.25 (7H, m); 4.00-4.24 (6H, m); 6.65-7.27 (3H, m); 15.00 (1H, brs).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[F:39][C:40]1[N:45]=[C:44]([F:46])[C:43]([F:47])=[C:42](F)[C:41]=1[F:49]>C(#N)C.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH:29][C:42]3[C:41]([F:49])=[C:40]([F:39])[N:45]=[C:44]([F:46])[C:43]=3[F:47])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2CNc2c(F)c(F)nc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol) was dissolved in 500 mL of acetonitrile. Then, triethylamine (20 L, 0.14 mmol) was added, followed by pentafluoropyridine (16 μL, 0.15 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted to 2 mL in volume with methanol and the mixture was purified by reverse phase HPLC to give 44 mg of the product as a white solid. 1H NMR (CDCl3) δ 7.87 (s, 2H), 7.51 (s, 1H), 7.29-7.36 (m, 2H), 7.16-7.21 (m, 2H), 6.78 (s, 1H), 5.90 (br s, 1H), 4.79 (d, 2H), 3.71 (m, 4H), 3.02 (t, 4H) ppm.
Reaction SMILES: [N+](C1C=[CH:8][C:7]([O:10][C:11](=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=CC=1)([O-])=O.OCC[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.CN1CCOCC1>C(Cl)Cl>[C:11](=[O:22])([O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[O:10][CH2:7][CH2:8][N:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
Bis(p-nitrophenyl)carbonate (1.52 g, 5.0 mmol) was dissolved in DCM (20 mL). tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate from the previous step (1.15 g, 5.0 mmol) and NMM (0.55 mL, 5.0 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (40 mL) and washed with sat aq NaHCO3 solution (5×50 mL), dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The oil was purified by recrystallisation from EtOAc and heptane to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (1.208 g, 61%) as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCCCCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution was prepared from 8.5 g of 6-(4-nitrophenyl)hexanol and 150 ml of ethanol and 0.42 g of 10% Pd/C catalyst was added. The resulting mixture was shaken under hydrogen (2.7-3.3 atmospheres) at room temperature for 2 hours. The catalyst was then removed by filtration and the solvent was evaporated from the filtrate to leave a crude tan solid. The solid was recrystallized from ethyl acetate/hexane to give 6-(4-aminophenyl)hexanol.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23]COC)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>CO>[ClH:27].[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([OH:23])=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a solution of 2-tert-butyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole (2.4 g) in methanol (30 mL) was added concentrated hydrochloric acid (0.8 mL) at room temperature, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give 4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (2.1 g, yield 91%) as pale-yellow crystals. melting point: 209-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>ClCCl.CCCCCCC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])=[CH:4][C:3]=1[Br:14]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCCCCCC
Solvent: ClCCl
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Temperature: 5 °C
Yield: 173.6 %

Procedure:
4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 l), the solution was cooled to 5° C. and, while stirring, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol) was introduced in several portions with ice cooling such that the internal temperature was kept at 3-8° C. (about 1 h). Subsequently, the mixture was stirred without external cooling for 1 h and allowed to warm to room temperature. The mixture was filtered through a bed of silica gel (volume about 1 l) and washed with dichloromethane (5.5 l), and the filtrate was concentrated under reduced pressure. About 700 g of a red-brown crystalline mass were obtained and were dissolved in n-heptane (600 ml) at 60° C. and then crystallized in a refrigerator at 4° C. Filtration with suction gave 590 g (85%) of 4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m.p. 59-59.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccncc3)CC2)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cnc(NC2CCN(Cc3ccncc3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 163.7 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate (308 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOHaq (2.3 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HClaq. The solution was evaporated under reduced pressure to give crude (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylic acid (469 mg, 164%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH2:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-c2ccc(C)cc2C(=O)OC)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccc(CBr)cc2C(=O)OC)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 4-methyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (2.26 g, 7.9 mmol) in CCl4 (50 mL) were added benzoyl peroxide (0.010 g, 0.04 mmol) and NBS (1.42 g, 8.0 mmol), and the mixture was refluxed for 3 days. The reaction mixture was allowed to cool to room temperature, filtered, and concentrated. The residue was purified by column chromatography (95:5 to 90:10 hexanes/EtOAc) to afford 4-bromomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.71 g, 60%): 1H NMR (DMSO-d6) δ 3.61(s, 3H), 3.88 (s, 3H), 4.84 (s, 2H), 7.48-7.50 (d, J=8.0 Hz, 1H), 7.59-7.60 (m, 2H), 7.72-7.75 (m, 1H), 7.85 (s, 1H), 7.90 (m, 1H), 7.97-7.99 (m, 1H).