Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])[C:9]=2[C:8]1=[O:20]
Reactant: OB(O)c1ccccc1F
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccccc3F)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 77.3 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-fluorophenylboronic acid (143 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (218 mg, 77%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH:11]([CH3:50])[O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:51][OH:52])([CH:11]([CH3:50])[O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC(C)[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC(C)[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.7 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-7-methyl-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 8c (258 mg, 0.37 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.21 mL, 1.82 mmol) and 10% Pd/C (19.3 mg, 0.18 mmol) in turn. The mixture was stirred at room temperature under H2 for 4.5 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound 8 as white powder (98 mg, 59%, HPLC: 97.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 451.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.43-7.36 (m, 2H), 7.30 (d, 1H), 7.09 (d, 2H), 6.82 (d, 2H), 5.15 (d, 1H), 4.99 (d, 1H), 4.92 (d, 1H), 4.74 (t, 1H), 3.96 (m, 5H), 3.76 (dd, 1H), 3.62 (m, 2H), 3.51 (dd, 1H), 3.40 (d, 1H), 1.36 (d, 3H), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]([C:16](O)=[O:17])=[N:12][C:11]3[CH:19]=[CH:20][CH:21]=[N:22][C:10]2=3)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[C:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C.CC(C)(O)C#N.[OH-].[Na+]>ClCCl.O.CN(C)C=O>[OH:36][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[C:30]=1[C:16]([C:13]1[C:14](=[O:15])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[N:22]=[CH:21][CH:20]=[CH:19][C:11]=2[N:12]=1)=[O:17]
Reactant: O=C1CCCC(=O)C1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2c(=O)c(C(=O)C3=C(O)CCCC3=O)nc3cccnc32)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
4.4 g (15 mmol) of 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid was dissolved in dichloromethane (100 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 3.8 g (30 mmol) of oxalyl chloride were added sequentially. The mixture was heated to reflux for one hour while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in dichloromethane (30 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 1.8 g (16 mmol) of 1,3-cyclohexanedione and 1.8 g (18 mmol) of triethylamine in dichloromethane (30 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then acetone cyanohydrin (1 mL) and 1.8 g (18 mmol) of triethylamine were further added thereto. The mixture was stirred for 12 hours at room temperature. After confirming the completion of the reaction, water (20 mL) was added to the reaction solution, the reaction solution was adjusted to pH 12 using a 10% aqueous solution of sodium hydroxide, and the reaction solution was separated. The aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and then the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 4.5 g (yield: 78%) of 2-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-4-(4-methoxyphenyl)-pyrido[2,3-b]pyrazin-3 (4H)-one.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCOc2ccc(Cl)cc2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(SCCOc2ccc(Cl)cc2)nc2ccccc21
Yield: 9.4 %

Procedure:
A solution tert-butyl{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor D-01b, 33 mg, 0.79 mmol) is stirred in TFA/dichloromethane (1:1, 0.8 ml) at rt for 3 h. The volatiles are removed in vacuo and the residue is purified by flash-chromatography on silica gel (AcOEt/heptane, 1:1; then pure AcOEt), yielding the title compound (27 mg) in 95% as a white solid: tR=5.73 min (LC-1), MS (pos.): m/z 362.8 [M+H]+, MS (neg.): m/z 360.8 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 3.88 (m, 2H, SCH2), 4.22 (t, 2H, OCH2), 4.88 (s, 2H, CH2CO2), 6.54 (d, 2H, Harom), 7.12 (d, 2 Harom), 7.32-7.46 (m, 3Harom), 7.82 (m, 1Harom).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(CCCl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 91.3 %

Procedure:
A mixture of 3-methoxy-3-phenyl-1-chloropropane (23.1 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave N-{3-[1-(3-methoxy-3-phenylpropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (45.4 mg, 91.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.34-7.25 (m, 5H), 7.25 (m, 2H), 6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49 (apparent sept, partially hidden, 4H, J=6.6 Hz), 2.3-2.1 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 395.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:33]=[CH:32][C:17]3[N:18]([CH3:31])[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=4)=[N:20][C:16]=3[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].C(#N)C.[C:43]1([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[C:43]1([CH2:49][S:50]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:33]=[CH:32][C:17]4[N:18]([CH3:31])[C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=5)=[N:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:6])(=[O:52])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(C(=O)NCCN)c4)ccc3n2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(C(=O)NCCNS(=O)(=O)Cc5ccccc5)c4)ccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture containing 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzo-imidazol-5-yloxy]-pyridine-2-carboxylic acid (2-amino-ethyl)-amide (1 eq) (prepared using previously described example 3), K2CO3 (5 eq), (0.2 M in a 5:1 mixture of acetonitrile and water) were added α-toluenesulfonyl chloride (1 eq) via syringe. The resulting heterogeneous mixture was allowed to stir for 1 hour at room temperature. The mixture was then diluted with water and extracted with dichloromethane. The organics were washed with water and a saturated solution of sodium chloride, dried with sodium sulfate and concentrated in vacuo to viscous oil. Purification by chromatography yielded 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl)-amide. MS: MH+599
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[C:22]([CH2:24][C:25]([O:27]CC)=[O:26])[N:23]=[C:3]12.[ClH:30]>O>[ClH:30].[O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=[C:3]12
Reactant: CCOC(=O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)OCC)c1C3
Agent: Cl
Solvent: O
Product: O=C(O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)O)c1C3

Procedure:
A mixture of 0.68 g of diethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetate and 20 ml of 6 N hydrochloric acid is heated for 16 hours at a temperature close to 100° C. The reaction mixture is cooled on a water and ice bath and the suspension is filtered. The insoluble matter is washed with 3×10 ml of acetone and dried under vacuum (1 mm Hg; 0.13 kPa) at close to 60° C. 0.43 g of 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetic acid hydrochloride is obtained in the form of a dark beige solid melting above 250° C. (Analysis: C17H13N3O5, HCl, % calculated C: 54.34, H: 3.76, Cl: 9.43, N: 11.18, O: 21.29, % found C: 53.9, H: 3.4, Cl: 9.8, N: 10.9, O: 20.9].
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[Cl:9][C:10]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18]([C:24]#[N:25])=[N:17][C:16]=2[C:15]([C:26]#[N:27])=[C:14]1[N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.S([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.O>[NH2:25][C:24]([C:18]1[N:19]([CH3:23])[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:10]=3[Cl:9])[C:14]([N:28]3[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:40])[CH3:38])[CH2:29]3)=[C:15]([C:26]#[N:27])[C:16]=2[N:17]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C#N)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(C(N)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Potassium carbonate (42 mg) and then an aqueous hydrogen peroxide solution (a 30-35% aqueous solution, 170 μl) were added dropwise to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-2,7-dicyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (162 mg) in a mixture of dimethyl sulfoxide (10 ml) and water (2 ml), and the resulting mixture was stirred overnight at room temperature. A 10% aqueous sodium sulfite solution was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (77 mg).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=O)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Cl[C:28](OCC)=[O:29].[Cl-].[NH4+].Cl.[BH4-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:29][CH2:28][C:4]1([CH2:7][OH:9])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate (10 g, 39 mmol) in tetrahydrofuran (100 mL) was added to a stirred, cooled (−78° C.) solution of lithium diisopropylamide in tetrahydrofuran (0.82M, 140 mL) and the mixture was stirred at −78° C. for 2 h, then at −40° C. for 3 hours. The mixture was cooled to −78° C., ethyl chloroformate (13 mL, 136 mmol) in tetrahydrofuran (80 mL) was added and the mixture was allowed to warm to room temperature over 16 hours. Saturated aqueous ammonium chloride (50 mL), hydrochloric acid (1M, 2000 mL) and ethyl acetate (3000 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene/tetrahydrofuran (1:1, 400 mL) and lithium borohydride (4.5 g, 207 mmol) was added. The mixture was heated at 60° C. for 16 hours, cooled and saturated aqueous ammonium chloride was added slowly until the organic layer was a clear solution. The mixture was adjusted to pH 12 with saturated aqueous sodium carbonate and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (6.1 g, 63%). m/z (ES+) 190 (M+1-C4H8).
Reaction SMILES: Br[C:2]([CH3:10])([CH2:8][Br:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[Br:9]/[CH:8]=[C:2](\[CH3:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Br)CBr
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/Br
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 37.7 g (137 mmol) of ethyl 2,3-dibromo-2-methylpropanoate in 176 ml of THF was added 25 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and refluxed for 2 hours. After cooling to room temperature, to the mixture was added 1N HCl and extracted with tert-butyl methyl ether. The organic layer was washed sequentially with a saturated NaHCO3 solution and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated under vacuum to obtain 23.8 g of (E)-ethyl 3-bromo-2-methyl-2-propenoate.
Reaction SMILES: FC(F)(F)C1C=C(NC(N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@@H]2CC3CCN2CC3)=O)C=C(C(F)(F)F)C=1.C=CC.[N+:43]([CH3:46])([O-:45])=[O:44].[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])/[CH:60]=[C:61](\[C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)/[C:62]([F:65])([F:64])[F:63])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]>O>[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])[CH2:60][C@@:61]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)([CH2:46][N+:43]([O-:45])=[O:44])[C:62]([F:64])([F:63])[F:65])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: COc1ccc2nccc([C@H](NC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]3CC4CCN3CC4)c2c1
Solvent: O
Solvent: C=CC
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Alternatively, to a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(S)-(6-methoxy-4-quinolyl)-[(2S)-quinuclidin-2-yl]methyl]urea; prop-1-ene (09 mg, prepared according to the literature: Organic Letters 2007, 9, (14), 2621-2624) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 3 days at 50° C. then allowed to stand at room temperature for 2 days. Water was then added and the resulting mixture was extracted with diethyl ether and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.43 minutes (major enantiomer), 7.78 minutes (minor enantiomer) indicated that the reaction proceeded with 95% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [NH2:1][C:2]1[N:33]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:39])[C:3]=1[C:40](=[O:42])[NH2:41].[ClH:43].CCOCC>ClCCl.O1CCOCC1>[ClH:43].[NH2:1][C:2]1[N:33]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:39])[C:3]=1[C:40]([NH2:41])=[O:42]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.28 g (3.92 mmol) of the product prepared in step 19.1 in 70 mL of dichloromethane is cooled on an ice-water bath, and 9.8 mL (39.20 mmol) of a 4N solution of hydrogen chloride in dioxane are added slowly. The mixture is stirred at room temperature for 1 hour, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 2.2 g of the expected product are obtained in the form of a beige-coloured solid, which is used as obtained in the following step. Yield (dihydrochloride)=quantitative.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)=[O:13].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)c1
Yield: 77.1 %

Procedure:
Triethylamine (0.101 g) was added to a stirred mixture of 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.135 g), 3-methoxybenzoyl chloride (0.13 g) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained the title compound as a solid (0.156 g); Mass Spectrum: M+H+ 404.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nc3ccccc3s2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To benzothiazole (3.46 g, 25.6 mmol) dissolved in dry THF under a nitrogen atmosphere at −78° C. was added butyl lithium (17.1 mL of 1.5M solution, 1 equiv.) dropwise. The reaction mixture was stirred for 1 h then 1,4-cyclohexanedione mono-ethylene ketal dissolved in dry THF (15 mL) in one portion. The reaction mixture was stirred at −78° C. for a further 3 h then water (10 mL) was added. The mixture was warmed to room temperature and the white precipitate was collected on a filter, washed with water (2×20 mL) then dried under vacuum to give 4-(benzothiazol-2-yl)-1,1-ethylenedioxy-4-hydroxycyclohexane. The yield was 4.403 g (59%); mp 165° C.; 1H NMR (CDCl3) δ 8.05 (1H, m, benzothiazole H-4/7), 7.89 (1H, m, benzothiazole H-4/7), 7.47 (1H, m, benzothiazole H-5/6), 7.39 (1H, m, benzothiazole H-5/6), 4.02 (4H, s, ethylene 2×CH2), 3.16 (1H, s, OH), 2.41–2.31 (4H, m, cyclohexanone 2×CH2), 1.82–1.72 (4H, m, cyclohexanone 2×CH2); IR (KBr disc) 2897, 1501, 1437, 1368, 1038, 997, 764 cm−1; MS (AP+) 292 (M++1), 274 (M++1-H2O); Anal. (C15H17NO3) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:46]=[CH:45][C:38]([O:39][CH2:40][C:41](=[N:43]O)[NH2:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]2[N:43]=[C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[O:11][N:42]=2)=[CH:45][CH:46]=1
Reactant: NC(COc1ccc(Cl)cc1)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. 2-(4-chlorophenoxy)-N′-hydroxyethanimidamide (U.S. Pat. No. 97-815671 970313) (197 mg, 0.98 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (220 mg).