Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CS(C)=O.C(OCC)C.O>[I:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([O:11][CH3:10])=[N:3][CH:4]=1
Reactant: Cc1cc(I)cnc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COc1ncc(I)cc1C
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution containing 2-bromo-5-iodo-3-methyl-pyridine (4.80 g, 16.0 mmol) in DMSO (15 mL) is added methanolic NaOMe (3.33 M, 5.3 mL, 17.7 mmol) at 0° C. The solution is allowed to warm to ambient temperature and then heated at 70° C. for 1 hour. The reaction mixture is diluted with diethyl ether (300 mL) and water (200 mL) and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 2.86 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ2.12 (s, 3H), 3.90 (s, 3H), 7.60 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H) ppm; MS (EI): m/z 249 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][N:3]=1.[Cl-:12].[Al+3].[Cl-:14].[Cl-:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:15])([Cl:14])[Cl:12])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: [Cl-]
Agent: [Al+3]
Product: Clc1ccc(C(Cl)(Cl)Cl)cn1
Temperature: 0 °C

Procedure:
To 18.2 g of 2-chloro-5-trifluoromethyl pyridine, 20 g of aluminum chloride was added in 2 hours, and they were reacted under the predetermined reaction conditions as shown in Table 1. After the completion of the reaction, the reaction product was cooled and then introduced into ice water, and the oil layer was separated by liquid separation. The solvent was removed by distillation to obtain 2-chloro-5-trichloromethyl pyridine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1[Cl:11].CC(C[AlH]CC(C)C)C.C([O-])([O-])=O.[Na+].[Na+].N>C1COCC1.C(#N)C.O>[Cl:11][C:5]1[C:4]([CH2:3][OH:2])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1c(C)ccnc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: N
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: Cc1ccnc(Cl)c1CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-methyl-nicotinic acid methyl ester (1 g. 5.4 mmol) was dissolved in THF (10 mL) and cooled to −78° C. and DIBAL (1 M in toluene) was added via a syringe (14.4 mL. 21.6 mmol). The reaction mixture was allowed to warm to RT over a period of 4 h. Additional DIBAL (5 mL. 5 mmol) was added and the reaction was stirred at RT for 1 h before cooled to −20° C. Water (2 mL). sat. Na2CO3 solution (1.5 mL). aqueous NH3 (3 mL) and ACN (70 mL) were added. After vigorous stirring for 30 min. the suspension was centrifuged and the precipitate suspended in a solution of ACN (100 mL) and concentrated aqueous NH3 (5 mL). After vigorous stirring for 30 min the suspension was centrifuged. The combined supernatants were concentrated in vacuo to yield crude (2-chloro-4-methyl-pyridin-3-yl)-methanol which was converted into the title compound according to the procedure described for the preparation of 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine. MS (m/z): 158.0 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:16])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1>C(O)(C)C>[Cl:16][C:7]1[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1)[N:3]=[C:2]2[O:12][CH:9]([CH3:10])[CH3:8]
Reactant: COc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC
Solvent: CC(C)O
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC

Procedure:
Similar procedure as described in example 376 was used, starting from (1,5-Dichloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropanol to give (5-Chloro-1-isopropoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 377 (MH+).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:31]=[CH:32][N:33]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1>O>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:31]=[CH:32][N:33]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([O-:27])=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1.[Na+:2]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)[O-])c3)nn3ccnc23)n1
Yield: 76 %

Procedure:
A solution of NaOH in water (0.05 mol/L, 1.2 mL) was added to 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (25 mg, 0.06 mmol) and the mixture stirred until the solid was completely dissolved. The solution was concentrated in vacuo to give sodium 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (20 mg, 76%) as a white solid. 1H NMR (300 MHz, D2O): δ 7.98-7.77 (m, 2H), 7.55-7.38 (m, 2H), 7.26-7.05 (m, 3H), 6.80 (brs, 1H), 5.50 (brs, 1H), 5.41-5.33 (m, 1H), 3.39 (brs, 1H), 2.91 (brs, 1H), 2.63 (brs, 1H), 1.58-1.30 (m, 4 h), 0.60 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)C(=N)[O:4][CH:5]([C:7]1[CH:8]=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[CH3:6].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([CH2:51]O)[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C1CCCCC1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([CH2:51][O:4][CH:5]([C:7]3[CH:8]=[C:9]([C:24]([F:26])([F:27])[F:25])[CH:10]=[C:11]4[C:15]=3[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:13]=[CH:12]4)[CH3:6])[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]2)=[CH:34][CH:33]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (361 mg, 0.716 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (244 mg, 0.788 mmol) at 0° C. was added cyclohexane (2 ml, 18.49 mmol) and fluoroboric acid diethyl ether complex (0.019 ml, 0.143 mmol). The reaction was stirred at 0° C. for 45 min and was judged complete by TLC. The reaction was quenched with aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 12% to 100%. The product (245 mg, 0.376 mmol, 52.5% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.77 (m, 1H), 7.34 (s, 1H), 7.18 (m, 2H), 7.08 (d, J=3.7 Hz, 1H), 6.94 (m, 2H), 6.54 (m, 1H), 5.29 (m, 2H), 5.18 (m, 1H), 3.65 (m, 2H), 3.33 (m, 2H), 3.24 (m, 1H), 3.14 (m, 1H), 3.00 (m, 2H), 2.03 (m, 2H), 1.86 (m, 2H), 1.44 (d, J=6.4 Hz, 3H), 1.419 (s, 9H), 0.74 (m, 2H), −0.09 (s, 9H); LC/MS (HPLC method 4): tR=4.871 min, 651.28(MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[N:45][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:24]=[C:25]([C:41]3[CH:42]=[CH:43][C:44]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[N:45][CH:46]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2cccc(I)c2)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2cccc(-c3ccc(N4CCOCC4)nc3)c2)ccc1Cl
Reaction time: 6 h
Yield: 74 %

Procedure:
The product from Example 187A (1.4 g, 2.396 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.695 g, 2.396 mmol), potassium phosphate (1.017 g, 4.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.022 g, 0.024 mmol) and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.021 g, 0.072 mmol) were combined in THF (18 mL)/water (6 mL). The mixture was sparged with nitrogen for 15 minutes, stirred for 6 hours diluted into EtOAc, washed with 1M sodium bicarbonate, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on an Isco 120 g silica cartridge eluting with 20-60% EtOAc in hexane gave the title compound as a yellow glass (1.1 g, 74%). MS (ESI) m/z 620 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=[O:13])[CH:5](Br)[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].[NH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[NH2:18][C:16]1[O:17][C:5]([C:4](=[O:13])[C:2]([CH3:14])([CH3:3])[CH3:1])=[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:15]=1
Reactant: NC(N)=O
Reactant: CC(C)(C)C(=O)C(Br)C(=O)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1oc(N)nc1C(C)(C)C
Temperature: 0 °C
Yield: 42.7 %

Procedure:
A mixture of 2,2,6,6-tetramethyl-4-bromo-3,5-heptanedione (70 g) and urea (77 g) in DMF (500 mL) is heated at 110°-120° C. overnight. The reaction mixture is cooled and poured into ice water (1500 mL) and the resulting precipitate is collected by filtration and air dried. The solid is rinsed with hexane (1000 mL) and then with isopropyl ether (200 mL) and dried under vacuum overnight to give 1-[2-amino-4-(1,1-dimethylethyl)-5-oxazolyl]-2,2-dimethyl-1-propanone (25.5 g, 42%); mp 248°-250° C.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:15])=O.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc(Cl)ccc21
Temperature: 75 °C
Reaction time: 1.25 h

Procedure:
Under nitrogen, 21.02 g (0.13 mol) of 7,8-dihydroquinoline-2,5(1H,6H)-dione were suspended in 100 ml of acetonitrile (anhydrous, <30 ppm H2O), and 135.28 ml (density 1.46 g/ml, 1.29 mol) of phosphorus oxychloride were added. The yellowish suspension was then heated to 75° C. and stirred at this temperature for 1.25 hours. The yellow clear solution was then cooled to room temperature, and 150 ml of toluene were added. The solution was then concentrated on a rotary evaporator to about 100 ml, and another 150 ml of toluene were added. The solution was then concentrated to dryness on a rotary evaporator. 300 ml of ethyl acetate were then added to the orange oil obtained. Subsequently, the solution was carefully (evolution of gas) added to 500 ml of saturated aqueous sodium bicarbonate solution and stirred for 15 min. The phases were separated and the aqueous phase was extracted with 200 ml of ethyl acetate. The combined organic phases were washed twice with 250 ml of water and once with 100 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This gave 22.58 g (0.12 mmol, 96% of theory) of the target compound as a slightly yellowish solid.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]=2[CH:8]=1)=O.C([O-])(=O)C.[NH4+:40]>CN(C=O)C.C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:30]1([C:2]2[NH:40][C:5]([C:7]3[CH:29]=[CH:28][C:10]4[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=5)(=[O:17])=[O:16])[C:9]=4[CH:8]=3)=[N:4][CH:3]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCS2)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCSc2ccc(-c3ncc(-c4ccccc4)[nH]3)cc21
Yield: 6.3 %

Procedure:
To a solution of N-(2-oxo-2-phenylethyl)-4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (20 mg, 38 μmol) in DMF (1 mL) was added ammonium acetate (30 mg, 380 μmol). The reaction mixture was subjected to microwave irradiation (150° C., 15 min). LCMS analysis of the reaction mixture indicated nearly complete conversion of the starting material. The reaction mixture diluted with saturated aqueous sodium bicarbonate (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography using a gradient elution of hexanes with 10-60% EtOAc to provide 6-(5-phenyl-1H-imidazol-2-yl)-4-(4-(trifluoro-methyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.2 mg, 2.4 μmol, 6% yield) as a yellow oil. LCMS (+ESI) m/z=502.5 [M+H]+; 1H-NMR (CDCl3) δ 8.10 (m, 2H), 7.90 (d, 2H), 7.80 (d, 2H), 7.4-7.5 (m, 4H), 7.25 (d, 1H), 7.00 (dd, 1H), 6.76 (d, 1H), 3.53 (t, 2H), 3.08 (t, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20](I)[CH:21]=[CH2:22]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:22][CH:21]=[CH2:20])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Yield: 69.7 %

Procedure:
Add to a solution of 4-benzyloxycarbonylpiperazin-2-one (1.6 g, 6.8 mmol) in dry THF (10 mL/mmol) under nitrogen, sodium hydride (188 mg, 7.4 mmol, 60% dispersion in mineral oil) in one portion and stir at room temperature for 30 min. Add allyl iodide (0.9 mL, 10 mmol) and stir at room temperature overnight. Concentrate, add ethyl acetate and wash with water, saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes/ethyl acetate) to give the title compound as an oil (1.3 g, 72%).
Reaction SMILES: FC(F)(F)S([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O>C(COC)OC.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=S(=O)(C1=CCCCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(F)c(C2=CCCCC2)c1
Temperature: 80 °C

Procedure:
1-Trifluoromethylsulphonylcyclohex-1-ene (3 g, 13 mmol), cesium carbonate (8.4 g, 26 mmol) and 2,5-difluorophenyl boronic acid (2.88 g, 18 mmol) were dissolved in dimethoxyethane/water [9:1] (200 ml). The flask was degassed and then tetrakistriphenylphosphine palladium (125 mg) was added, the mixture warmed to 80° C. over 4 hr and then cooled to r.t. The solution was filtered through Celite™, diluted with water (20 ml) and the solution washed with ethyl acetate (2×100 ml). The organic phase was washed with brine (100 ml), dried (MgSO4) and evaporated. The clear oil obtained was purified by column chromatography on silica gel eluting with hexanes, to give 1-(2,5-difluorophenyl)cyclohex-1-ene. 1H NMR (CDCl3) 6.97-6.73 (3H, m), 5.97-5.96 (1H, m), 2.35-2.31 (2H, m), 2.23-2.14 (2H, m) and 1.79-1.68 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH:37](N2CCC(C(O)=O)CC2)[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([CH:37]4[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 578.2 [M]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH2:9][OH:10])[CH3:3]>C(#N)C.[O-2].[O-2].[Mn+4]>[CH3:1][CH:2]([C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH:9]=[O:10])[CH3:3]
Reactant: CC(C)c1ncsc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CC(C)c1ncsc1C=O

Procedure:
Portions of manganese dioxide (330 mg, 3.8 mmol) were added to a stirred solution of 4-(1-methylethyl)thiazole-5-methanol (Example 26; 330 mg, 2.1 mmol) in acetonitrile (10 mL) at hourly intervals for 4 h. One h after the last addition, the reaction mixture was filtered through Celite® and evaporated to dryness to give 4-(1-methylethyl)thiazole-5-carboxaldehyde (360 mg, 110% of the theoretical amount). Examination of the product by NMR indicated the presence of acetonitrile. This material was used with further purification in subsequent transformations.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:29][C:30]1[CH:31]=[C:32]([C:8]2[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)c(F)c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (195 mg, crude) in dioxane (3 mL) was added 3,4-difluorophenylboronic acid (130 mg, 0.80 mmol), K3PO4 (180 mg, 0.8 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and water (5 drops) under a nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (86.0 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:27]
Reactant: CNC
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: Cc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 7, 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 96.6%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Br)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
tert-Butyl 4-(2-bromo-4-nitrophenoxy)piperidine-1-carboxylate (12.21 mmol, 4.9 g) was dissolved in dichloromethane (40 mL) and trifluoroacetic acid (73.3 mmol, 8.35 g) added. The mixture was stirred at room temperature for 3 hours before concentrating under reduced pressure. The resulting residue was dissolved in dichloromethane (150 mL) and washed with a saturated solution of sodium bicarbonate (3×50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (3.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])[CH:2]=1.C(O)(=O)C1C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[CH2:10][OH:11])[CH:2]=1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Product: OCc1cccc(-c2cccnc2)c1
Yield: 53.7 %

Procedure:
To a 100 mL recovery flask was added 3-(3-pyridyl)-benzoic acid 45 (2.00 g, 10.0 mmol, 1.0 eq.) and THF (20 mL). The resulting suspension is stirred. BH3 (1.0 M in THF, 15 mL, 15 mmol, 1.5 eq.) was added the resulting mixture was refluxed overnight. Incomplete reduction was observed by LC/MS. Additional BH3 (10 mL) was added and the mixture was refluxed for an additional 6 h. LC/MS indicates complete reduction of the benzoic acid. The reaction mixture was concentrated and diluted with EtOAc. The organic layer was washed with a succession of water, HCl, brine. The combined aqueous layers were extracted with EtOAc. The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a clear oil. The crude material was purified via flash chromatography (40% to 60% EtOAc/Hex) to give a white solid (995 mg, 53%).